%0 Journal Article %J J Card Fail %D 2017 %T Incident Heart Failure and Cognitive Decline: The Atherosclerosis Risk in Communities Study. %A Bressler, Jan %A Knopman, David S %A Sharrett, A Richey %A Gottesman, Rebecca F %A Penman, Alan %A Chang, Patricia P %A Rosamond, Wayne D %A Boerwinkle, Eric %A Mosley, Thomas H %K Adult %K Aged %K Atherosclerosis %K Cognition %K Cognitive Dysfunction %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Middle Aged %K Neuropsychological Tests %K Prospective Studies %K Residence Characteristics %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

BACKGROUND: Cognitive impairment is found in a significant proportion of patients with heart failure (HF). Although cognitive impairment may be a consequence of HF, early signs of cognitive impairment may also indicate subclinical vascular disease, and thus a risk factor for future cardiovascular events.

METHODS AND RESULTS: The Atherosclerosis Risk in Communities Study is a prospective cohort study of the development of atherosclerosis. Cox proportional hazards regression was used to examine the association between mean 6-year change in cognitive function and incident HF in 7962 white and 1933 African-American men and women aged 46 to 70 years and free of clinical stroke. Scores were obtained for the Delayed Word Recall Test, the Digit Symbol Substitution Test (DSST), and the Word Fluency Test. There was a significantly increased risk of developing HF during the mean 12.6-year follow-up period after adjustment for age, gender, race, and education for those in the quartile with the greatest decline in DSST scores (hazard ratio [HR] = 1.17, P = .009), and in the quartile with the lowest baseline DSST scores (HR = 1.43, P < .001).

CONCLUSIONS: The results suggest that relatively low performance on a test of information processing speed may serve as an indicator of HF risk in middle age.

%B J Card Fail %V 23 %P 47-55 %8 2017 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27864030?dopt=Abstract %R 10.1016/j.cardfail.2016.11.002 %0 Journal Article %J PLoS One %D 2015 %T Metabolomics and Incidence of Atrial Fibrillation in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study. %A Alonso, Alvaro %A Yu, Bing %A Qureshi, Waqas T %A Grams, Morgan E %A Selvin, Elizabeth %A Soliman, Elsayed Z %A Loehr, Laura R %A Chen, Lin Y %A Agarwal, Sunil K %A Alexander, Danny %A Boerwinkle, Eric %K Atherosclerosis %K Atrial Fibrillation %K Black or African American %K Female %K Humans %K Incidence %K Male %K Metabolomics %K Middle Aged %K Residence Characteristics %X

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia. Application of metabolomic approaches, which may identify novel pathways and biomarkers of disease risk, to a longitudinal epidemiologic study of AF has been limited.

METHODS: We determined the prospective association of 118 serum metabolites identified through untargeted metabolomics profiling with the incidence of newly-diagnosed AF in 1919 African-American men and women from the Atherosclerosis Risk in Communities study without AF at baseline (1987-1989). Incident AF cases through 2011 were ascertained from study electrocardiograms, hospital discharge codes, and death certificates.

RESULTS: During a median follow-up of 22 years, we identified 183 incident AF cases. In Cox proportional hazards models adjusted for age, sex, smoking, body mass index, systolic blood pressure, use of antihypertensive medication, diabetes, prevalent heart failure, prevalent coronary heart disease, and kidney function, two conjugated bile acids (glycolithocholate sulfate and glycocholenate sulfate) were significantly associated with AF risk after correcting for multiple comparisons (p<0.0004). Multivariable-adjusted hazard ratios (95% confidence intervals) of AF were 1.22 (1.12-1.32) for glycolithocholate sulfate and 1.22 (1.10-1.35) for glycocholenate sulfate per 1-standard deviation higher levels. Associations were not appreciably different after additional adjustment for alcohol consumption or concentrations of circulating albumin and liver enzymes.

CONCLUSION: We found an association of higher levels of two bile acids with an increased risk of AF, pointing to a potential novel pathway in AF pathogenesis. Replication of results in independent studies is warranted.

%B PLoS One %V 10 %P e0142610 %8 2015 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26544570?dopt=Abstract %R 10.1371/journal.pone.0142610 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Association of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies. %A Yu, Bing %A Barbalic, Maja %A Brautbar, Ariel %A Nambi, Vijay %A Hoogeveen, Ron C %A Tang, Weihong %A Mosley, Thomas H %A Rotter, Jerome I %A deFilippi, Christopher R %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Rice, Ken %A Heckbert, Susan R %A Ballantyne, Christie M %A Psaty, Bruce M %A Boerwinkle, Eric %K Atherosclerosis %K Black People %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nuclear Receptor Coactivator 2 %K Polymorphism, Single Nucleotide %K Prospective Studies %K Residence Characteristics %K Risk Factors %K Troponin T %K White People %X

BACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.

METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).

CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.

%B Circ Cardiovasc Genet %V 6 %P 82-8 %8 2013 Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/23247143?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963058 %0 Journal Article %J Ann Neurol %D 2011 %T Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. %A Fornage, Myriam %A Debette, Stephanie %A Bis, Joshua C %A Schmidt, Helena %A Ikram, M Arfan %A Dufouil, Carole %A Sigurdsson, Sigurdur %A Lumley, Thomas %A DeStefano, Anita L %A Fazekas, Franz %A Vrooman, Henri A %A Shibata, Dean K %A Maillard, Pauline %A Zijdenbos, Alex %A Smith, Albert V %A Gudnason, Haukur %A de Boer, Renske %A Cushman, Mary %A Mazoyer, Bernard %A Heiss, Gerardo %A Vernooij, Meike W %A Enzinger, Christian %A Glazer, Nicole L %A Beiser, Alexa %A Knopman, David S %A Cavalieri, Margherita %A Niessen, Wiro J %A Harris, Tamara B %A Petrovic, Katja %A Lopez, Oscar L %A Au, Rhoda %A Lambert, Jean-Charles %A Hofman, Albert %A Gottesman, Rebecca F %A Garcia, Melissa %A Heckbert, Susan R %A Atwood, Larry D %A Catellier, Diane J %A Uitterlinden, André G %A Yang, Qiong %A Smith, Nicholas L %A Aspelund, Thor %A Romero, Jose R %A Rice, Kenneth %A Taylor, Kent D %A Nalls, Michael A %A Rotter, Jerome I %A Sharrett, Richey %A van Duijn, Cornelia M %A Amouyel, Philippe %A Wolf, Philip A %A Gudnason, Vilmundur %A van der Lugt, Aad %A Boerwinkle, Eric %A Psaty, Bruce M %A Seshadri, Sudha %A Tzourio, Christophe %A Breteler, Monique M B %A Mosley, Thomas H %A Schmidt, Reinhold %A Longstreth, W T %A DeCarli, Charles %A Launer, Lenore J %K Aged %K Aged, 80 and over %K Cerebral Cortex %K Chromosomes, Human, Pair 17 %K Cognition Disorders %K Cohort Studies %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Movement Disorders %K Nerve Fibers, Myelinated %K Polymorphism, Single Nucleotide %K Residence Characteristics %K RNA, Messenger %K White People %X

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

%B Ann Neurol %V 69 %P 928-39 %8 2011 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract %R 10.1002/ana.22403 %0 Journal Article %J Am J Epidemiol %D 2010 %T Genetic variants identified in a European genome-wide association study that were found to predict incident coronary heart disease in the atherosclerosis risk in communities study. %A Bressler, Jan %A Folsom, Aaron R %A Couper, David J %A Volcik, Kelly A %A Boerwinkle, Eric %K Black or African American %K Case-Control Studies %K Coronary Artery Disease %K Female %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Residence Characteristics %K Risk %K Risk Assessment %K Risk Factors %K United Kingdom %K United States %K White People %X

In 2007, the Wellcome Trust Case Control Consortium (WTCCC) performed a genome-wide association study in 2,000 British coronary heart disease (CHD) cases and 3,000 controls after genotyping 469,557 single nucleotide polymorphisms (SNPs). Seven variants associated with CHD were initially identified, and 5 SNPs were later found in replication studies. In the current study, the authors aimed to determine whether the 12 SNPs reported by the WTCCC predicted incident CHD through 2004 in a biracial, prospective cohort study (Atherosclerosis Risk in Communities) comprising 15,792 persons aged 45-64 years who had been selected by probability sampling from 4 different US communities in 1987-1989. Cox proportional hazards models with adjustment for age and gender were used to estimate CHD hazard rate ratios (HRRs) over a 17-year period (1,362 cases in whites and 397 cases in African Americans) under an additive genetic model. The results showed that 3 SNPs in whites (rs599839, rs1333049, and rs501120; HRRs were 1.10 (P = 0.044), 1.14 (P < 0.001), and 1.14 (P = 0.030), respectively) and 1 SNP in African Americans (rs7250581; HRR = 1.60, P = 0.05) were significantly associated with incident CHD. This study demonstrates that genetic variants revealed in a case-control genome-wide association study enriched for early disease onset may play a role in the genetic etiology of CHD in the general population.

%B Am J Epidemiol %V 171 %P 14-23 %8 2010 Jan 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/19955471?dopt=Abstract %R 10.1093/aje/kwp377