@article {734, title = {The prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study.}, journal = {Ophthalmology}, volume = {110}, year = {2003}, month = {2003 Apr}, pages = {658-66}, abstract = {

PURPOSE: To describe the prevalence of retinal microvascular characteristics and their associations with atherosclerosis in elderly, nondiabetic persons.

DESIGN AND PARTICIPANTS: Population-based, cross-sectional study comprising 2050 men and women aged 69 to 97 years without diabetes, living in four communities.

METHODS: Participants underwent retinal photography and standardized grading of retinal microvascular characteristics, including retinopathy (e.g., microaneurysms, retinal hemorrhages), focal arteriolar narrowing, and arteriovenous nicking. In addition, calibers of retinal arterioles and venules were measured on digitized photographs to obtain an estimate of generalized arteriolar narrowing. Atherosclerosis and its risk factors were obtained from clinical examination and laboratory investigations.

MAIN OUTCOME MEASURES: Prevalence of retinal microvascular abnormalities and their associations with measures of atherosclerosis.

RESULTS: The prevalence of retinal microvascular abnormalities was 8.3\% for retinopathy, 9.6\% for focal arteriolar narrowing, and 7.7\% for arteriovenous nicking. All retinal lesions were associated with hypertension (odds ratios [OR] were 1.8 for retinopathy, 2.1 for focal arteriolar narrowing, 1.5 for arteriovenous nicking, and 1.7 for generalized arteriolar narrowing). After controlling for age, gender, race, mean arterial blood pressure, and antihypertensive medication use, retinopathy was associated with prevalent coronary heart disease (OR, 1.7), prevalent myocardial infarction (OR, 1.7), prevalent stroke (OR, 2.0), presence of carotid artery plaque (OR, 1.9), and increased intima-media thickness of the common carotid (OR, 2.3; fourth vs. first quartile) and internal carotid (OR, 1.8; fourth vs. first quartile) arteries. In contrast, focal arteriolar narrowing, arteriovenous nicking, and generalized arteriolar narrowing were not associated with any measures of atherosclerosis.

CONCLUSIONS: Retinal microvascular abnormalities are common in older persons without diabetes and are related to hypertension. Retinopathy is associated with prevalent coronary heart disease, stroke, and carotid artery thickening, but focal and generalized arteriolar narrowing and arteriovenous nicking are not related to most measures of atherosclerosis. These data suggest that retinal microvascular abnormalities reflect processes associated with hypertension but distinct from atherosclerosis.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Coronary Artery Disease, Cross-Sectional Studies, Female, Humans, Hypertension, Male, Prevalence, Retinal Diseases, Retinal Vessels, Risk Factors, United States}, issn = {0161-6420}, doi = {10.1016/S0161-6420(02)01931-0}, author = {Wong, Tien Yin and Klein, Ronald and Sharrett, A Richey and Manolio, Teri A and Hubbard, Larry D and Marino, Emily K and Kuller, Lewis and Burke, Gregory and Tracy, Russell P and Polak, Joseph F and Gottdiener, John S and Siscovick, David S} } @article {1028, title = {Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.}, journal = {Am J Hum Genet}, volume = {82}, year = {2008}, month = {2008 May}, pages = {1193-201}, abstract = {

Data from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study and the Cardiovascular Health Study (CHS) provide independent and confirmatory evidence for association between common polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha and plasma C-reactive protein (CRP) concentration. Analyses with the use of imputation-based methods to combine genotype data from both studies and to test untyped SNPs from the HapMap database identified several SNPs within a 5 kb region of HNF1A intron 1 with the strongest evidence of association with CRP phenotype.

}, keywords = {Aged, Bayes Theorem, C-Reactive Protein, Female, Hepatocyte Nuclear Factor 1-alpha, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Pravastatin, Simvastatin}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2008.03.017}, author = {Reiner, Alexander P and Barber, Mathew J and Guan, Yongtao and Ridker, Paul M and Lange, Leslie A and Chasman, Daniel I and Walston, Jeremy D and Cooper, Gregory M and Jenny, Nancy S and Rieder, Mark J and Durda, J Peter and Smith, Joshua D and Novembre, John and Tracy, Russell P and Rotter, Jerome I and Stephens, Matthew and Nickerson, Deborah A and Krauss, Ronald M} } @article {1386, title = {Plasma fatty acid-binding protein 4, nonesterified fatty acids, and incident diabetes in older adults.}, journal = {Diabetes Care}, volume = {35}, year = {2012}, month = {2012 Aug}, pages = {1701-7}, abstract = {

OBJECTIVE: To examine the relation of fatty acid-binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.

RESEARCH DESIGN AND METHODS: We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992-2007) based on the use of hypoglycemic medications, fasting glucose >= 126 mg/dL, or nonfasting glucose >= 200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.

RESULTS: Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95\% CI 1.10-1.65) for women and 1.45 (1.13-1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m(2) (HR per SD: 1.78 [95\% CI 1.13-2.81]). There was a modest and nonsignificant association of NEFA with diabetes (P(trend) = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95\% CI 1.12-2.53), and 1.63 (1.07-2.50) across consecutive tertiles of NEFA (P(trend) = 0.03).

CONCLUSIONS: Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, Body Mass Index, Diabetes Mellitus, Fatty Acid-Binding Proteins, Fatty Acids, Nonesterified, Female, Humans, Male, Prospective Studies}, issn = {1935-5548}, doi = {10.2337/dc11-1690}, author = {Djouss{\'e}, Luc and Khawaja, Owais and Bartz, Traci M and Biggs, Mary L and Ix, Joachim H and Zieman, Susan J and Kizer, Jorge R and Tracy, Russell P and Siscovick, David S and Mukamal, Kenneth J} } @article {1379, title = {Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {110}, year = {2012}, month = {2012 Jul 15}, pages = {212-6}, abstract = {

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women >=65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 {\textpm} 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95\% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults.

}, keywords = {Aged, Atrial Fibrillation, C-Reactive Protein, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Hypertension, Incidence, Lipoproteins, HDL, Lipoproteins, LDL, Male, Natriuretic Peptide, Brain, Obesity, Peptide Fragments, Prospective Studies, Sex Factors, Triglycerides, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2012.03.010}, author = {Khawaja, Owais and Bartz, Traci M and Ix, Joachim H and Heckbert, Susan R and Kizer, Jorge R and Zieman, Susan J and Mukamal, Kenneth J and Tracy, Russell P and Siscovick, David S and Djouss{\'e}, Luc} } @article {6211, title = {Plasma Fatty Acid binding protein 4 and risk of sudden cardiac death in older adults.}, journal = {Cardiol Res Pract}, volume = {2013}, year = {2013}, month = {2013}, pages = {181054}, abstract = {

Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95\% CI: 0.95-1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95\% CI: 1.07-1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95\% CI: 0.62-1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.

}, issn = {2090-8016}, doi = {10.1155/2013/181054}, author = {Djouss{\'e}, Luc and Maziarz, Marlena and Biggs, Mary L and Ix, Joachim H and Zieman, Susan J and Kizer, Jorge R and Lemaitre, Rozenn N and Mozaffarian, Dariush and Tracy, Russell P and Mukamal, Kenneth J and Siscovick, David S and Sotoodehnia, Nona} } @article {6064, title = {Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {6}, year = {2013}, month = {2013 Sep 01}, pages = {964-9}, abstract = {

BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF).

METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12\% (95\% confidence interval, 6\%-19\%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95\% confidence interval, 1.09-1.23]).

CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Comorbidity, Fatty Acids, Nonesterified, Female, Heart Failure, Humans, Incidence, Kaplan-Meier Estimate, Linear Models, Male, Multivariate Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Time Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.113.000521}, author = {Djouss{\'e}, Luc and Benkeser, David and Arnold, Alice and Kizer, Jorge R and Zieman, Susan J and Lemaitre, Rozenn N and Tracy, Russell P and Gottdiener, John S and Mozaffarian, Dariush and Siscovick, David S and Mukamal, Kenneth J and Ix, Joachim H} } @article {6212, title = {Plasma free fatty acids and risk of stroke in the Cardiovascular Health Study.}, journal = {Int J Stroke}, volume = {9}, year = {2014}, month = {2014 Oct}, pages = {917-20}, abstract = {

BACKGROUND: Although free fatty acids have been positively associated with risk factors for stroke, the role of plasma free fatty acids in the development of stroke has not been elucidated in older adults.

AIMS: We sought to examine the association between plasma free fatty acids and incident stroke.

METHODS: Prospective cohort of 4369 men and women>=65 years of age in the Cardiovascular Health Study. Plasma levels of free fatty acids were measured at the 1992-1993 examination and stroke events were adjudicated by a committee of experts including neurologists and neuroradiologists. Cox regression was used to estimate the relative risk of stroke associated with free fatty acids concentrations.

RESULTS: The average age among participants was 75{\textpm}5{\textperiodcentered}2 years. During a median follow-up of 11{\textperiodcentered}4 years, 732 incident strokes occurred. The crude incidence rates of stroke were 14{\textperiodcentered}5, 14{\textperiodcentered}9, and 17{\textperiodcentered}6 per 1000 person-years across increasing tertiles of plasma free fatty acids. The adjusted hazard ratio (95\% confidence interval) for incident stroke was 1{\textperiodcentered}05 (0{\textperiodcentered}97-1{\textperiodcentered}14) per standard deviation increase in plasma free fatty acids. Restriction to ischemic stroke did not alter the results [hazard ratio (95\% confidence interval): 1{\textperiodcentered}04 (0{\textperiodcentered}96-1{\textperiodcentered}14) per standard deviation higher free fatty acids], and there was no effect modification by adiposity (P interaction=0{\textperiodcentered}18) or by diabetes (P interaction=0{\textperiodcentered}15).

CONCLUSION: Our data did not show an association of plasma free fatty acids with incident stroke among community dwelling older adults.

}, keywords = {Aged, Biomarkers, Brain Ischemia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Prospective Studies, Risk, Stroke}, issn = {1747-4949}, doi = {10.1111/ijs.12216}, author = {Khawaja, Owais and Maziarz, Marlena and Biggs, Mary L and Longstreth, William T and Ix, Joachim H and Kizer, Jorge R and Zieman, Susan and Tracy, Russell P and Mozaffarian, Dariush and Mukamal, Kenneth J and Siscovick, David S and Djouss{\'e}, Luc} } @article {6584, title = {Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {114}, year = {2014}, month = {2014 Sep 15}, pages = {843-8}, abstract = {

Plasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95\% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95\% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95\% CI 1.08 to 1.26 for men; HR 1.02, 95\% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality.

}, keywords = {Age Distribution, Age Factors, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cause of Death, Fatty Acid-Binding Proteins, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Health Status, Humans, Male, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Survival Rate, Time Factors, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2014.06.012}, author = {Miedema, Michael D and Maziarz, Marlena and Biggs, Mary L and Zieman, Susan J and Kizer, Jorge R and Ix, Joachim H and Mozaffarian, Dariush and Tracy, Russell P and Psaty, Bruce M and Siscovick, David S and Mukamal, Kenneth J and Djouss{\'e}, Luc} } @article {6809, title = {Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {35}, year = {2015}, month = {2015 Oct}, pages = {2246-53}, abstract = {

OBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5{\texttimes}10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31{\texttimes}10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.

}, keywords = {Adult, African Americans, Age Distribution, Aged, Cardiovascular Diseases, Cohort Studies, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Interleukin-2 Receptor alpha Subunit, Kaplan-Meier Estimate, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Risk Assessment, Sex Distribution, Survival Analysis}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.115.305289}, author = {Durda, Peter and Sabourin, Jeremy and Lange, Ethan M and Nalls, Mike A and Mychaleckyj, Josyf C and Jenny, Nancy Swords and Li, Jin and Walston, Jeremy and Harris, Tamara B and Psaty, Bruce M and Valdar, William and Liu, Yongmei and Cushman, Mary and Reiner, Alex P and Tracy, Russell P and Lange, Leslie A} } @article {7139, title = {Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {40-55}, abstract = {

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets{\textquoteright} important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.005}, author = {Eicher, John D and Chami, Nathalie and Kacprowski, Tim and Nomura, Akihiro and Chen, Ming-Huei and Yanek, Lisa R and Tajuddin, Salman M and Schick, Ursula M and Slater, Andrew J and Pankratz, Nathan and Polfus, Linda and Schurmann, Claudia and Giri, Ayush and Brody, Jennifer A and Lange, Leslie A and Manichaikul, Ani and Hill, W David and Pazoki, Raha and Elliot, Paul and Evangelou, Evangelos and Tzoulaki, Ioanna and Gao, He and Vergnaud, Anne-Claire and Mathias, Rasika A and Becker, Diane M and Becker, Lewis C and Burt, Amber and Crosslin, David R and Lyytik{\"a}inen, Leo-Pekka and Nikus, Kjell and Hernesniemi, Jussi and K{\"a}h{\"o}nen, Mika and Raitoharju, Emma and Mononen, Nina and Raitakari, Olli T and Lehtim{\"a}ki, Terho and Cushman, Mary and Zakai, Neil A and Nickerson, Deborah A and Raffield, Laura M and Quarells, Rakale and Willer, Cristen J and Peloso, Gina M and Abecasis, Goncalo R and Liu, Dajiang J and Deloukas, Panos and Samani, Nilesh J and Schunkert, Heribert and Erdmann, Jeanette and Fornage, Myriam and Richard, Melissa and Tardif, Jean-Claude and Rioux, John D and Dub{\'e}, Marie-Pierre and de Denus, Simon and Lu, Yingchang and Bottinger, Erwin P and Loos, Ruth J F and Smith, Albert Vernon and Harris, Tamara B and Launer, Lenore J and Gudnason, Vilmundur and Velez Edwards, Digna R and Torstenson, Eric S and Liu, Yongmei and Tracy, Russell P and Rotter, Jerome I and Rich, Stephen S and Highland, Heather M and Boerwinkle, Eric and Li, Jin and Lange, Ethan and Wilson, James G and Mihailov, Evelin and M{\"a}gi, Reedik and Hirschhorn, Joel and Metspalu, Andres and Esko, T{\~o}nu and Vacchi-Suzzi, Caterina and Nalls, Mike A and Zonderman, Alan B and Evans, Michele K and Engstr{\"o}m, Gunnar and Orho-Melander, Marju and Melander, Olle and O{\textquoteright}Donoghue, Michelle L and Waterworth, Dawn M and Wallentin, Lars and White, Harvey D and Floyd, James S and Bartz, Traci M and Rice, Kenneth M and Psaty, Bruce M and Starr, J M and Liewald, David C M and Hayward, Caroline and Deary, Ian J and Greinacher, Andreas and V{\"o}lker, Uwe and Thiele, Thomas and V{\"o}lzke, Henry and van Rooij, Frank J A and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Dehghan, Abbas and Edwards, Todd L and Ganesh, Santhi K and Kathiresan, Sekar and Faraday, Nauder and Auer, Paul L and Reiner, Alex P and Lettre, Guillaume and Johnson, Andrew D} } @article {7453, title = {Physical activity predicts reduced plasma β amyloid in the Cardiovascular Health Study.}, journal = {Ann Clin Transl Neurol}, volume = {4}, year = {2017}, month = {2017 May}, pages = {284-291}, abstract = {

OBJECTIVE: Higher levels of physical activity (PA) reduce the risk of cognitive impairment, but the underlying mechanisms are unclear. Using longitudinal data from the Cardiovascular Health Study, we examined whether PA predicted plasma Aβ levels and risk for cognitive decline 9-13 years later.

METHODS: Linear and logistic regressions (controlling for APOE status, age, gender, body mass index, cardiovascular disease, brain white matter lesions, and cystatin C levels) tested associations between PA, Aβ, and cognitive impairment in a sample of 149 cognitively normal older adults (mean age 83 years).

RESULTS: More PA at baseline predicted lower levels of Aβ 9-13 years later. Higher Aβ levels at year 9 predicted greater risk for cognitive impairment at year 13. Levels of Aβ at year 9 mediated the relationship between PA and cognitive impairment.

INTERPRETATION: Greater PA may reduce plasma levels of a neurotoxic peptide at an age when the risk for cognitive impairment is especially high.

}, issn = {2328-9503}, doi = {10.1002/acn3.397}, author = {Stillman, Chelsea M and Lopez, Oscar L and Becker, James T and Kuller, Lewis H and Mehta, Pankaj D and Tracy, Russell P and Erickson, Kirk I} } @article {9170, title = {Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 08 02}, pages = {e024012}, abstract = {

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}, issn = {2047-9980}, doi = {10.1161/JAHA.121.024012}, author = {Lamprea-Montealegre, Julio A and Arnold, Alice M and McClelland, Robyn L and Mukamal, Kenneth J and Djouss{\'e}, Luc and Biggs, Mary L and Siscovick, David S and Tracy, Russell P and Beisswenger, Paul J and Psaty, Bruce M and Ix, Joachim H and Kizer, Jorge R} } @article {9255, title = {Plasma proteomic signature of decline in gait speed and grip strength.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Dec}, pages = {e13736}, abstract = {

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 {\texttimes} 10 ), pleiotrophin (1.23 {\texttimes} 10 ), and TIMP-1 (5.97 {\texttimes} 10 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 {\texttimes} 10 ), CDON (2.38 {\texttimes} 10 ), and SMOC1 (7.47 {\texttimes} 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}, issn = {1474-9726}, doi = {10.1111/acel.13736}, author = {Liu, Xiaojuan and Pan, Stephanie and Xanthakis, Vanessa and Vasan, Ramachandran S and Psaty, Bruce M and Austin, Thomas R and Newman, Anne B and Sanders, Jason L and Wu, Chenkai and Tracy, Russell P and Gerszten, Robert E and Odden, Michelle C} } @article {9086, title = {Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing.}, journal = {Eur J Epidemiol}, year = {2022}, month = {2022 Jul 05}, abstract = {

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.

METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61\% women, mean age 74~years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.

CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

}, issn = {1573-7284}, doi = {10.1007/s10654-022-00888-z}, author = {Austin, Thomas R and McHugh, Caitlin P and Brody, Jennifer A and Bis, Joshua C and Sitlani, Colleen M and Bartz, Traci M and Biggs, Mary L and Bansal, Nisha and B{\r u}zkov{\'a}, Petra and Carr, Steven A and deFilippi, Christopher R and Elkind, Mitchell S V and Fink, Howard A and Floyd, James S and Fohner, Alison E and Gerszten, Robert E and Heckbert, Susan R and Katz, Daniel H and Kizer, Jorge R and Lemaitre, Rozenn N and Longstreth, W T and McKnight, Barbara and Mei, Hao and Mukamal, Kenneth J and Newman, Anne B and Ngo, Debby and Odden, Michelle C and Vasan, Ramachandran S and Shojaie, Ali and Simon, Noah and Smith, George Davey and Davies, Neil M and Siscovick, David S and Sotoodehnia, Nona and Tracy, Russell P and Wiggins, Kerri L and Zheng, Jie and Psaty, Bruce M} } @article {9640, title = {Plasma proteomic signature of human longevity.}, journal = {Aging Cell}, year = {2024}, month = {2024 Mar 05}, pages = {e14136}, abstract = {

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

}, issn = {1474-9726}, doi = {10.1111/acel.14136}, author = {Liu, Xiaojuan and Axelsson, Gisli Thor and Newman, Anne B and Psaty, Bruce M and Boudreau, Robert M and Wu, Chenkai and Arnold, Alice M and Aspelund, Thor and Austin, Thomas R and Gardin, Julius M and Siggeirsdottir, Kristin and Tracy, Russell P and Gerszten, Robert E and Launer, Lenore J and Jennings, Lori L and Gudnason, Vilmundur and Sanders, Jason L and Odden, Michelle C} }