Epigenetic Age and the Risk of Incident Atrial Fibrillation. - Roberts, Jason D; Vittinghoff, Eric; Lu, Ake T; Alonso, Alvaro; Wang, Biqi; Sitlani, Colleen M; Mohammadi-Shemirani, Pedrum; Fornage, Myriam; Kornej, Jelena; Brody, Jennifer A; Arking, Dan E; Lin, Honghuang; et al. (Circulation, 2021)
BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.
Keywords: Aged; Aging; Atrial Fibrillation; DNA Methylation; Epigenesis, Genetic; Epigenomics; Female; Follow-Up Studies; Humans; Incidence; Male; Mendelian Randomization Analysis; Middle Aged; Models, Cardiovascular; Models, Genetic

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. - Tin, Adrienne; Schlosser, Pascal; Matias-Garcia, Pamela R; Thio, Chris H L; Joehanes, Roby; Liu, Hongbo; Yu, Zhi; Weihs, Antoine; Hoppmann, Anselm; Grundner-Culemann, Franziska; Min, Josine L; Kuhns, Victoria L Halperin; et al. (Nat Commun, 2021)
Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Keywords: Amino Acid Transport System y+; Cohort Studies; CpG Islands; DNA Methylation; Epigenome; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Glucose Transport Proteins, Facilitative; Gout; Humans; Male; Uric Acid

Identification of putative causal loci in whole-genome sequencing data via knockoff statistics. - He, Zihuai; Liu, Linxi; Wang, Chen; Le Guen, Yann; Lee, Justin; Gogarten, Stephanie; Lu, Fred; Montgomery, Stephen; Tang, Hua; Silverman, Edwin K; Cho, Michael H; Greicius, Michael; et al. (Nat Commun, 2021)
The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.
Keywords: Algorithms; Causality; Computer Simulation; Data Interpretation, Statistical; Datasets as Topic; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Markov Chains; Models, Genetic; Polymorphism, Single Nucleotide; Reproducibility of Results; Whole Genome Sequencing

Meta-analyses identify DNA methylation associated with kidney function and damage. - Schlosser, Pascal; Tin, Adrienne; Matias-Garcia, Pamela R; Thio, Chris H L; Joehanes, Roby; Liu, Hongbo; Weihs, Antoine; Yu, Zhi; Hoppmann, Anselm; Grundner-Culemann, Franziska; Min, Josine L; Adeyemo, Adebowale A; et al. (Nat Commun, 2021)
Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Keywords: Adult; Aged; CpG Islands; DNA Methylation; Female; Glomerular Filtration Rate; Humans; Interferon Regulatory Factors; Kidney; Kidney Function Tests; LIM Domain Proteins; Male; Membrane Proteins; Middle Aged; Renal Insufficiency, Chronic; Transcription Factors

Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences. - Zhan, Lingyu; Li, Jiajin; Jew, Brandon; Sul, Jae Hoon (PLoS Genet, 2021)
Late-onset Alzheimer's disease (LOAD) is the most common type of dementia causing irreversible brain damage to the elderly and presents a major public health challenge. Clinical research and genome-wide association studies have suggested a potential contribution of the endocytic pathway to AD, with an emphasis on common loci. However, the contribution of rare variants in this pathway to AD has not been thoroughly investigated. In this study, we focused on the effect of rare variants on AD by first applying a rare-variant gene-set burden analysis using genes in the endocytic pathway on over 3,000 individuals with European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations of rare-variant burden within the endocytic pathway with AD, which were successfully replicated in independent datasets. We further demonstrated that this endocytic rare-variant enrichment is associated with neurofibrillary tangles (NFTs) and age-related phenotypes, increasing the risk of obtaining severer brain damage, earlier age-at-onset, and earlier age-of-death. Next, by aggregating rare variants within each gene, we sought to identify single endocytic genes associated with AD and NFTs. Careful examination using NFTs revealed one significantly associated gene, ANKRD13D. To identify functional associations, we integrated bulk RNA-Seq data from over 600 brain tissues and found two endocytic expression genes (eGenes), HLA-A and SLC26A7, that displayed significant influences on their gene expressions. Differential expressions between AD patients and controls of these three identified genes were further examined by incorporating scRNA-Seq data from 48 post-mortem brain samples and demonstrated distinct expression patterns across cell types. Taken together, our results demonstrated strong rare-variant effect in the endocytic pathway on AD risk and progression and functional effect of gene expression alteration in both bulk and single-cell resolution, which may bring more insight and serve as valuable resources for future AD genetic studies, clinical research, and therapeutic targeting.
Keywords: Alzheimer Disease; Endocytosis; Genome-Wide Association Study; Humans; Phenotype; Polymorphism, Single Nucleotide; Whole Genome Sequencing

Serum Nonesterified Fatty Acids and Incident Stroke: The CHS. - Huang, Neil K; Biggs, Mary L; Matthan, Nirupa R; Djoussé, Luc; Longstreth, W T; Mukamal, Kenneth J; Siscovick, David S; Lichtenstein, Alice H (J Am Heart Assoc, 2021)
Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996-1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)-6 polyunsaturated, n-3 polyunsaturated, and fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5-year follow-up period. Total n-3 (hazard ratio [HR], 0.77 [95% CI, 0.61-0.97]) and n-6 (HR, 1.32 [95% CI, 1.01-1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo-γ-linolenic acid (20:3n-6) was associated with higher risk (HR, 1.29 [95% CI, 1.02-1.63]), whereas -7-hexadecenoic acid (16:1n-9) and arachidonic acid (20:4n-6) were associated with a lower risk (HR, 0.67 [95% CI, 0.47-0.97]; HR, 0.81 [95% CI. 0.65-1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n-3 subclass and dihomo-γ-linolenic acid are diet derived and may be potential biomarkers for total stroke risk.
Keywords: 8,11,14-Eicosatrienoic Acid; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Hemorrhagic Stroke; Humans; Prospective Studies; Risk Factors; Stroke; Trans Fatty Acids

Serum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS). - Huang, Neil K; Bůzková, Petra; Matthan, Nirupa R; Djoussé, Luc; Kizer, Jorge R; Mukamal, Kenneth J; Polak, Joseph F; Lichtenstein, Alice H (Nutrients, 2021)
Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with ( = 255 for carotid IMT, 301 for FMD) or without ( = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. In multivariable adjusted linear regression models per SD increment, the non-esterified fatty acid conjugated linoleic acid (-18:2 CLA) was positively associated with carotid IMT [β (95% CI): 44.8 (19.2, 70.4), = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), = 1.000]. Non-esterified -palmitoleic acid (16:1n-7) was positively associated with FMD [19.7 (8.34, 31.0), = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Brachial Artery; Carotid Artery, Common; Carotid Intima-Media Thickness; Dilatation; Fatty Acids, Monounsaturated; Fatty Acids, Nonesterified; Female; Humans; Linoleic Acid; Male; Regional Blood Flow; Risk Factors; Ultrasonography

Sex Differences in Cognitive Decline Among US Adults. - Levine, Deborah A; Gross, Alden L; Briceño, Emily M; Tilton, Nicholas; Giordani, Bruno J; Sussman, Jeremy B; Hayward, Rodney A; Burke, James F; Hingtgen, Stephanie; Elkind, Mitchell S V; Manly, Jennifer J; Gottesman, Rebecca F; et al. (JAMA Netw Open, 2021)
Importance: Sex differences in dementia risk are unclear, but some studies have found greater risk for women. Objective: To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk. Design, Setting, and Participants: This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020. Exposure: Sex. Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Results: Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61). Conclusions and Relevance: The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.
Keywords: Aged; Cognitive Dysfunction; Cognitive Reserve; Cohort Studies; Executive Function; Humans; Memory; Middle Aged; Risk; Sex Factors; Time Factors; United States

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. - Yu, Bing; Roberts, Mary B; Raffield, Laura M; Zekavat, Seyedeh Maryam; Nguyen, Ngoc Quynh H; Biggs, Mary L; Brown, Michael R; Griffin, Gabriel; Desai, Pinkal; Correa, Adolfo; Morrison, Alanna C; Shah, Amil M; et al. (J Am Coll Cardiol, 2021)
BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.
Keywords: Aged; Clonal Hematopoiesis; Correlation of Data; Demography; DNA-Binding Proteins; Female; Heart Failure; Humans; Janus Kinase 2; Male; Middle Aged; Mutation; Proportional Hazards Models; Proto-Oncogene Proteins; Repressor Proteins; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left; Whole Exome Sequencing

Total carotenoid intake is associated with reduced loss of grip strength and gait speed over time in adults: The Framingham Offspring Study. - Sahni, Shivani; Dufour, Alyssa B; Fielding, Roger A; Newman, Anne B; Kiel, Douglas P; Hannan, Marian T; Jacques, Paul F (Am J Clin Nutr, 2021)
BACKGROUND: Lower antioxidant serum concentrations have been linked to declines in lean mass and physical function in older adults. Yet population data on the effect of dietary antioxidants on loss of muscle strength and physical function are lacking. OBJECTIVE: We sought to determine the association of antioxidant intake [vitamin C, vitamin E, and total and individual carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin)] with annualized change in grip strength and gait speed in adults from the Framingham Offspring study. METHODS: This prospective cohort study included participants with a valid FFQ at the index examination and up to 2 prior examinations and at ≥2 measures of primary outcomes: grip strength (n = 2452) and/or gait speed (n = 2422) measured over 3 subsequent examinations. Annualized change in grip strength (kg/y) and change in gait speed (m/s/y) over the follow-up period were used. Linear regression was used to calculate β coefficients and P values, adjusting for covariates. RESULTS: Mean ± SD age of participants was 61 ± 9 y (range: 33-88 y). Median intakes (IQR, mg/d) of vitamin C, vitamin E, and total carotenoid across available examinations were 209.2 (133.1-394.2), 27.1 (7.4-199.0), and 15.3 (10.4-21.3), respectively. The mean follow-up time was ∼12 ± 2 y (range: 4.5-15.4 y). In the sex-combined sample, higher intakes of total carotenoids, lycopene, and lutein + zeaxanthin were associated with increased annualized change in grip strength [β (SE) per 10-mg higher intake/d, range: 0.0316 (0.0146) to 0.1223 (0.0603) kg/y)]. All antioxidants except for vitamin C were associated with faster gait speed [β (SE) per 10-mg higher intake/d, range: 0.00008 (0.00004) to 0.0187 (0.0081) m/s/y]. CONCLUSIONS: Higher antioxidant intake was associated with increase in grip strength and faster gait speed in this cohort of adults. This finding highlights the need for a randomized controlled trial of dietary antioxidants and their effect on muscle strength and physical function.
Keywords: Adult; Aged; Aged, 80 and over; Carotenoids; Cohort Studies; Diet; Female; Hand Strength; Humans; Male; Middle Aged; Prospective Studies; Walking Speed

What Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium. - Cawthon, Peggy M; Patel, Sheena M; Kritchevsky, Stephen B; Newman, Anne B; Santanasto, Adam; Kiel, Douglas P; Travison, Thomas G; Lane, Nancy; Cummings, Steven R; Orwoll, Eric S; Duchowny, Kate A; Kwok, Timothy; et al. (J Gerontol A Biol Sci Med Sci, 2021)
BACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion. METHODS: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not. RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants. CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.
Keywords: Aged; Female; Gait; Humans; Independent Living; Male; Mobility Limitation; Sarcopenia; Walking; Walking Speed

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. - Hu, Yao; Stilp, Adrienne M; McHugh, Caitlin P; Rao, Shuquan; Jain, Deepti; Zheng, Xiuwen; Lane, John; Méric de Bellefon, Sébastian; Raffield, Laura M; Chen, Ming-Huei; Yanek, Lisa R; Wheeler, Marsha; et al. (Am J Hum Genet, 2021)
Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
Keywords: Adult; Aged; Chromosomes, Human, Pair 16; Datasets as Topic; Erythrocytes; Female; Gene Editing; Genetic Variation; Genome-Wide Association Study; HEK293 Cells; Humans; Male; Middle Aged; National Heart, Lung, and Blood Institute (U.S.); Phenotype; Quality Control; Reproducibility of Results; United States

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program. - Mikhaylova, Anna V; McHugh, Caitlin P; Polfus, Linda M; Raffield, Laura M; Boorgula, Meher Preethi; Blackwell, Thomas W; Brody, Jennifer A; Broome, Jai; Chami, Nathalie; Chen, Ming-Huei; Conomos, Matthew P; Cox, Corey; et al. (Am J Hum Genet, 2021)
Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
Keywords: Asthma; Biomarkers; Dermatitis, Atopic; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Leukocytes; National Heart, Lung, and Blood Institute (U.S.); Phenotype; Polymorphism, Single Nucleotide; Prognosis; Proteome; Pulmonary Disease, Chronic Obstructive; Quantitative Trait Loci; United Kingdom; United States; Whole Genome Sequencing

The association of hearing problems with social network strength and depressive symptoms: the cardiovascular health study. - Dobrota, Sylvie D; Biggs, Mary L; Pratt, Sheila; Popat, Rita; Odden, Michelle C (Age Ageing, 2022)
BACKGROUND: research on the association between hearing impairment and psychosocial outcomes is not only limited but also yielded mixed results. METHODS: we investigated associations between annual self-reports of hearing problems, depressive symptoms and social network strength among 5,888 adults from the Cardiovascular Health Study over a period of 9 years. Social network strength and depressive symptoms were defined using the Lubben Social Network Scale (LSNS), and the Center for Epidemiological Studies Depression Scale (CES-D). RESULTS: hearing problems were associated with weaker social networks and more depressive symptoms. These association differed for prevalent versus incident hearing problems. Participants with prevalent hearing problems scored an adjusted 0.47 points lower (95% CI: -2.20, -0.71) on the LSNS and 0.71 points higher (95% CI: 0.23, 1.19) on the CES-D than those without hearing problems. Participants with incident hearing problems had a greater decline of 0.12 points (95% CI: -0.12, -0.03) per year in social network score than individuals with no hearing problems after adjusting for confounders. Females appeared to be more vulnerable to changes in social network strength than males (P-value for interaction = 0.02), but not for changes in depressive score. Accounting for social network score did not appear to attenuate the association between hearing problems and depressive score. CONCLUSION: findings suggest that older adults with prevalent hearing problems may be more at risk for depression, but individuals with incident hearing problems may be at greater risk for a winnowing of their social network.
Keywords: Aged; Depression; Female; Hearing Loss; Humans; Male; Self Report; Social Networking

The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study. - Barzilay, Joshua I; Tressel, William; Biggs, Mary L; Stein, Phyllis K; Kizer, Jorge R; Shitole, Sanyog G; Bene-Alhasan, Yakubu; Mukamal, Kenneth J (Diabetes Care, 2022)
OBJECTIVE: The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes. RESEARCH DESIGN AND METHODS: Heart rate (HR) and measures of HR variability (HRV) were derived from 24-h electrocardiographic monitoring. Blood pressure, seated and standing, was measured. Cox proportional hazards models and linear mixed models were used to analyze the associations between HRV, HR, and orthostatic hypotension (SBP >20 mmHg decline) and incident diabetes or longitudinal FG change. RESULTS: The mean annual unadjusted FG change was 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged over 4-11 (DFA1) or 12-20 beats (DFA2)-reflecting greater versus less organization of beat-to-beat intervals-were associated with less FG increase over time (per 1-SD increment: DFA1: -0.49 mg/dL/year [-0.96, -0.03]; DFA2: -0.55 mg/dL/year [-1.02, -0.09]). In mutually adjusted analyses, higher SD of the N-N interval (SDNN) was associated with less FG increase over time (per 1-SD increment: SDNN: -0.62 mg/dL/year [-1.22, -0.03]). Higher values of DFA1, DFA2, and SDNN were each associated with greater insulin secretion and insulin sensitivity but not with incident diabetes. We observed no association of HR or orthostatic hypotension with diabetes or FG change. CONCLUSIONS: Specific measures of cardiac autonomic function are prospectively related to FG level changes and insulin secretion and action.
Keywords: Aged; Autonomic Nervous System; Blood Glucose; Diabetes Mellitus; Glucose; Heart Rate; Humans; Hypotension, Orthostatic; Insulin Resistance

Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults. - Fretts, Amanda M; Hazen, Stanley L; Jensen, Paul; Budoff, Matthew; Sitlani, Colleen M; Wang, Meng; de Oliveira Otto, Marcia C; DiDonato, Joseph A; Lee, Yujin; Psaty, Bruce M; Siscovick, David S; Sotoodehnia, Nona; et al. (JAMA Netw Open, 2022)
Importance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population. Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US. Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021. Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models. Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3%) were male, 3184 (59.7%) were female, 848 (15.9%) were African American, 4450 (83.4%) were White, and 35 (0.01%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95% CI, 1.17-1.44) for TMAO, 1.19 (95% CI, 1.08-1.32) for choline, 1.26 (95% CI, 1.15-1.40) for carnitine, and 1.26 (95% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality. Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.
Keywords: Aged; Betaine; Cardiovascular Diseases; Carnitine; Choline; Cohort Studies; Female; Humans; Male; Methylamines; Prospective Studies

Body Composition and Incident Heart Failure in Older Adults: Results From 2 Prospective Cohorts. - Zhang, Lili; Bartz, Traci M; Santanasto, Adam; Djoussé, Luc; Mukamal, Kenneth J; Forman, Daniel E; Hirsch, Calvin H; Newman, Anne B; Gottdiener, John S; Kizer, Jorge R (J Am Heart Assoc, 2022)
Background Aging is associated with central fat redistribution and skeletal muscle decline, yet the relationships of tissue compartments with heart failure (HF) remain incompletely characterized. We assessed the contribution of body composition to incident HF in elders. Methods and Results Participants from 2 older cohorts who completed dual-energy X-ray absorptiometry (DEXA) and, in one cohort, computed tomography were included. We evaluated associations with incident HF for DEXA principal components (PCs) and total lean, appendicular lean, total fat and trunk fat mass; and for computed tomography measures of abdominal visceral and subcutaneous fat, thigh muscle, intermuscular fat area and thigh muscle density. DEXA analysis included 3621, and computed tomography analysis 2332 participants. During median follow-up of 11.8 years, 927 participants developed HF. DEXA principal components showed no relationship with HF. After adjustment for height, weight, and cardiovascular risk factors, total lean mass was near significantly associated with higher HF (hazard ratio [HR], 1.25 per SD [1.00-1.56]), whereas total fat mass and thigh muscle density were significantly related to lower HF (HR, 0.82 [0.68-0.99] and HR, 0.87 [0.78-0.97], respectively). Patterns were similar for HF subtypes. The relationships with HF for total lean and fat mass were attenuated after adjusting for intercurrent atrial fibrillation or excluding high natriuretic peptide levels. Conclusions Total lean mass was positively associated, while total fat mass and thigh muscle density were inversely associated, with incident HF. These findings highlight the limitations of DEXA for assessment of HF risk in elders and support the preeminence of computed tomography-measured skeletal muscle quality over mass as a determinant of HF incidence.
Keywords: Absorptiometry, Photon; Aged; Aging; Body Composition; Body Mass Index; Heart Failure; Humans; Muscle, Skeletal; Prospective Studies

CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer. - Kunihiro, Andrew G; Sarrett, Samantha M; Lastwika, Kristin J; Solan, Joell L; Pisarenko, Tatyana; Keinänen, Outi; Rodriguez, Cindy; Taverne, Lydia R; Fitzpatrick, Annette L; Li, Christopher I; Houghton, A McGarry; Zeglis, Brian M; et al. (J Nucl Med, 2022)
Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged using near-infrared fluorescence (NIRF) immunoimaging, and Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both and NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted Zr-immunoPET could be an effective early detection screening strategy for SCLC.
Keywords: Animals; Autoantibodies; Biomarkers; Cell Line, Tumor; Disease Models, Animal; Early Detection of Cancer; Humans; Lung Neoplasms; Mice; Mice, Nude; Neuroendocrine Tumors; Positron-Emission Tomography; RNA, Messenger; Small Cell Lung Carcinoma

Circulating Androgen Concentrations and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study. - Njoroge, Joyce N; Tressel, William; Biggs, Mary L; Matsumoto, Alvin M; Smith, Nicholas L; Rosenberg, Emily; Hirsch, Calvin H; Gottdiener, John S; Mukamal, Kenneth J; Kizer, Jorge R (J Am Heart Assoc, 2022)
Background Circulating androgen concentrations in men decline with age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone and incident heart failure (HF) but remains unstudied for free testosterone or the more potent androgen dihydrotestosterone (DHT). We hypothesized that total/free testosterone are inversely related, sex hormone-binding globulin is positively related, and total/free DHT bear a U-shaped relationship with incident HF. Methods and Results In a sample of men from the CHS (Cardiovascular Health Study) without atherosclerotic cardiovascular disease or HF, serum testosterone and DHT concentrations were measured by liquid chromatography-tandem mass spectrometry, and sex hormone-binding globulin by immunoassay. Free testosterone or DHT was calculated from total testosterone or total DHT, sex hormone-binding globulin, and albumin. We used Cox regression to estimate relative risks of HF after adjustment for potential confounders. In 1061 men (aged 76±5 years) followed for a median of 9.6 years, there were 368 HF events. After adjustment, lower calculated free testosterone was significantly associated with higher risk of HF (hazard ratio [HR], 1.14 [95% CI, 1.01-1.28]). Risk estimates for total testosterone (HR, 1.12 [95% CI, 0.99-1.26]), total DHT (HR, 1.10 [95% CI, 0.97-1.24]), calculated free dihydrotestosterone (HR, 1.09 [95% CI, 0.97-1.23]), and sex hormone-binding globulin (HR, 1.07 [95% CI, 0.95-1.21]) were directionally similar but not statistically significant. Conclusions Calculated free testosterone was inversely associated with incident HF, suggesting a contribution of testosterone deficiency to HF incidence among older men. Additional research is necessary to determine whether testosterone replacement therapy might be an effective strategy to lower HF risk in older men.
Keywords: Aged; Androgens; Cardiovascular Diseases; Dihydrotestosterone; Estradiol; Heart Failure; Humans; Male; Sex Hormone-Binding Globulin; Testosterone

Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study. - Durda, Peter; Raffield, Laura M; Lange, Ethan M; Olson, Nels C; Jenny, Nancy Swords; Cushman, Mary; Deichgraeber, Pia; Grarup, Niels; Jonsson, Anna; Hansen, Torben; Mychaleckyj, Josyf C; Psaty, Bruce M; et al. (J Am Heart Assoc, 2022)
Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near (top result rs62165726, =3.3×10),19 variants near chromosome 17 gene (rs55714927, =1.5×10), and 18 variants near chromosome 11 gene . These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 =7.1×10) in the region, and 3 variants (rs115391969 =4.3×10) near the chromosome 16 gene Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.
Keywords: Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Asialoglycoprotein Receptor; Biomarkers; Cardiovascular Diseases; Female; Genome-Wide Association Study; Heart Failure; Humans; Longitudinal Studies; Male

Correlations between complex human phenotypes vary by genetic background, gender, and environment. - Elgart, Michael; Goodman, Matthew O; Isasi, Carmen; Chen, Han; Morrison, Alanna C; de Vries, Paul S; Xu, Huichun; Manichaikul, Ani W; Guo, Xiuqing; Franceschini, Nora; Psaty, Bruce M; Rich, Stephen S; et al. (Cell Rep Med, 2022)
We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.
Keywords: Female; Genetic Background; Humans; Male; Phenotype

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. - Thibord, Florian; Klarin, Derek; Brody, Jennifer A; Chen, Ming-Huei; Levin, Michael G; Chasman, Daniel I; Goode, Ellen L; Hveem, Kristian; Teder-Laving, Maris; Martinez-Perez, Angel; Aïssi, Dylan; Daian-Bacq, Delphine; et al. (Circulation, 2022)
BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
Keywords: Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Thrombosis; Venous Thromboembolism

Diabetes Status Modifies the Association Between Different Measures of Obesity and Heart Failure Risk Among Older Adults: A Pooled Analysis of Community-Based NHLBI Cohorts. - Patel, Kershaw V; Segar, Matthew W; Lavie, Carl J; Kondamudi, Nitin; Neeland, Ian J; Almandoz, Jaime P; Martin, Corby K; Carbone, Salvatore; Butler, Javed; Powell-Wiley, Tiffany M; Pandey, Ambarish (Circulation, 2022)
BACKGROUND: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity-overall obesity, central obesity, fat mass (FM)-and diabetes status for HF risk are not well-established. METHODS: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI≥30 kg/m), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes. RESULTS: The study included 10 387 participants (52.9% ARIC; 25.1% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high (=0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI ( interaction=0.04) and WC ( interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95% CI] per 1 SD higher BMI=1.29 [1.14-1.47]; WC=1.48 [1.29-1.70]; FM=1.25 [1.09-1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8%, 29.9%, and 13.7%, respectively) versus those without diabetes (≤1% for each). CONCLUSIONS: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes.
Keywords: Aged; Cohort Studies; Diabetes Mellitus; Female; Heart Failure; Humans; Male; National Heart, Lung, and Blood Institute (U.S.); Obesity; Risk Factors; United States

Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study. - Wang, Meng; Wang, Zeneng; Lee, Yujin; Lai, Heidi T M; de Oliveira Otto, Marcia C; Lemaitre, Rozenn N; Fretts, Amanda; Sotoodehnia, Nona; Budoff, Matthew; DiDonato, Joseph A; McKnight, Barbara; Tang, W H Wilson; et al. (Arterioscler Thromb Vasc Biol, 2022)
BACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways. METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways. RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95% CI) of 10.6% (1.0-114.5), 7.8% (1.0-32.7), and 9.2% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association. CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.
Keywords: Animals; Atherosclerosis; Cardiovascular Diseases; Carnitine; Humans; Meat; Methylamines; Risk Factors

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. - Winkler, Thomas W; Rasheed, Humaira; Teumer, Alexander; Gorski, Mathias; Rowan, Bryce X; Stanzick, Kira J; Thomas, Laurent F; Tin, Adrienne; Hoppmann, Anselm; Chu, Audrey Y; Tayo, Bamidele; Thio, Chris H L; et al. (Commun Biol, 2022)
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
Keywords: Creatinine; Diabetes Mellitus; Diabetic Nephropathies; Genome-Wide Association Study; Glomerular Filtration Rate; Humans; Kidney

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. - Halford, Jennifer L; Morrill, Valerie N; Choi, Seung Hoan; Jurgens, Sean J; Melloni, Giorgio; Marston, Nicholas A; Weng, Lu-Chen; Nauffal, Victor; Hall, Amelia W; Gunn, Sophia; Austin-Tse, Christina A; Pirruccello, James P; et al. (Nat Commun, 2022)
Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.
Keywords: Disease Susceptibility; Endophenotypes; Humans; Long QT Syndrome; Virulence

Epilepsy, Vascular Risk Factors, and Cognitive Decline in Older Adults: The Cardiovascular Health Study. - Choi, Hyunmi; Elkind, Mitchell S V; Longstreth, W T; Boehme, Amelia K; Hafen, Rebekah; Hoyt, Emma J; Thacker, Evan L (Neurology, 2022)
BACKGROUND AND OBJECTIVES: Recent studies have shown that global cognitive ability tends to decline faster over time in older adults (≥65 years) with epilepsy compared with older adults without epilepsy. Scarce data exist about the role of vascular risk factors (VRFs) on cognitive course in epilepsy. We assessed whether the associations of individual VRFs with cognitive trajectory differed depending on the presence of prevalent epilepsy. METHODS: The Cardiovascular Health Study is a population-based longitudinal cohort study of 5,888 US adults aged ≥65 years. Cognitive function was assessed annually with modified Mini-Mental State Examination (3MS; global cognitive ability) and Digit Symbol Substitution Test (DSST; information processing speed). We used linear mixed models to estimate the individual and joint associations of epilepsy and VRFs with cognitive decline by modeling epilepsy × VRF interactions one by one, each adjusted for all other VRFs considered, including demographics, health behaviors, clinical characteristics, and comorbid diagnoses. From these models, we estimated excess mean cognitive decline due to interaction of epilepsy with each VRF. RESULTS: We observed excess mean decline in global cognitive ability (3MS) due to interactions of epilepsy with hypertension (6.6 points greater mean 8-year decline than expected if no interaction; 95% CI 1.3-12.0) and with abstaining from alcohol (5.8 points greater than expected; 95% CI 0.3-11.3). We also observed excess mean decline in information processing speed (DSST) due to interactions of epilepsy with prior stroke (18.1 points greater mean 9-year decline than expected; 95% CI 7.6-28.5), with abstaining from alcohol (6.1 points greater than expected; 95% CI 2.5-9.8), and with higher triglyceride levels (2.4 points greater than expected per SD; 95% CI 0.4-4.3). DISCUSSION: Associations of some VRFs with cognitive decline in older adults are stronger in the presence of epilepsy, suggesting a need for greater attention to vascular protection for preserving brain health in older adults with epilepsy.
Keywords: Aged; Cognition; Cognitive Dysfunction; Epilepsy; Humans; Longitudinal Studies; Neuropsychological Tests; Risk Factors

Fasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults. - Shitole, Sanyog G; Biggs, Mary L; Ix, Joachim H; Fretts, Amanda M; Tracy, Russell P; Siscovick, David S; Djoussé, Luc; Mukamal, Kenneth J; Kizer, Jorge R (Am J Epidemiol, 2022)
To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.
Keywords: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Glucose; Humans; Insulin; Insulin Resistance; Male; Prospective Studies

A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. - Li, Zilin; Li, Xihao; Zhou, Hufeng; Gaynor, Sheila M; Selvaraj, Margaret Sunitha; Arapoglou, Theodore; Quick, Corbin; Liu, Yaowu; Chen, Han; Sun, Ryan; Dey, Rounak; Arnett, Donna K; et al. (Nat Methods, 2022)
Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
Keywords: Genetic Variation; Genome; Genome-Wide Association Study; Humans; Phenotype; Whole Genome Sequencing

Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study. - Garg, Parveen K; Biggs, Mary L; Kizer, Jorge R; Shah, Sanjiv J; Psaty, Bruce; Carnethon, Mercedes; Gottdiener, John S; Siscovick, David; Mukamal, Kenneth J (Cardiovasc Diabetol, 2022)
OBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population. METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics. RESULTS: Mean age for the 2433 included participants was 72.0 years, 33.6% were male, and 3.7% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95% confidence interval = 0.03-0.33). CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.
Keywords: Aged; Cross-Sectional Studies; Female; Glucose; Humans; Insulin Resistance; Male; Ventricular Dysfunction, Left; Ventricular Function, Left

Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults. - Shivakoti, Rupak; Biggs, Mary L; Djoussé, Luc; Durda, Peter Jon; Kizer, Jorge R; Psaty, Bruce; Reiner, Alex P; Tracy, Russell P; Siscovick, David; Mukamal, Kenneth J (JAMA Netw Open, 2022)
Importance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date. Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD). Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed. Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit). Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis. Results: Of 4125 individuals, 0.1% (n = 3) were Asian or Pacific Islander, 4.4% (n = 183) were Black, 0.3% (n = 12) were Native American, 95.0% (n = 3918) were White, and 0.2% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4%]; and 3942 individuals of other races and ethnicitites [95.6%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5% for interleukin 18 to 14.2% for C-reactive protein, and 16.1% for their primary principal component. Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.
Keywords: Adult; Aged; Cardiovascular Diseases; Cohort Studies; Dietary Fiber; Female; Humans; Inflammation; Middle Aged; Risk Factors

Integrative analysis of clinical and epigenetic biomarkers of mortality. - Huan, Tianxiao; Nguyen, Steve; Colicino, Elena; Ochoa-Rosales, Carolina; Hill, W David; Brody, Jennifer A; Soerensen, Mette; Zhang, Yan; Baldassari, Antoine; Elhadad, Mohamed Ahmed; Toshiko, Tanaka; Zheng, Yinan; et al. (Aging Cell, 2022)
DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P  = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.
Keywords: Biomarkers; Cardiovascular Diseases; DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Male; Neoplasms

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. - Tcheandjieu, Catherine; Zhu, Xiang; Hilliard, Austin T; Clarke, Shoa L; Napolioni, Valerio; Ma, Shining; Lee, Kyung Min; Fang, Huaying; Chen, Fei; Lu, Yingchang; Tsao, Noah L; Raghavan, Sridharan; et al. (Nat Med, 2022)
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
Keywords: Coronary Artery Disease; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Risk Factors

Longitudinal Changes in Hearing and Visual Impairments and Risk of Dementia in Older Adults in the United States. - Hwang, Phillip H; Longstreth, W T; Thielke, Stephen M; Francis, Courtney E; Carone, Marco; Kuller, Lewis H; Fitzpatrick, Annette L (JAMA Netw Open, 2022)
Importance: Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known. Objective: To evaluate whether DSI is associated with incident dementia in older adults. Design, Setting, and Participants: This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020. Exposures: Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits. Main Outcomes and Measures: All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria. Results: A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P < .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P < .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05). Conclusions and Relevance: In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.
Keywords: Aged; Alzheimer Disease; Cohort Studies; Female; Hearing; Hearing Loss; Humans; Male; Medicare; Prospective Studies; United States; Vision Disorders

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study. - Eckhardt, Christina M; Balte, Pallavi P; Barr, Robert Graham; Bertoni, Alain G; Bhatt, Surya P; Cuttica, Michael; Cassano, Patricia A; Chaves, Paolo; Couper, David; Jacobs, David R; Kalhan, Ravi; Kronmal, Richard; et al. (Eur Heart J, 2022)
AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.
Keywords: Adult; Heart Failure; Hospitalization; Humans; Lung; National Heart, Lung, and Blood Institute (U.S.); Prognosis; Risk Factors; Stroke Volume; United States

Monocyte subsets, T cell activation profiles, and stroke in men and women: The Multi-Ethnic Study of Atherosclerosis and Cardiovascular Health Study. - Feinstein, Matthew J; Bůzková, Petra; Olson, Nels C; Doyle, Margaret F; Sitlani, Colleen M; Fohner, Alison E; Huber, Sally A; Floyd, James; Sinha, Arjun; Thorp, Edward B; Landay, Alan; Freiberg, Matthew S; et al. (Atherosclerosis, 2022)
BACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke. METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models. RESULTS: We observed associations of intermediate monocytes, early-activated CD4 T cells, and both CD4 and CD8 T cells producing interleukin-4 after cytokine stimulation (T and T, respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women. CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.
Keywords: Atherosclerosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Female; Follow-Up Studies; Humans; Incidence; Inflammation; Interleukin-4; Ischemic Stroke; Lymphocyte Activation; Male; Monocytes; Stroke; T-Lymphocyte Subsets

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. - Mahajan, Anubha; Spracklen, Cassandra N; Zhang, Weihua; Ng, Maggie C Y; Petty, Lauren E; Kitajima, Hidetoshi; Yu, Grace Z; Rüeger, Sina; Speidel, Leo; Kim, Young Jin; Horikoshi, Momoko; Mercader, Josep M; et al. (Nat Genet, 2022)
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
Keywords: Diabetes Mellitus, Type 2; Ethnicity; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Risk Factors

A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. - Kurniansyah, Nuzulul; Goodman, Matthew O; Kelly, Tanika N; Elfassy, Tali; Wiggins, Kerri L; Bis, Joshua C; Guo, Xiuqing; Palmas, Walter; Taylor, Kent D; Lin, Henry J; Haessler, Jeffrey; Gao, Yan; et al. (Nat Commun, 2022)
In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.
Keywords: Adult; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hypertension; Multifactorial Inheritance; Prevalence; Risk Factors

Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease. - Liu, Jiahao; Nair, Viji; Zhao, Yi-Yang; Chang, Dong-Yuan; Limonte, Christine; Bansal, Nisha; Fermin, Damian; Eichinger, Felix; Tanner, Emily C; Bellovich, Keith A; Steigerwalt, Susan; Bhat, Zeenat; et al. (Diabetes, 2022)
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.
Keywords: Angiopoietin-1; Angiopoietin-2; Angiopoietins; Biomarkers; Cohort Studies; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Endothelial Cells; Humans; Kidney Failure, Chronic; Receptor, TIE-2; Signal Transduction

New insights into the genetic etiology of Alzheimer's disease and related dementias. - Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf; Naj, Adam C; Campos-Martin, Rafael; Grenier-Boley, Benjamin; Andrade, Victor; Holmans, Peter A; Boland, Anne; et al. (Nat Genet, 2022)
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Keywords: Alzheimer Disease; Cognitive Dysfunction; Genome-Wide Association Study; Humans; tau Proteins

Non-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations. - Elgart, Michael; Lyons, Genevieve; Romero-Brufau, Santiago; Kurniansyah, Nuzulul; Brody, Jennifer A; Guo, Xiuqing; Lin, Henry J; Raffield, Laura; Gao, Yan; Chen, Han; de Vries, Paul; Lloyd-Jones, Donald M; et al. (Commun Biol, 2022)
Polygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.
Keywords: Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Machine Learning; Multifactorial Inheritance; Polymorphism, Single Nucleotide

Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study. - Lemaitre, Rozenn N; Jensen, Paul N; Zeigler, Maxwell; Fretts, Amanda M; Umans, Jason G; Howard, Barbara V; Sitlani, Colleen M; McKnight, Barbara; Gharib, Sina A; King, Irena B; Siscovick, David S; Psaty, Bruce M; et al. (EBioMedicine, 2022)
BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS). METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression. FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses. INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations. FUNDING: US National Institutes of Health.
Keywords: Animals; Arachidonic Acids; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Eicosanoids; Humans; Ischemic Stroke; Prospective Studies

Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts. - Lamprea-Montealegre, Julio A; Arnold, Alice M; McClelland, Robyn L; Mukamal, Kenneth J; Djoussé, Luc; Biggs, Mary L; Siscovick, David S; Tracy, Russell P; Beisswenger, Paul J; Psaty, Bruce M; Ix, Joachim H; Kizer, Jorge R (J Am Heart Assoc, 2022)
Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α-dicarbonyl-derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new-onset CVD in 2 population-based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case-cohort sample (n=1631) from the Multi-Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi-Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow-up of 11 years, 439 participants in the Multi-Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl-lysine, 3-deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi-Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α-dicarbonyl-derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle-aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α-dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high-risk older populations.
Keywords: Atherosclerosis; Cardiovascular Diseases; Cohort Studies; Glycation End Products, Advanced; Humans; Middle Aged; Risk Factors

Plasma proteomic signature of decline in gait speed and grip strength. - Liu, Xiaojuan; Pan, Stephanie; Xanthakis, Vanessa; Vasan, Ramachandran S; Psaty, Bruce M; Austin, Thomas R; Newman, Anne B; Sanders, Jason L; Wu, Chenkai; Tracy, Russell P; Gerszten, Robert E; Odden, Michelle C (Aging Cell, 2022)
The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 × 10 ), pleiotrophin (1.23 × 10 ), and TIMP-1 (5.97 × 10 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10 ), CDON (2.38 × 10 ), and SMOC1 (7.47 × 10 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline.
Keywords: Adult; Female; Gait; Hand Strength; Humans; Independent Living; Male; Proteomics; Walking Speed

Pooled Cohort Probability Score for Subclinical Airflow Obstruction. - Bhatt, Surya P; Balte, Pallavi P; Schwartz, Joseph E; Jaeger, Byron C; Cassano, Patricia A; Chaves, Paulo H; Couper, David; Jacobs, David R; Kalhan, Ravi; Kaplan, Robert; Lloyd-Jones, Donald; Newman, Anne B; et al. (Ann Am Thorac Soc, 2022)
Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events ( = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.
Keywords: Adult; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Nutrition Surveys; Pulmonary Disease, Chronic Obstructive; Risk Factors; Spirometry; Vital Capacity

PUFA ω-3 and ω-6 biomarkers and sleep: a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE). - Murphy, Rachel A; Tintle, Nathan; Harris, William S; Darvishian, Maryam; Marklund, Matti; Virtanen, Jyrki K; Hantunen, Sari; de Mello, Vanessa D; Tuomilehto, Jaakko; Lindström, Jaana; Bolt, Matthew A; Brouwer, Ingeborg A; et al. (Am J Clin Nutr, 2022)
BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium. METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis. RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified. CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.
Keywords: Biomarkers; Cohort Studies; Cross-Sectional Studies; Fatty Acids; Fatty Acids, Omega-3; Humans; Outcome Assessment, Health Care; Sleep

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. - Hindy, George; Dornbos, Peter; Chaffin, Mark D; Liu, Dajiang J; Wang, Minxian; Selvaraj, Margaret Sunitha; Zhang, David; Park, Joseph; Aguilar-Salinas, Carlos A; Antonacci-Fulton, Lucinda; Ardissino, Diego; Arnett, Donna K; et al. (Am J Hum Genet, 2022)
Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
Keywords: Alleles; Blood Glucose; Case-Control Studies; Computational Biology; Databases, Genetic; Diabetes Mellitus, Type 2; Exome; Genetic Predisposition to Disease; Genetic Variation; Genetics, Population; Genome-Wide Association Study; Humans; Lipid Metabolism; Lipids; Liver; Molecular Sequence Annotation; Multifactorial Inheritance; Open Reading Frames; Phenotype; Polymorphism, Single Nucleotide

Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study. - Elam, Rachel E; Bůzková, Petra; Barzilay, Joshua I; Wang, Zeneng; Nemet, Ina; Budoff, Matthew J; Cauley, Jane A; Fink, Howard A; Lee, Yujin; Robbins, John A; Wang, Meng; Hazen, Stanley L; et al. (Bone, 2022)
CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain. OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults. DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study. PARTICIPANTS: 5019 U.S. adults aged ≥65 years. EXPOSURE: Plasma TMAO. MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n = 1400). RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26 years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42 g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P < 0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI ≥ 25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight. CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.
Keywords: Absorptiometry, Photon; Aged; Bone Density; Female; Hip Fractures; Humans; Male; Methylamines; Risk Factors

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. - Wang, Zhe; Choi, Shing Wan; Chami, Nathalie; Boerwinkle, Eric; Fornage, Myriam; Redline, Susan; Bis, Joshua C; Brody, Jennifer A; Psaty, Bruce M; Kim, Wonji; McDonald, Merry-Lynn N; Regan, Elizabeth A; et al. (Front Endocrinol (Lausanne), 2022)
Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.
Keywords: Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Obesity; Whole Genome Sequencing

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. - DiCorpo, Daniel; Gaynor, Sheila M; Russell, Emily M; Westerman, Kenneth E; Raffield, Laura M; Majarian, Timothy D; Wu, Peitao; Sarnowski, Chloe; Highland, Heather M; Jackson, Anne; Hasbani, Natalie R; de Vries, Paul S; et al. (Commun Biol, 2022)
The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
Keywords: Diabetes Mellitus, Type 2; Fasting; Glucose; Humans; Insulin; National Heart, Lung, and Blood Institute (U.S.); Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Precision Medicine; Receptors, Immunologic; United States

Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. - Wheeler, Marsha M; Stilp, Adrienne M; Rao, Shuquan; Halldorsson, Bjarni V; Beyter, Doruk; Wen, Jia; Mihkaylova, Anna V; McHugh, Caitlin P; Lane, John; Jiang, Min-Zhi; Raffield, Laura M; Jun, Goo; et al. (Nat Commun, 2022)
Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
Keywords: Blood Cells; Genome-Wide Association Study; Humans; Whole Genome Sequencing

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. - Weinstock, Joshua S; Gopakumar, Jayakrishnan; Burugula, Bala Bharathi; Uddin, Md Mesbah; Jahn, Nikolaus; Belk, Julia A; Bouzid, Hind; Daniel, Bence; Miao, Zhuang; Ly, Nghi; Mack, Taralynn M; Luna, Sofia E; et al. (Nature, 2023)
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
Keywords: Alleles; Animals; Clonal Hematopoiesis; Genome-Wide Association Study; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mice; Mutation; Promoter Regions, Genetic

Association between 5-year change in cardiovascular risk and the incidence of atherosclerotic cardiovascular diseases: a multi-cohort study. - Yi, Jiayi; Wang, Lili; Guo, Xinli; Ren, Xiangpeng (J Transl Med, 2023)
BACKGROUND: The influence of the historical cardiovascular risk status on future risk of atherosclerotic cardiovascular disease (ASCVD) is poorly understood. We aimed to investigate the association between 5-year changes in cardiovascular risk and ASCVD incidence. METHODS: We analyzed pooled data from seven community-based prospective cohort studies with up to 20 years of follow-up data. The study populations included White or Black participants aged 40-75 years without prevalent ASCVD. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (< 20%) or high risk (≥ 20%). Changes in cardiovascular disease (CVD) risk over a 5-year interval were recorded. The main outcome was incident ASCVD. RESULTS: Among 11,026 participants (mean [SD] age, 60.0 [8.1] years), 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up period of 9.9 years, 2560 (23.2%) ASCVD events occurred. In comparison with individuals showing a consistently high CVD risk, participants whose CVD risk changed from non-high to high (hazard ratio [HR], 0.67; 95% confidence interval [CI] 0.59-0.77) or high to non-high (HR, 0.57; 95% CI 0.41-0.80) and those with a consistently non-high risk (HR, 0.33; 95% CI 0.29-0.37) had a lower risk of incident ASCVD. In comparison with individuals showing a consistently non-high CVD risk, participants whose CVD risk changed from high to non-high (HR, 1.74; 95% CI 1.26-2.41) or from non-high to high risk (HR, 2.04; 95% CI 1.84-2.27) and those with a consistently high risk (HR 3.03; 95% CI 2.69-3.42) also showed an increased risk of incident ASCVD. CONCLUSIONS: Individuals with the same current CVD risk status but different historical CVD risks exhibited varying risks of future ASCVD incidents. Dynamic risk evaluation may enable more accurate cardiovascular risk stratification, and decision-making regarding preventive interventions should take the historical risk status into account.
Keywords: Atherosclerosis; Cardiovascular Diseases; Cohort Studies; Female; Heart Disease Risk Factors; Humans; Incidence; Male; Middle Aged; Prospective Studies; Risk Factors

Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study. - Sheets, Kerry M; Bůzková, Petra; Chen, Zhao; Carbone, Laura D; Cauley, Jane A; Barzilay, Joshua I; Starks, Jamie L; Miller, Lindsay M; Fink, Howard A (Osteoporos Int, 2023)
UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture. INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture. METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive). RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90). CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.
Keywords: Aged; Brain Infarction; Frailty; Hip Fractures; Humans; Prospective Studies; Risk Factors; White Matter

Association of Obesity With Cognitive Decline in Black and White Americans. - Quaye, Emmanuel; Galecki, Andrzej T; Tilton, Nicholas; Whitney, Rachael; Briceño, Emily M; Elkind, Mitchell S V; Fitzpatrick, Annette L; Gottesman, Rebecca F; Griswold, Michael; Gross, Alden L; Heckbert, Susan R; Hughes, Timothy M; et al. (Neurology, 2023)
BACKGROUND AND OBJECTIVES: There are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts. METHODS: We pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15). RESULTS: Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline ( = 0.34). DISCUSSION: These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.
Keywords: Aged; Black or African American; Cognition; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Obesity; Risk Factors; United States; White

Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. - Ong, Kwok Leung; Marklund, Matti; Huang, Liping; Rye, Kerry-Anne; Hui, Nicholas; Pan, Xiong-Fei; Rebholz, Casey M; Kim, Hyunju; Steffen, Lyn M; van Westing, Anniek C; Geleijnse, Johanna M; Hoogeveen, Ellen K; et al. (BMJ, 2023)
OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate. RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
Keywords: alpha-Linolenic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Humans; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors

Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease. - Zhang, Yiyi; Dron, Jacqueline S; Bellows, Brandon K; Khera, Amit V; Liu, Junxiu; Balte, Pallavi P; Oelsner, Elizabeth C; Amr, Sami Samir; Lebo, Matthew S; Nagy, Anna; Peloso, Gina M; Natarajan, Pradeep; et al. (Circulation, 2023)
Keywords: Coronary Disease; Genotype; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II

The associations of markers of endothelial dysfunction with hip fracture risk. - Barzilay, Joshua I; Bůzková, Petra; Fink, Howard A; Cauley, Jane A; Carbone, Laura; Elam, Rachel; Robbins, John A; Stein, Phyllis; Sheets, Kerry; Jalal, Diana; Mukamal, Kenneth J (Arch Osteoporos, 2023)
UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them. PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.
Keywords: Aged; Forearm; Hip Fractures; Humans; Osteoporotic Fractures; Vascular Diseases

CHARGE-AF: A Useful Score For Atrial Fibrillation Prediction? - Goudis, Christos; Daios, Stylianos; Dimitriadis, Fotios; Liu, Tong (Curr Cardiol Rev, 2023)
Atrial fibrillation (AF) is the commonest arrhythmia in clinical practice and is associated with increased morbidity and mortality. Various predictive scores for new-onset AF have been proposed, but so far, none have been widely used in clinical practice. CHARGE-AF score was developed from a pooled diverse population from three large cohorts (Atherosclerosis Risk in Communities study, Cardiovascular Health Study and Framingham Heart Study). A simple 5-year predictive model includes the variables of age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes mellitus, history of myocardial infarction and heart failure. Recent studies report that the CHARGE-AF score has good discrimination for incident AF and seems to be a promising prediction model for this arrhythmia. New screening tools (smartphone apps, smartwatches) are rapidly developing for AF detection. Therefore, the wide application of the CHARGE-AF score in clinical practice and the upcoming usage of mobile health technologies and smartwatches may result in better AF prediction and adequate stroke prevention, especially in high-risk patients.
Keywords: Atherosclerosis; Atrial Fibrillation; Heart Failure; Humans; Incidence; Myocardial Infarction; Risk Assessment; Risk Factors

CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk. - Huque, Md Hamidul; Kootar, Scherazad; Eramudugolla, Ranmalee; Han, S Duke; Carlson, Michelle C; Lopez, Oscar L; Bennett, David A; Peters, Ruth; Anstey, Kaarin J (JAMA Netw Open, 2023)
IMPORTANCE: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited. OBJECTIVE: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI). DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023. MAIN OUTCOMES AND MEASURES: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk. RESULTS: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar. CONCLUSIONS AND RELEVANCE: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Australia; Cohort Studies; Female; Heart Disease Risk Factors; Humans; Male; Risk Factors

Effect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart Failure in a Pooled Community Cohort. - Mohebi, Reza; Wang, Dongyu; Lau, Emily S; Parekh, Juhi K; Allen, Norrina; Psaty, Bruce M; Benjamin, Emelia J; Levy, Daniel; Wang, Thomas J; Shah, Sanjiv J; Gottdiener, John S; Januzzi, James L; et al. (J Am Coll Cardiol, 2023)
BACKGROUND: The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical practice guideline proposed an updated definition for heart failure (HF) stages. OBJECTIVES: This study aimed to compare prevalence and prognosis of HF stages according to classification/definition originally described in 2013 and 2022 ACC/AHA/HFSA definitions. METHODS: Study participants from 3 longitudinal cohorts (the MESA [Multi-Ethnic Study of Atherosclerosis], CHS [Cardiovascular Health Study], and the FHS [Framingham Heart Study]), were categorized into 4 HF stages according to the 2013 and 2022 criteria. Cox proportional hazards regression was used to assess predictors of progression to symptomatic HF and adverse clinical outcomes associated with each HF stage. RESULTS: Among 11,618 study participants, according to the 2022 staging, 1,943 (16.7%) were healthy, 4,348 (37.4%) were in stage A (at risk), 5,019 (43.2%) were in stage B (pre-HF), and 308 (2.7%) were in stage C/D (symptomatic HF). Compared to the classification/definition originally described in 2013, the 2022 ACC/AHA/HFSA approach resulted in a higher proportion of individuals with stage B HF (increase from 15.9% to 43.2%); this shift disproportionately involved women as well as Hispanic and Black individuals. Despite the 2022 criteria designating a greater proportion of individuals as stage B, the relative risk of progression to symptomatic HF remained similar (HR: 10.61; 95% CI: 9.00-12.51; P < 0.001). CONCLUSIONS: New standards for HF staging resulted in a substantial shift of community-based individuals from stage A to stage B. Those with stage B HF in the new system were at high risk for progression to symptomatic HF.
Keywords: American Heart Association; Atherosclerosis; Cardiology; Female; Heart Failure; Humans; Longitudinal Studies; Prognosis; United States

Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS. - Niezen, Sebastian; Connelly, Margery A; Hirsch, Calvin; Kizer, Jorge R; Benitez, Maria E; Minchenberg, Scott; Perez-Matos, Maria Camila; Jiang, Zhenghui Gordon; Mukamal, Kenneth J (J Am Heart Assoc, 2023)
Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0-1.9]; =0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0-1.3]; =0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95% CI, 1.1-2.7]; =0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.
Keywords: Aged; Aging; Cardiovascular Diseases; Heart Failure; Humans; Incidence; Ketone Bodies

Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. - Kurniansyah, Nuzulul; Goodman, Matthew O; Khan, Alyna T; Wang, Jiongming; Feofanova, Elena; Bis, Joshua C; Wiggins, Kerri L; Huffman, Jennifer E; Kelly, Tanika; Elfassy, Tali; Guo, Xiuqing; Palmas, Walter; et al. (Nat Commun, 2023)
We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.
Keywords: Blood Pressure; Ethnicity; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Multifactorial Inheritance; Population Health; Risk Factors

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. - Young, William J; Haessler, Jeffrey; Benjamins, Jan-Walter; Repetto, Linda; Yao, Jie; Isaacs, Aaron; Harper, Andrew R; Ramirez, Julia; Garnier, Sophie; Van Duijvenboden, Stefan; Baldassari, Antoine R; Concas, Maria Pina; et al. (Nat Commun, 2023)
The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
Keywords: Arrhythmias, Cardiac; Atrioventricular Block; Biomarkers; Cardiovascular Diseases; Electrocardiography; Genome-Wide Association Study; Humans; Risk Factors

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. - Weinstock, Joshua S; Laurie, Cecelia A; Broome, Jai G; Taylor, Kent D; Guo, Xiuqing; Shuldiner, Alan R; O'Connell, Jeffrey R; Lewis, Joshua P; Boerwinkle, Eric; Barnes, Kathleen C; Chami, Nathalie; Kenny, Eimear E; et al. (Sci Adv, 2023)
Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.
Keywords: Germ-Line Mutation; Hematopoiesis; Humans; Middle Aged; Mutation; Mutation, Missense; Phenotype

High-risk carotid plaques and incident ischemic stroke in patients with atrial fibrillation in the Cardiovascular Health Study. - Noubiap, Jean Jacques; Thomas, Gijo; Kamtchum-Tatuene, Joseph; Middeldorp, Melissa E; Sanders, Prashanthan (Eur J Neurol, 2023)
BACKGROUND AND PURPOSE: Whether carotid artery disease could improve stroke risk stratification tools in patients with atrial fibrillation (AF) remains uncertain. This study was undertaken to investigate the risk of ischemic stroke associated with occlusive and nonocclusive carotid atherosclerotic disease in patients with AF in the prospective population-based Cardiovascular Health Study. METHODS: We included participants aged ≥65 years with AF. We used multivariable Cox regression analysis to explore the risk of ischemic stroke associated with the percentage of carotid stenosis, plaque irregularity, echogenicity, and vulnerability (markedly irregular, ulcerated, or hypoechoic plaques). RESULTS: A total of 1398 participants were included (55.2% female, 61.7% aged 65-74 years). The maximum carotid stenosis was <50%, 50%-99%, and 100% in 94.5%, 5%, and 0.5% of participants, respectively. High-risk plaques based on echogenicity and plaque irregularity were found in 25.6% and 8.9% of participants, respectively. After a median follow-up of 10.9 years (interquartile range = 7.5-15.6), 298 ischemic strokes were recorded. There was no difference in the incidence of ischemic stroke according to the degree of carotid artery stenosis (p = 0.44), plaque echogenicity (low vs. high risk, p = 0.68), plaque irregularity (low vs. high risk, p = 0.55), and plaque vulnerability (p = 0.86). The CHA₂DS₂-VASc score was associated with an increased risk of ischemic stroke (adjusted hazard ratio = 1.28, 95% confidence interval = 1.18-1.40, p < 0.001). Both maximum grade of stenosis and plaque vulnerability were not associated with incident ischemic stroke (all p > 0.05). CONCLUSIONS: Neither the degree of carotid stenosis nor the presence of vulnerable plaques was associated with incident ischemic stroke in this cohort of individuals with AF. This suggests that carotid disease was probably not a significant contributor to ischemic stroke in this population.
Keywords: Atrial Fibrillation; Carotid Artery Diseases; Carotid Stenosis; Female; Humans; Ischemic Stroke; Male; Plaque, Atherosclerotic; Prospective Studies; Risk Factors; Stroke

Inflammation and Incident Conduction Disease. - Frimodt-Møller, Emilie K; Gottdiener, John S; Soliman, Elsayed Z; Kizer, Jorge R; Vittinghoff, Eric; Psaty, Bruce M; Biering-Sørensen, Tor; Marcus, Gregory M (J Am Heart Assoc, 2023)
Keywords: Cardiac Conduction System Disease; Electrocardiography; Heart Block; Humans; Inflammation

Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. - Jakubek, Yasminka A; Zhou, Ying; Stilp, Adrienne; Bacon, Jason; Wong, Justin W; Ozcan, Zuhal; Arnett, Donna; Barnes, Kathleen; Bis, Joshua C; Boerwinkle, Eric; Brody, Jennifer A; Carson, April P; et al. (Nat Genet, 2023)
Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
Keywords: Black People; Genome, Human; Genome-Wide Association Study; Hispanic or Latino; Humans; Mosaicism; Precision Medicine

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. - Chen, Fang; Wang, Xingyan; Jang, Seon-Kyeong; Quach, Bryan C; Weissenkampen, J Dylan; Khunsriraksakul, Chachrit; Yang, Lina; Sauteraud, Renan; Albert, Christine M; Allred, Nicholette D D; Arnett, Donna K; Ashley-Koch, Allison E; et al. (Nat Genet, 2023)
Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.
Keywords: Biology; Drug Repositioning; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Tobacco Use; Transcriptome

Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study. - Bockus, Lee B; Jensen, Paul N; Fretts, Amanda M; Hoofnagle, Andrew N; McKnight, Barbara; Sitlani, Colleen M; Siscovick, David S; King, Irena B; Psaty, Bruce M; Sotoodehnia, Nona; Lemaitre, Rozenn N (JAMA Netw Open, 2023)
IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known. OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023. EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons. MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk. RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]). CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.
Keywords: Aged; Ceramides; Cohort Studies; Death, Sudden, Cardiac; Eicosanoic Acids; Fatty Acids; Female; Humans; Male; Sphingolipids; Sphingomyelins

Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis. - Lemaitre, Rozenn N; Jensen, Paul N; Wang, Zeneng; Fretts, Amanda M; Sitlani, Colleen M; Nemet, Ina; Sotoodehnia, Nona; de Oliveira Otto, Marcia C; Zhu, Weifei; Budoff, Matt; Longstreth, W T; Psaty, Bruce M; et al. (J Am Heart Assoc, 2023)
Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60% (CHS) and 53% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.
Keywords: Aged; Atherosclerosis; Female; Humans; Ischemic Stroke; Methylamines; Oxides; Prospective Studies; Risk Factors; Stroke; United States

Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer. - Lastwika, Kristin J; Kunihiro, Andrew; Solan, Joell L; Zhang, Yuzheng; Taverne, Lydia R; Shelley, David; Rho, Jung-Hyun; Randolph, Timothy W; Li, Christopher I; Grogan, Eric L; Massion, Pierre P; Fitzpatrick, Annette L; et al. (Sci Transl Med, 2023)
Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.
Keywords: Autoantibodies; Humans; Lung Neoplasms; Protein Processing, Post-Translational; Small Cell Lung Carcinoma

A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study). - Jonmundsson, Thorarinn; Steindorsdottir, Anna E; Austin, Thomas R; Frick, Elisabet A; Axelsson, Gisli T; Launer, Lenore; Psaty, Bruce M; Loureiro, Joseph; Orth, Anthony P; Aspelund, Thor; Emilsson, Valur; Floyd, James S; et al. (Europace, 2023)
AIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study. METHODS AND RESULTS: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points. CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.
Keywords: Atrial Fibrillation; Biomarkers; Endosomal Sorting Complexes Required for Transport; Humans; Natriuretic Peptide, Brain; Oxidoreductases Acting on Sulfur Group Donors; Peptide Fragments; Prognosis; Prospective Studies; Proteomics; Risk Factors

Substitution of self-reported measures for objectively assessed grip strength and slow walk in the Physical Frailty Phenotype: ramifications for validity. - Bandeen-Roche, Karen; Tian, Jing; Buta, Brian; Walston, Jeremy; Xue, Qian-Li (BMC Geriatr, 2023)
BACKGROUND: Frailty assessment promises to identify older adults at risk for adverse consequences following stressors and target interventions to improve health outcomes. The Physical Frailty Phenotype (PFP) is a widely-studied, well validated assessment but incorporates performance-based slow walk and grip strength criteria that challenge its use in some clinical settings. Variants replacing performance-based elements with self-reported proxies have been proposed. Our study evaluated whether commonly available disability self-reports could be substituted for the performance-based criteria in the PFP while still identifying as "frail" the same subpopulations of individuals. METHODS: Parallel analyses were conducted in 3393 female and 2495 male Cardiovascular Health Study, Round 2 participants assessed in 1989-90. Candidate self-reported proxies for the phenotype's "slowness" and "weakness" criteria were evaluated for comparable prevalence and agreement by mode of measurement. For best-performing candidates: Frailty status (3 + positive criteria out of 5) was compared for prevalence and agreement between the PFP and mostly self-reported versions. Personal characteristics were compared between those adjudicated as frail by (a) only a self-reported version; (b) only the PFP; (c) both, using bivariable analyses and multinomial logistic regression. RESULTS: Self-reported difficulty walking ½ mile was selected as a proxy for the phenotype's slowness criterion. Two self-reported weakness proxies were examined: difficulty transferring from a bed or chair or gripping with hands, and difficulty as just defined or in lifting a 10-pound bag. Prevalences matched to within 4% between self-reported and performance-based criteria in the whole sample, but in all cases the self-reported prevalence for women exceeded that for men by 11% or more. Cross-modal agreement was moderate, with by-criterion and frailty-wide Kappa statistics of 0.55-0.60 in all cases. Frail subgroups (a), (b), (c) were independently discriminated (p < 0.05) by race, BMI, and depression in women; by age in men; and by self-reported health for both. CONCLUSIONS: Commonly used self-reported disability items cannot be assumed to stand in for performance-based criteria in the PFP. We found subpopulations identified as frail by resultant phenotypes versus the original phenotype to systematically differ. Work to develop self-reported proxies that more closely replicate their objective phenotypic counterparts than standard disability self-reports is needed.
Keywords: Advance Directives; Female; Frailty; Hand Strength; Humans; Male; Phenotype; Self Report

Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations. - Kootar, S; Huque, M H; Eramudugolla, R; Rizzuto, D; Carlson, M C; Odden, M C; Lopez, O L; Qiu, C; Fratiglioni, L; Han, S D; Bennett, D A; Peters, R; et al. (J Prev Alzheimers Dis, 2023)
BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research. OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model. RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project. CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.
Keywords: Aging; Alzheimer Disease; Cohort Studies; Dementia; Humans; Independent Living

Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations. - Feofanova, Elena V; Brown, Michael R; Alkis, Taryn; Manuel, Astrid M; Li, Xihao; Tahir, Usman A; Li, Zilin; Mendez, Kevin M; Kelly, Rachel S; Qi, Qibin; Chen, Han; Larson, Martin G; et al. (Nat Commun, 2023)
Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.
Keywords: Ethnicity; Genome-Wide Association Study; Humans; Metabolome; Polymorphism, Single Nucleotide; Quantitative Trait Loci

Association of serum levels of phenylalanine and tyrosine with hip fractures and frailty in older adults: The cardiovascular health study. - Carbone, Laura; Bůzková, Petra; Robbins, John A; Fink, Howard A; Barzilay, Joshua I; Elam, Rachel E; Isales, Carlos (Arch Osteoporos, 2024)
UNLABELLED: This study examined if the amino acids phenylalanine or tyrosine contribute to risk of hip fracture or frailty in older adults. We determined that neither phenylalanine nor tyrosine are important predictors of hip fracture or frailty. We suggest advice on protein intake for skeletal health consider specific amino acid composition. PURPOSE: Protein is essential for skeletal health, but the specific amino acid compositions of protein may have differential associations with fracture risk. The aim of this study was to determine the association of serum levels of the aromatic amino acids phenylalanine and tyrosine with risk for incident hip fractures over twelve years of follow-up and cross sectional associations with frailty. METHODS: We included 131 older men and women from the Cardiovascular Health Study (CHS) who sustained a hip fracture over twelve years of follow-up and 131 men and women without an incident hip fracture over this same period of time. 42% of this cohort were men and 95% were Caucasian. Weighted multivariable Cox hazards molecules were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher serum level of phenylalanine or tyrosine. Relative risk regression was used to determine the cross-sectional association of these amino acids with Freid's frailty index. RESULTS: Neither serum levels of phenylalanine (HR 0.85 (95% CI 0.62-1.16) or tyrosine (HR 0.82 (95% CI 0.62-1.1) were significantly associated with incident hip fractures or cross sectionally with frailty (frail compared with prefrail/not frail) (HR 0.92 (95% CI 0.48-1.76) and HR (0.86 (95% CI 0.46-1.61) respectively. CONCLUSION: Phenylalanine and tyrosine are not significant contributors to hip fractures or frailty in older men and women.
Keywords: Aged; Aged, 80 and over; Cross-Sectional Studies; Female; Frail Elderly; Frailty; Hip Fractures; Humans; Male; Phenylalanine; Risk Factors; Tyrosine

Associations between toxicity-weighted concentrations and dementia risk: Results from the Cardiovascular Health Cognition Study. - Crane, Breanna M; Moored, Kyle D; Donahue, Patrick T; Corrigan, Anne E; Curriero, Frank C; Shields, Timothy M; Desjardins, Michael R; Richards, Emily A; Rosso, Andrea L; Lovasi, Gina S; Odden, Michelle C; Lopez, Oscar L; et al. (Sci Total Environ, 2024)
BACKGROUND: Air pollution is a modifiable risk factor for dementia. Yet, studies on specific sources of air pollution (i.e., toxic chemical emissions from industrial facilities) and dementia risk are scarce. We examined associations between toxicity-weighted concentrations of industrial pollution and dementia outcomes among a large, multi-site cohort of older adults. METHODS: Participants (n = 2770) were ≥ 65 years old (Mean = 75.3, SD = 5.1 years) from the Cardiovascular Health Cognition Study (1992-1999). Toxicity-weighted concentrations were estimated using the Risk Screening Environmental Indicator (RSEI) model which incorporates total reported chemical emissions with toxicity, fate, and transport models. Estimates were aggregated to participants' baseline census tract, averaged across 1988-1992, and log2-transformed. Dementia status was clinically adjudicated in 1998-1999 and categorized by subtype (Alzheimer's, vascular, mixed). We assessed whether RSEI-estimated toxicity-weighted concentrations were associated with 1) odds of prevalent dementia and 2) incident dementia risk by subtype. RESULTS: After adjusting for individual and census-tract level covariates, a doubling in toxicity-weighted concentrations was associated with 9 % higher odds of prevalent dementia (OR = 1.09, 95 % CI: 1.00, 1.19). In discrete-time survival models, each doubling in toxicity-weighted concentrations was associated with a 16 % greater hazard of vascular dementia (HR = 1.16, 95 % CI: 1.01, 1.34) but was not significantly associated with all-cause, Alzheimer's disease, or mixed dementia (p's > 0.05). DISCUSSION: Living in regions with higher toxicity-weighted concentrations was associated with higher odds of prevalent dementia and a higher risk of incident vascular dementia in this large, community-based cohort of older adults. These findings support the need for additional studies to examine whether toxic chemical emissions from industrial and federal facilities may be a modifiable target for dementia prevention.
Keywords: Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Dementia; Environmental Exposure; Female; Humans; Male; Risk Factors

A comparative study of structural variant calling in WGS from Alzheimer's disease families. - Malamon, John S; Farrell, John J; Xia, Li Charlie; Dombroski, Beth A; Das, Rueben G; Way, Jessica; Kuzma, Amanda B; Valladares, Otto; Leung, Yuk Yee; Scanlon, Allison J; Lopez, Irving Antonio Barrera; Brehony, Jack; et al. (Life Sci Alliance, 2024)
Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines, Scalpel and Parliament, for SV/indel calling, we assessed sensitivity through sample replicates (N = 9) with in silico variant spike-ins. We developed a novel metric, D-score, to evaluate caller specificity for deletions. The accuracy of deletions was evaluated by Sanger sequencing. We generated a high-quality call set of 152,301 deletions of diverse sizes. Sanger sequencing validated 114 of 146 detected deletions (78.1%). Scalpel excelled in accuracy for deletions ≤100 bp, whereas Parliament was optimal for deletions >900 bp. Overall, 83.0% and 72.5% of calls by Scalpel and Parliament were validated, respectively, including all 11 deletions called by both Parliament and Scalpel between 101 and 900 bp. Our flexible protocol successfully generated a high-quality deletion call set and a truth set of Sanger sequencing-validated deletions with precise breakpoints spanning 1-17,000 bp.
Keywords: Alzheimer Disease; Humans; Whole Genome Sequencing

Cumulative Systolic Blood Pressure and Incident Stroke Type Variation by Race and Ethnicity. - Johnson, Kimson E; Li, Hanyu; Zhang, Min; Springer, Mellanie V; Galecki, Andrzej T; Whitney, Rachael T; Gottesman, Rebecca F; Hayward, Rodney A; Sidney, Stephen; Elkind, Mitchell S V; Longstreth, W T; Heckbert, Susan R; et al. (JAMA Netw Open, 2024)
IMPORTANCE: Stroke risk varies by systolic blood pressure (SBP), race, and ethnicity. The association between cumulative mean SBP and incident stroke type is unclear, and whether this association differs by race and ethnicity remains unknown. OBJECTIVE: To examine the association between cumulative mean SBP and first incident stroke among 3 major stroke types-ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH)-and explore how these associations vary by race and ethnicity. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data from 6 US longitudinal cohorts (January 1, 1971, to December 31, 2019) were pooled. The analysis was performed from January 1, 2022, to January 2, 2024. The median follow-up was 21.6 (IQR, 13.6-31.8) years. EXPOSURE: Time-dependent cumulative mean SBP. MAIN OUTCOMES AND MEASURES: The primary outcome was time from baseline visit to first incident stroke. Secondary outcomes consisted of time to first incident IS, ICH, and SAH. RESULTS: Among 40 016 participants, 38 167 who were 18 years or older at baseline with no history of stroke and at least 1 SBP measurement before the first incident stroke were included in the analysis. Of these, 54.0% were women; 25.0% were Black, 8.9% were Hispanic of any race, and 66.2% were White. The mean (SD) age at baseline was 53.4 (17.0) years and the mean (SD) SBP at baseline was 136.9 (20.4) mm Hg. A 10-mm Hg higher cumulative mean SBP was associated with a higher risk of overall stroke (hazard ratio [HR], 1.20 [95% CI, 1.18-1.23]), IS (HR, 1.20 [95% CI, 1.17-1.22]), and ICH (HR, 1.31 [95% CI, 1.25-1.38]) but not SAH (HR, 1.13 [95% CI, 0.99-1.29]; P = .06). Compared with White participants, Black participants had a higher risk of IS (HR, 1.20 [95% CI, 1.09-1.33]) and ICH (HR, 1.67 [95% CI, 1.30-2.13]) and Hispanic participants of any race had a higher risk of SAH (HR, 3.81 [95% CI, 1.29-11.22]). There was no consistent evidence that race and ethnicity modified the association of cumulative mean SBP with first incident stroke and stroke type. CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that cumulative mean SBP was associated with incident stroke type, but the associations did not differ by race and ethnicity. Culturally informed stroke prevention programs should address modifiable risk factors such as SBP along with social determinants of health and structural inequities in society.
Keywords: Adult; Aged; Black or African American; Blood Pressure; Cerebral Hemorrhage; Ethnicity; Female; Hispanic or Latino; Humans; Hypertension; Incidence; Ischemic Stroke; Longitudinal Studies; Male; Middle Aged; Racial Groups; Risk Factors; Stroke; Subarachnoid Hemorrhage; United States; White; White People

Development and Validation of the American Heart Association's PREVENT Equations. - Khan, Sadiya S; Matsushita, Kunihiro; Sang, Yingying; Ballew, Shoshana H; Grams, Morgan E; Surapaneni, Aditya; Blaha, Michael J; Carson, April P; Chang, Alexander R; Ciemins, Elizabeth; Go, Alan S; Gutierrez, Orlando M; et al. (Circulation, 2024)
BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; =0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.
Keywords: Adult; Aged; Albumins; American Heart Association; Atherosclerosis; Cardiovascular Diseases; Creatinine; Female; Glycated Hemoglobin; Heart Failure; Humans; Male; Middle Aged; Risk Assessment; Risk Factors

Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia. - Sargurupremraj, Muralidharan; Soumaré, Aïcha; Bis, Joshua C; Surakka, Ida; Jürgenson, Tuuli; Joly, Pierre; Knol, Maria J; Wang, Ruiqi; Yang, Qiong; Satizabal, Claudia L; Gudjonsson, Alexander; Mishra, Aniket; et al. (JAMA Netw Open, 2024)
IMPORTANCE: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. OBJECTIVE: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. DESIGN, SETTING, AND PARTICIPANTS: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. EXPOSURES: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. MAIN OUTCOMES AND MEASURES: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. RESULTS: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. CONCLUSIONS: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Blood Pressure; Cerebral Small Vessel Diseases; Dementia; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Mendelian Randomization Analysis; Prospective Studies; Risk Factors; Stroke

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life. - Ramonfaur, Diego; Buckley, Leo F; Arthur, Victoria; Yang, Yimin; Claggett, Brian L; Ndumele, Chiadi E; Walker, Keenan A; Austin, Thomas; Odden, Michelle C; Floyd, James S; Sanders-van Wijk, Sandra; Njoroge, Joyce; et al. (JAMA Cardiol, 2024)
IMPORTANCE: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions. OBJECTIVE: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023. EXPOSURES: Protein aptamers, measured at study V3 and V5. MAIN OUTCOMES AND MEASURES: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty. RESULTS: A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF. CONCLUSIONS AND RELEVANCE: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.
Keywords: Aged; Biomarkers; Female; Frailty; Heart Failure; Humans; Incidence; Male; Middle Aged; Proteomics; Risk Factors

Human whole-exome genotype data for Alzheimer's disease. - Leung, Yuk Yee; Naj, Adam C; Chou, Yi-Fan; Valladares, Otto; Schmidt, Michael; Hamilton-Nelson, Kara; Wheeler, Nicholas; Lin, Honghuang; Gangadharan, Prabhakaran; Qu, Liming; Clark, Kaylyn; Kuzma, Amanda B; et al. (Nat Commun, 2024)
The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.
Keywords: Alzheimer Disease; Computational Biology; Data Accuracy; Exome; Genotype; Humans

Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis. - Shelbaya, Khaled; Arthur, Victoria; Yang, Yimin; Dorbala, Pranav; Buckley, Leo; Claggett, Brian; Skali, Hicham; Dufresne, Line; Yang, Ta-Yu; Engert, James C; Thanassoulis, George; Floyd, James; et al. (J Am Coll Cardiol, 2024)
BACKGROUND: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms. OBJECTIVES: The aim of this study was to discover novel biomarkers with potentially causal associations with AS. METHODS: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue. RESULTS: Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis. CONCLUSIONS: These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression.
Keywords: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Biomarkers; Calcinosis; Humans; Matrix Metalloproteinase 12; Middle Aged; Proteomics; Risk Factors

Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study. - Harrington, Laura B; Ehlert, Alexa N; Thacker, Evan L; Jenny, Nancy S; Lopez, Oscar; Cushman, Mary; Olson, Nels C; Fitzpatrick, Annette; Mukamal, Kenneth J; Jensen, Majken K (Thromb Res, 2024)
INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. RESULTS: At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.
Keywords: Aged; Anticoagulants; Antithrombin III; Antithrombins; Dementia; Factor VIIa; Fibrinogen; Hemostatics; Humans; Prospective Studies; Thrombin

Machine learning models for predicting blood pressure phenotypes by combining multiple polygenic risk scores. - Hrytsenko, Yana; Shea, Benjamin; Elgart, Michael; Kurniansyah, Nuzulul; Lyons, Genevieve; Morrison, Alanna C; Carson, April P; Haring, Bernhard; Mitchell, Braxton D; Psaty, Bruce M; Jaeger, Byron C; Gu, C Charles; et al. (Sci Rep, 2024)
We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.
Keywords: Blood Pressure; Female; Genetic Predisposition to Disease; Genetic Risk Score; Genome-Wide Association Study; Humans; Hypertension; Machine Learning; Male; Middle Aged; Models, Genetic; Multifactorial Inheritance; Phenotype; Risk Factors

Methylation patterns associated with C-reactive protein in racially and ethnically diverse populations. - Lundin, Jessica I; Peters, Ulrike; Hu, Yao; Ammous, Farah; Avery, Christy L; Benjamin, Emelia J; Bis, Joshua C; Brody, Jennifer A; Carlson, Chris; Cushman, Mary; Gignoux, Chris; Guo, Xiuqing; et al. (Epigenetics, 2024)
Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total  = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (, , and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level ( < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of and CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with , , and . Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.
Keywords: C-Reactive Protein; CpG Islands; DNA; DNA Methylation; Epigenesis, Genetic; Genome-Wide Association Study; Humans; Inflammation; Intracellular Signaling Peptides and Proteins

A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma. - Verma, Shefali S; Gudiseva, Harini V; Chavali, Venkata R M; Salowe, Rebecca J; Bradford, Yuki; Guare, Lindsay; Lucas, Anastasia; Collins, David W; Vrathasha, Vrathasha; Nair, Rohini M; Rathi, Sonika; Zhao, Bingxin; et al. (Cell, 2024)
Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.
Keywords: Black People; Genetic Predisposition to Disease; Genome-Wide Association Study; Glaucoma, Open-Angle; Humans; Polymorphism, Single Nucleotide

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. - Mei, Hao; Simino, Jeannette; Li, Lianna; Jiang, Fan; Bis, Joshua C; Davies, Gail; Hill, W David; Xia, Charley; Gudnason, Vilmundur; Yang, Qiong; Lahti, Jari; Smith, Jennifer A; et al. (Alzheimers Res Ther, 2024)
BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
Keywords: Aged; Cognition; Genome-Wide Association Study; Humans; Memory; MicroRNAs; Multiomics; Polymorphism, Single Nucleotide

Rare variant contribution to the heritability of coronary artery disease. - Rocheleau, Ghislain; Clarke, Shoa L; Auguste, Gaëlle; Hasbani, Natalie R; Morrison, Alanna C; Heath, Adam S; Bielak, Lawrence F; Iyer, Kruthika R; Young, Erica P; Stitziel, Nathan O; Jun, Goo; Laurie, Cecelia; et al. (Nat Commun, 2024)
Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.
Keywords: Case-Control Studies; Coronary Artery Disease; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; White People; Whole Genome Sequencing

Sociodemographic, lifestyle, and medical factors associated with calculated free testosterone concentrations in men: individual participant data meta-analyses. - Narinx, Nick; Marriott, Ross J; Murray, Kevin; Adams, Robert J; Ballantyne, Christie M; Bauer, Douglas C; Bhasin, Shalender; Biggs, Mary L; Cawthon, Peggy M; Couper, David J; Dobs, Adrian S; Flicker, Leon; et al. (Eur J Endocrinol, 2024)
OBJECTIVE: Sociodemographic, lifestyle, and medical variables influence total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations. The relationship between these factors and "free" T remains unclear. We examined 21 sociodemographic, lifestyle, and medical predictors influencing calculated free T (cFT) in community-dwelling men across ages. DESIGN: This is a cross-sectional analysis in 20 631 participants in the Androgens in Men Study. METHODS: Individual participant data (IPD) were provided by 9 cohorts. Total T was determined using mass spectrometry, SHBG using immunoassays, and cFT using the Vermeulen formula. Associations were analyzed using 2-stage random effects IPD meta-analyses. RESULTS: Cohort median ages ranged from 40 to 76 years and median cFT concentrations from 174.3 to 422.8 pmol/L. In men aged 17-99 years, there was a linear inverse association of cFT with age (-57.2 pmol/L [95% confidence interval, -69.4, -44.9] per 1 SD increase in age). Calculated free T increased with increasing baseline body mass index (BMI) among men with BMI < 23.6 kg/m2, but decreased among men with BMI > 23.6 kg/m2 (-24.7 pmol/L [-29.1, -20.3] per 1 SD increase in the 25.4-29.6 kg/m2 BMI range). Calculated free T was lower in younger men, who were married or in a de facto relationship (-18.4 pmol/L [-27.6, -9.3]) and in men who formerly smoked (-5.7 pmol/L [-8.9, -2.6]), were in poor general health (-14.0 pmol/L [-20.1, -7.8]), and had diabetes (-19.6 pmol/L [-23.0, -16.3]), cardiovascular disease (-5.8 pmol/L [-8.3, -3.2]), or cancer (-19.2 pmol/L [-24.4, -14.1]). CONCLUSIONS: Calculated free T was most prominently associated with age and BMI. The linear, inverse association with age, nonlinear association with BMI, and presence of diabetes, cancer, and sociodemographic factors should be considered when interpreting cFT values.
Keywords: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Body Mass Index; Cohort Studies; Cross-Sectional Studies; Humans; Life Style; Male; Middle Aged; Sex Hormone-Binding Globulin; Sociodemographic Factors; Socioeconomic Factors; Testosterone; Young Adult

Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism. - Tan, Marcus C B; Isom, Chelsea A; Liu, Yangzi; Trégouët, David-Alexandre; Wu, Lang; Zhou, Dan; Gamazon, Eric R (EBioMedicine, 2024)
BACKGROUND: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE). METHODS: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls). FINDINGS: Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e). No evidence of a causal effect of PDAC on VTE was found. INTERPRETATION: These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC. FUNDING: National Institutes of Health (USA).
Keywords: Diabetes Mellitus, Type 2; Female; Gene Expression Profiling; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Mendelian Randomization Analysis; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Transcriptome; Venous Thromboembolism

Trimethylamine -Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations. - Tang, W H Wilson; Lemaitre, Rozenn N; Jensen, Paul N; Wang, Meng; Wang, Zeneng; Li, Xinmin S; Nemet, Ina; Lee, Yujin; Lai, Heidi T M; de Oliveira Otto, Marcia C; Fretts, Amanda M; Sotoodehnia, Nona; et al. (Circ Heart Fail, 2024)
BACKGROUND: Growing evidence indicates that trimethylamine -oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine -oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF). METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors. RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine -oxide (hazard ratio, 1.15 [95% CI, 1.09-1.20]; <0.001), choline (hazard ratio, 1.44 [95% CI, 1.26-1.64]; <0.001), and crotonobetaine (hazard ratio, 1.24 [95% CI, 1.16-1.32]; <0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race. CONCLUSIONS: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine -oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF. REGISTRATION: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.
Keywords: Aged; Aged, 80 and over; Betaine; Biomarkers; Carnitine; Choline; Female; Gastrointestinal Microbiome; Heart Failure; Humans; Incidence; Male; Methylamines; Middle Aged; Risk Factors; United States

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements. - Scholz, Markus; Horn, Katrin; Pott, Janne; Wuttke, Matthias; Kühnapfel, Andreas; Nasr, M Kamal; Kirsten, Holger; Li, Yong; Hoppmann, Anselm; Gorski, Mathias; Ghasemi, Sahar; Li, Man; et al. (Nat Commun, 2024)
X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
Keywords: Androgens; Chromosomes, Human, X; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Kidney; Male; Polymorphism, Single Nucleotide; Response Elements; Tetraspanins

Association Between Cigarette Smoking and Subclinical Markers of Cardiovascular Harm. - Yao, Zhiqi; Tasdighi, Erfan; Dardari, Zeina A; Jha, Kunal K; Osuji, Ngozi; Rajan, Tanuja; Boakye, Ellen; Rodriguez, Carlos J; Matsushita, Kunihiro; Simonsick, Eleanor M; Lima, João A C; Widome, Rachel; et al. (J Am Coll Cardiol, 2025)
BACKGROUND: Cigarette smoking is a strong risk factor for cardiovascular harm. OBJECTIVES: The study sought to explore the detailed relationships between smoking intensity, pack-years, and time since cessation with inflammation, thrombosis, and subclinical atherosclerosis markers of cardiovascular harm. METHODS: We included 182,364 participants (mean age 58.2 years, 69.0% female) from 22 cohorts of the Cross Cohort Collaboration with self-reported smoking status, including smoking intensity and/or pack-years, and concurrent subclinical marker measurements. Markers were categorized into 3 domains: inflammation (high-sensitivity C-reactive protein, interleukin-6, glycoprotein acetylation), thrombosis (fibrinogen, D-dimer), and subclinical atherosclerosis (coronary artery calcium, carotid intima-media thickness, carotid plaque, and ankle-brachial index). Utilizing multivariate regression models and restricted cubic splines, we assessed associations of smoking status, intensity, pack-years, time since cessation, and subclinical markers. RESULTS: A total of 15.3% of participants currently smoke (mean 16.7 cigarettes/day, mean 30.0 pack-years), and 34.6% of participants formerly smoked (median 19.0 years since quitting, mean 22.4 pack-years). Participants with a history of smoking showed higher levels of all subclinical markers compared with those who have never smoked, with stronger associations observed in those currently smoke. Among participants who currently smoke, smoking intensity showed a clear dose-response relationship with all markers, except for D-dimer, specifically with incremental 1% to 9% higher levels of subclinical markers per 10 cigarettes. After 20 cigarettes, the patterns appeared to plateau for blood markers, while they continued to increase for atherosclerosis markers. Among those who have ever smoked, robust dose-response relationships were observed for pack-years with all subclinical markers, with incremental 1% to 9% higher levels per 10 pack-years. The dose-response effects persisted after 20 pack-years for all markers, though with a milder slope. Among participants who smoked formerly, there were substantially lower levels of biomarkers with longer time since quitting, and most markers were not different compared with those who have never smoked by 30 years, except for the coronary artery calcium score, which remained 19% higher even beyond quitting after 30 years. CONCLUSIONS: Smoking-relevant parameters show strong and dose-response relationships across 3 domains of subclinical markers of cardiovascular harm. The sensitivity of the tested subclinical markers to small increments in cigarette exposure suggests potential value in the regulation of new and existing tobacco products.
Keywords: Aged; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cigarette Smoking; Cohort Studies; Female; Humans; Male; Middle Aged; Risk Factors

Cardiac Troponins and Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis. - Shah, Anoop S V; Keene, Spencer J; Pennells, Lisa; Kaptoge, Stephen; Kimenai, Dorien M; Walker, Matthew; Halley, Julianne D; Rocha, Sara; Hoogeveen, Ron C; Gudnason, Vilmundur; Bakker, Stephan J L; Wannamethee, Sasiwarang G; et al. (J Am Coll Cardiol, 2025)
BACKGROUND: The extent to which high-sensitivity cardiac troponin can predict cardiovascular disease (CVD) is uncertain. OBJECTIVES: We aimed to quantify the potential advantage of adding information on cardiac troponins to conventional risk factors in the prevention of CVD. METHODS: We meta-analyzed individual-participant data from 15 cohorts, comprising 62,150 participants without prior CVD. We calculated HRs, measures of risk discrimination, and reclassification after adding cardiac troponin T (cTnT) or I (cTnI) to conventional risk factors. The primary outcome was first-onset CVD (ie, coronary heart disease or stroke). We then modeled the implications of initiating statin therapy using incidence rates from 2.1 million individuals from the United Kingdom. RESULTS: Among participants with cTnT or cTnI measurements, 8,133 and 3,749 incident CVD events occurred during a median follow-up of 11.8 and 9.8 years, respectively. HRs for CVD per 1-SD higher concentration were 1.31 (95% CI: 1.25-1.37) for cTnT and 1.26 (95% CI: 1.19-1.33) for cTnI. Addition of cTnT or cTnI to conventional risk factors was associated with C-index increases of 0.015 (95% CI: 0.012-0.018) and 0.012 (95% CI: 0.009-0.015) and continuous net reclassification improvements of 6% and 5% in cases and 22% and 17% in noncases. One additional CVD event would be prevented for every 408 and 473 individuals screened based on statin therapy in those whose CVD risk is reclassified from intermediate to high risk after cTnT or cTnI measurement, respectively. CONCLUSIONS: Measurement of cardiac troponin results in a modest improvement in the prediction of first-onset CVD that may translate into population health benefits if used at scale.
Keywords: Biomarkers; Cardiovascular Diseases; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Risk Assessment; Risk Factors; Troponin I; Troponin T

Cardiovascular Risk Factors and Genetic Risk in Transthyretin V142I Carriers. - Shetty, Naman S; Gaonkar, Mokshad; Pampana, Akhil; Patel, Nirav; Morrison, Alanna C; Reiner, Alexander P; Carson, April P; Yu, Bing; Psaty, Bruce M; Kooperberg, Charles; Fatkin, Diane; Boerwinkle, Eric; et al. (JACC Heart Fail, 2025)
BACKGROUND: Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown. OBJECTIVES: This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers. METHODS: This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference. RESULTS: The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14). CONCLUSIONS: A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.
Keywords: Aged; Black or African American; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus; Female; Genotype; Heart Disease Risk Factors; Heart Failure; Heterozygote; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Obesity; Prealbumin; Risk Factors; United States

Circulating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis. - Moseholm, Kristine F; Jensen, Majken K; Bůzková, Petra; Aroner, Sarah A; Fitzpatrick, Annette L; Longstreth, W T; Lopez, Oscar; Siscovick, David S; Kizer, Jorge R; Ix, Joachim H; Hughes, Timothy M; Hayden, Kathleen M; et al. (Neurobiol Aging, 2025)
Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 % CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.'
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Cognition; Cognitive Dysfunction; Cohort Studies; Dementia; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Humans; Male; Middle Aged; Risk; Risk Factors

Clinical and Imaging Markers of Cardiac Function and Brain Health: A Meta-Analysis of Community-Based Studies. - Yaqub, Amber; Bis, Joshua C; Frenzel, Stefan; Koini, Marisa; Mbangdadji, Djass; Peloso, Gina M; Talluri, Rajesh; Alonso, Alvaro; Bahls, Martin; Bülow, Robin; Dörr, Marcus; Felix, Stephan; et al. (Neurology, 2025)
BACKGROUND AND OBJECTIVES: Cardiac dysfunction and heart failure are linked to cognitive impairment, but the underlying brain pathology remains undetermined. We investigated associations between cardiac function (measured by echocardiography or cardiac MRI), clinical heart failure, and structural markers on brain MRI, including volumes of gray and white matter (WM), the hippocampus, and white matter hyperintensities (WMHs). METHODS: We leverage data from 7 prospective, community-based cohorts across Europe and the United States, all part of the Cross-Cohort Collaboration. The included cohorts were the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in Communities study, Austrian Stroke Prevention Study, Cardiovascular Health Study, Framingham Heart Study, Rotterdam Study, and Study of Health in Pomerania (SHIP-START and SHIP-TREND). Each cohort performed cross-sectional multivariable linear regression analyses, after which estimates were pooled through random-effects meta-analysis. Heterogeneity was assessed by the index (%). RESULTS: Among 10,889 participants (mean age: 66.8 years, range 52.0-76.0; 56.7% women), markers of systolic dysfunction were consistently associated with smaller total brain volume (TBV) (e.g., adjusted standardized mean difference for moderate to severe dysfunction -0.19, 95% CI -0.31 to -0.07, = 20%). Impaired relaxation and restrictive diastolic dysfunction were also associated with smaller TBV (e.g., for impaired relaxation -0.08, 95% CI -0.15 to -0.01, = 32%) and hippocampal volume (-0.18, 95% CI -0.33 to -0.03, = 0%), with similar results for the E/A-ratio. Systolic and diastolic dysfunction was not consistently associated with volume of WMHs. Among 5 cohorts with available data, 302 (3.4%) participants had clinical heart failure, which was associated with smaller brain volumes, particularly in the hippocampus (-0.13, 95% CI -0.23 to -0.02, = 1%). DISCUSSION: In this large study among community-dwelling adults, subclinical cardiac dysfunction was associated with brain imaging markers of neurodegeneration. These findings encourage longitudinal investigations on the effect of maintaining cardiac function on brain health.
Keywords: Aged; Brain; Cohort Studies; Echocardiography; Female; Heart Failure; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Prospective Studies; White Matter

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood. - Jakubek, Yasminka A; Ma, Xiaolong; Stilp, Adrienne M; Yu, Fulong; Bacon, Jason; Wong, Justin W; Aguet, Francois; Ardlie, Kristin; Arnett, Donna K; Barnes, Kathleen; Bis, Joshua C; Blackwell, Tom; et al. (Am J Hum Genet, 2025)
Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.
Keywords: Alleles; Chromosome Deletion; Chromosomes, Human, Y; Genomics; Haplotypes; Humans; Male; Mosaicism; Phenotype; Whole Genome Sequencing

The impact of common and rare genetic variants on bradyarrhythmia development. - Weng, Lu-Chen; Rämö, Joel T; Jurgens, Sean J; Khurshid, Shaan; Chaffin, Mark; Hall, Amelia Weber; Morrill, Valerie N; Wang, Xin; Nauffal, Victor; Sun, Yan V; Beer, Dominik; Lee, Simon; et al. (Nat Genet, 2025)
To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.
Keywords: Bradycardia; Cardiac Conduction System Disease; Female; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Male; Pacemaker, Artificial; Phenotype; Polymorphism, Single Nucleotide; Sick Sinus Syndrome

Low Lung Function Is Associated with High Population Attributable Fraction for Cardiovascular Mortality. - Bhatt, Surya P; Wu, Chaoqi; Sun, Yifei; Balte, Pallavi P; Schwartz, Joseph E; Divo, Miguel J; Jaeger, Byron C; Chaves, Paulo H; Couper, David; Jacobs, David R; Lloyd-Jones, Donald; Kalhan, Ravi; et al. (Ann Am Thorac Soc, 2025)
Chronic lung diseases are associated with increased risk of mortality due to coronary heart disease (CHD). Nonetheless, the population attributable fraction (PAF) of lung function impairment relative to other established cardiovascular risk factors is unclear. To evaluate the PAF of low lung function for CHD mortality We harmonized and pooled lung function and clinical data across eight U.S. general population cohorts. Impaired lung function was defined as forced expiratory volume in 1 second (FEV) and/or forced vital capacity ≤ 95% predicted on baseline spirometry. The association between CHD mortality and risk factors was assessed using cause-specific proportional hazards and Fine-Gray proportional subdistribution hazard models, treating non-CHD mortality as a competing risk. Models were adjusted for lung function as well as age, sex, race/ethnicity, educational attainment, body mass index, smoking status, pack-years of smoking, diabetes mellitus, high-density lipoprotein, and high low-density lipoprotein (≥130 mg/dl). PAF was calculated as the relative change in the average absolute risk of 10-year CHD mortality by elimination of lung function lower than 95% predicted. Among 35,143 participants, 1,844 of 13,174 (14.0%) deaths were due to CHD. Compared with percentage predicted FEV (FEVpp) > 95%, the subdistribution adjusted hazard ratio for low FEVpp was 1.30 (95% confidence interval, 1.18-1.44). The PAF for FEVpp ≤ 95% was 12%, ranking low FEV third on the list of PAF for CHD mortality, after hypertension and diabetes. Low FEVpp ranked second in the subgroup of active smokers (PAF 14%), after hypertension. Low lung function, even in the range considered clinically normal, ranks high on the list of attributable risk factors for CHD mortality and should be considered in cardiovascular risk stratification.
Keywords: Adult; Aged; Coronary Disease; Female; Forced Expiratory Volume; Humans; Lung; Lung Diseases; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Smoking; Spirometry; United States; Vital Capacity

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases. - Roselli, Carolina; Surakka, Ida; Olesen, Morten S; Sveinbjornsson, Gardar; Marston, Nicholas A; Choi, Seung Hoan; Holm, Hilma; Chaffin, Mark; Gudbjartsson, Daniel; Hill, Matthew C; Aegisdottir, Hildur; Albert, Christine M; et al. (Nat Genet, 2025)
Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.
Keywords: Atrial Fibrillation; Chromatin; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Multifactorial Inheritance; Myocytes, Cardiac; Polymorphism, Single Nucleotide; Risk Factors

Methylome-wide association analyses of lipids and modifying effects of behavioral factors in diverse race and ethnicity participants. - Hu, Yao; Haessler, Jeff; Lundin, Jessica I; Darst, Burcu F; Whitsel, Eric A; Grove, Megan; Guan, Weihua; Xia, Rui; Szeto, Mindy; Raffield, Laura M; Ratliff, Scott; Wang, Yuxuan; et al. (Clin Epigenetics, 2025)
Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.
Keywords: Adult; Aged; Alcohol Drinking; CpG Islands; DNA Methylation; Ethnicity; Female; Genome-Wide Association Study; Humans; Lipids; Male; Middle Aged; Racial Groups; Smoking; White People

Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults. - Bortnick, Anna E; Austin, Thomas R; Hamerton, Emily; Gudmundsdottir, Valborg; Emilsson, Valur; Jennings, Lori L; Gudnason, Vilmundur; Owens, David S; Massera, Daniele; Dufresne, Line; Yang, Ta-Yu; Engert, James C; et al. (J Am Heart Assoc, 2025)
BACKGROUND: Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions. METHODS AND RESULTS: We undertook large-scale plasma proteomics in a cohort study of adults ≥65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer-based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES-RS (Age, Gene/Environment Susceptibility-Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2-sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomography-quantified AVC or AS as outcomes. Six proteins showed Bonferroni-corrected significant relationships with AVC in CHS. Three of these, CXCL-12 (C-X-C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES-RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near-significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=-0.25, =0.009). CONCLUSIONS: This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.
Keywords: Age Factors; Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Biomarkers; Blood Proteins; Calcinosis; Chemokine CXCL12; Echocardiography; Female; Humans; Male; Mendelian Randomization Analysis; Proteomics; Severity of Illness Index

Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk. - Georgakis, Marios K; Malik, Rainer; Bounkari, Omar El; Hasbani, Natalie R; Li, Jiang; Huffman, Jennifer E; Shakt, Gabrielle; Tack, Reinier W P; Kimball, Tamara N; Asare, Yaw; Morrison, Alanna C; Tsao, Noah L; et al. (Genome Med, 2025)
BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease. METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595). RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p = 6.1 × 10) and coronary artery disease (OR: 0.74, 95%CI: 0.63-0.87, p = 2.9 × 10) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers. CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.
Keywords: Aged; Cardiovascular Diseases; Chemokine CCL2; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Monocytes; Receptors, CCR2

Robust Automated Harmonization of Heterogeneous Data Through Ensemble Machine Learning: Algorithm Development and Validation Study. - Yang, Doris; Zhou, Doudou; Cai, Steven; Gan, Ziming; Pencina, Michael; Avillach, Paul; Cai, Tianxi; Hong, Chuan (JMIR Med Inform, 2025)
BACKGROUND: Cohort studies contain rich clinical data across large and diverse patient populations and are a common source of observational data for clinical research. Because large scale cohort studies are both time and resource intensive, one alternative is to harmonize data from existing cohorts through multicohort studies. However, given differences in variable encoding, accurate variable harmonization is difficult. OBJECTIVE: We propose SONAR (Semantic and Distribution-Based Harmonization) as a method for harmonizing variables across cohort studies to facilitate multicohort studies. METHODS: SONAR used semantic learning from variable descriptions and distribution learning from study participant data. Our method learned an embedding vector for each variable and used pairwise cosine similarity to score the similarity between variables. This approach was built off 3 National Institutes of Health cohorts, including the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and the Women's Health Initiative. We also used gold standard labels to further refine the embeddings in a supervised manner. RESULTS: The method was evaluated using manually curated gold standard labels from the 3 National Institutes of Health cohorts. We evaluated both the intracohort and intercohort variable harmonization performance. The supervised SONAR method outperformed existing benchmark methods for almost all intracohort and intercohort comparisons using area under the curve and top-k accuracy metrics. Notably, SONAR was able to significantly improve harmonization of concepts that were difficult for existing semantic methods to harmonize. CONCLUSIONS: SONAR achieves accurate variable harmonization within and between cohort studies by harnessing the complementary strengths of semantic learning and variable distribution learning.
Keywords: Algorithms; Cohort Studies; Female; Humans; Machine Learning; Semantics

Selected social and lifestyle correlates of brain health markers: the Cross-Cohort Collaboration Consortium. - Grasset, Leslie; Bis, Joshua C; Frenzel, Stefan; Kojis, Daniel; Simino, Jeannette; Yaqub, Amber; Beiser, Alexa; Berr, Claudine; Bressler, Jan; Bülow, Robin; DeCarli, Charles S; Fohner, Alison E; et al. (Alzheimers Dement, 2025)
INTRODUCTION: To investigate the associations of education level, marital status, and physical activity with dementia risk and brain MRI markers. METHODS: Data from six community-based samples from the Cross-Cohort Collaboration Consortium were analyzed. Self-reported education level, marital status, and physical activity at age 60 to 75 years were harmonized. Subsamples of participants with brain MRI markers at time of exposure were selected. Associations with dementia risk and cross-sectional MRI markers were meta-analyzed. RESULTS: Higher education level was associated with lower dementia risk (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.59; 0.72 vs low level) but not significantly with brain MRI markers. Compared with being unmarried, being married was only associated with higher total brain and hippocampal volumes. Being physically active was associated with lower dementia risk (HR = 0.73, 95% CI = 0.52; 1.04), as well as larger total brain volume and smaller white matter hyperintensity volume. DISCUSSION: This study provides further evidence regarding the contribution of education level and physical activity to dementia resilience. HIGHLIGHTS: Education level, marital status, and physical activity are thought to contribute to resilience against ADRD. We used random-effects meta-analysis to summarize results from six community-based samples from the CCC. In this cross-cohort meta-analysis, higher education level and being physically active were associated with lower risk of dementia. In cross-sectional analyses, being married was associated with larger TBV and HV, while being physically active was associated with larger TBV and lower WMHV.
Keywords: Aged; Brain; Cohort Studies; Cross-Sectional Studies; Dementia; Educational Status; Exercise; Female; Humans; Life Style; Magnetic Resonance Imaging; Male; Marital Status; Middle Aged; Risk Factors

Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. - Choi, Seung Hoan; Jurgens, Sean J; Xiao, Ling; Hill, Matthew C; Haggerty, Christopher M; Sveinbjörnsson, Garðar; Morrill, Valerie N; Marston, Nicholas A; Weng, Lu-Chen; Pirruccello, James P; Arnar, David O; Gudbjartsson, Daniel Fannar; et al. (Nat Genet, 2025)
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.
Keywords: Atrial Fibrillation; Case-Control Studies; Exome Sequencing; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Myocytes, Cardiac; Risk Factors

A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies. - Li, Xihao; Chen, Han; Selvaraj, Margaret Sunitha; Van Buren, Eric; Zhou, Hufeng; Wang, Yuxuan; Sun, Ryan; McCaw, Zachary R; Yu, Zhi; Jiang, Min-Zhi; DiCorpo, Daniel; Gaynor, Sheila M; et al. (Nat Comput Sci, 2025)
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.
Keywords: Genetic Variation; Genome, Human; Genome-Wide Association Study; Humans; Lipids; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Whole Genome Sequencing

Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele. - Zhang, Xinruo; Brody, Jennifer A; Graff, Mariaelisa; Highland, Heather M; Chami, Nathalie; Xu, Hanfei; Wang, Zhe; Ferrier, Kendra R; Chittoor, Geetha; Josyula, Navya Shilpa; Meyer, Mariah; Gupta, Shreyash; et al. (Nat Commun, 2025)
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.
Keywords: Adult; African People; Alleles; Body Mass Index; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Population Groups; Whole Genome Sequencing