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

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

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

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

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

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