%0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2019 %T Metabolomic Pattern Predicts Incident Coronary Heart Disease. %A Wang, Zhe %A Zhu, Cong %A Nambi, Vijay %A Morrison, Alanna C %A Folsom, Aaron R %A Ballantyne, Christie M %A Eric Boerwinkle %A Yu, Bing %K Atherosclerosis %K Coronary Disease %K Female %K Humans %K Male %K Metabolomics %K Middle Aged %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %X

Objective- Alterations in the serum metabolome may be detectable in at-risk individuals before the onset of coronary heart disease (CHD). Identifying metabolomic signatures associated with CHD may provide insight into disease pathophysiology and prevention. Approach and Results- Metabolomic profiling (chromatography-mass spectrometry) was performed in 2232 African Americans and 1366 European Americans from the ARIC study (Atherosclerosis Risk in Communities). We applied Cox regression with least absolute shrinkage and selection operator to select metabolites associated with incident CHD. A metabolite risk score was constructed to evaluate whether the metabolite risk score predicted CHD risk beyond traditional risk factors. After 30 years of follow-up, we observed 633 incident CHD cases. Thirty-two metabolites were selected by least absolute shrinkage and selection operator to be associated with CHD, and 19 of the 32 showed significant individual associations with CHD, including a sugar substitute, erythritol. Theophylline (hazard ratio [95% CI] =1.16 [1.09-1.25]) and gamma-linolenic acid (hazard ratio [95% CI] =0.89 [0.81-0.97]) showed the greatest positive and negative associations with CHD, respectively. A 1 SD greater standardized metabolite risk score was associated with a 1.37-fold higher risk of CHD (hazard ratio [95% CI] =1.37 [1.27-1.47]). Adding the metabolite risk score to the traditional risk factors significantly improved model predictive performance (30-year risk prediction: Δ C statistics [95% CI] =0.016 [0.008-0.024], continuous net reclassification index [95% CI] =0.522 [0.480-0.556], integrated discrimination index [95% CI] =0.038 [0.019-0.065]). Conclusions- We identified 19 metabolites from known and novel metabolic pathways that collectively improved CHD risk prediction. Visual Overview- An online visual overview is available for this article.

%B Arterioscler Thromb Vasc Biol %V 39 %P 1475-1482 %8 2019 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/31092011?dopt=Abstract %R 10.1161/ATVBAHA.118.312236 %0 Journal Article %J Atherosclerosis %D 2017 %T The association of lipoprotein(a) with incident heart failure hospitalization: Atherosclerosis Risk in Communities study. %A Agarwala, Anandita %A Pokharel, Yashashwi %A Saeed, Anum %A Sun, Wensheng %A Virani, Salim S %A Nambi, Vijay %A Ndumele, Chiadi %A Shahar, Eyal %A Heiss, Gerardo %A Boerwinkle, Eric %A Konety, Suma %A Hoogeveen, Ron C %A Ballantyne, Christie M %K Biomarkers %K Chi-Square Distribution %K Comorbidity %K Female %K Heart Failure %K Hospitalization %K Humans %K Incidence %K Linear Models %K Lipoprotein(a) %K Male %K Middle Aged %K Multivariate Analysis %K Myocardial Infarction %K Prevalence %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Time Factors %K United States %K Up-Regulation %K Vascular Stiffness %X

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is a proatherogenic lipoprotein associated with coronary heart disease, ischemic stroke, and more recently aortic stenosis and heart failure (HF). We examined the association of Lp(a) levels with incident HF hospitalization in the Atherosclerosis Risk in Communities (ARIC) study. We also assessed the relationship between Lp(a) levels and arterial stiffness as a potential mechanism for development of HF.

METHODS: Lp(a) was measured in 14,154 ARIC participants without prevalent HF at ARIC visit 1 (1987-1989). The association of Lp(a) quintiles with incident HF hospitalization was assessed using Cox proportional-hazards models. Arterial stiffness parameters were stratified based on Lp(a) quintiles, and p-trend was calculated across ordered groups.

RESULTS: At a median follow-up of 23.4 years, there were 2605 incident HF hospitalizations. Lp(a) levels were directly associated with incident HF hospitalization in models adjusted for age, race, gender, systolic blood pressure, history of hypertension, diabetes, smoking status, body mass index, heart rate, and high-density lipoprotein cholesterol (quintile 5 vs. quintile 1: hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.09-1.41; p-trend across increasing quintiles <0.01), but not after excluding prevalent and incident myocardial infarction cases (HR 1.07, 95% CI 0.91-1.27; p-trend = 0.70). When adjusted for age, gender, and race, Lp(a) quintiles were not significantly associated with arterial stiffness parameters.

CONCLUSIONS: Increased Lp(a) levels were associated with increased risk of incident HF hospitalization. After excluding prevalent and incident myocardial infarction, the association was no longer significant. Lp(a) levels were not associated with arterial stiffness parameters.

%B Atherosclerosis %V 262 %P 131-137 %8 2017 Jul %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/28554015?dopt=Abstract %R 10.1016/j.atherosclerosis.2017.05.014 %0 Journal Article %J PLoS One %D 2016 %T Causal Role of Alcohol Consumption in an Improved Lipid Profile: The Atherosclerosis Risk in Communities (ARIC) Study. %A Vu, Khanh N %A Ballantyne, Christie M %A Hoogeveen, Ron C %A Nambi, Vijay %A Volcik, Kelly A %A Boerwinkle, Eric %A Morrison, Alanna C %K Alcohol Dehydrogenase %K Alcohol Drinking %K Atherosclerosis %K Female %K Humans %K Lipids %K Male %K Middle Aged %X

INTRODUCTION: Health benefits of low-to-moderate alcohol consumption may operate through an improved lipid profile. A Mendelian randomization (MR) approach was used to examine whether alcohol consumption causally affects lipid levels.

METHODS: This analysis involved 10,893 European Americans (EA) from the Atherosclerosis Risk in Communities (ARIC) study. Common and rare variants in alcohol dehydrogenase and acetaldehyde dehydrogenase genes were evaluated for MR assumptions. Five variants, residing in the ADH1B, ADH1C, and ADH4 genes, were selected as genetic instruments and were combined into an unweighted genetic score. Triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c) and its subfractions (HDL2-c and HDL3-c), low-density lipoprotein cholesterol (LDL-c), small dense LDL-c (sdLDL-c), apolipoprotein B (apoB), and lipoprotein (a) (Lp(a)) levels were analyzed.

RESULTS: Alcohol consumption significantly increased HDL2-c and reduced TG, total cholesterol, LDL-c, sdLDL-c, and apoB levels. For each of these lipids a non-linear trend was observed. Compared to the first quartile of alcohol consumption, the third quartile had a 12.3% lower level of TG (p < 0.001), a 7.71 mg/dL lower level of total cholesterol (p = 0.007), a 10.3% higher level of HDL2-c (p = 0.007), a 6.87 mg/dL lower level of LDL-c (p = 0.012), a 7.4% lower level of sdLDL-c (p = 0.037), and a 3.5% lower level of apoB (p = 0.058, poverall = 0.022).

CONCLUSIONS: This study supports the causal role of regular low-to-moderate alcohol consumption in increasing HDL2-c, reducing TG, total cholesterol, and LDL-c, and provides evidence for the novel finding that low-to-moderate consumption of alcohol reduces apoB and sdLDL-c levels among EA. However, given the nonlinearity of the effect of alcohol consumption, even within the range of low-to-moderate drinking, increased consumption does not always result in a larger benefit.

%B PLoS One %V 11 %P e0148765 %8 2016 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26849558?dopt=Abstract %R 10.1371/journal.pone.0148765 %0 Journal Article %J Eur J Prev Cardiol %D 2016 %T The impact of multiple single day blood pressure readings on cardiovascular risk estimation: The Atherosclerosis Risk in Communities study. %A Ogunwale, Abayomi N %A Morrison, Alanna C %A Sun, Wensheng %A Dodge, Rhiannon C %A Virani, Salim S %A Taylor, Addison %A Gottesman, Rebecca F %A Yang, Eric %A Wei, Peng %A McEvoy, John W %A Heiss, Gerardo %A Boerwinkle, Eric %A Ballantyne, Christie M %A Nambi, Vijay %K Atherosclerosis %K Blood Pressure %K Blood Pressure Determination %K Cardiovascular Diseases %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Risk Assessment %K Risk Factors %K United States %X

AIMS: The aim of this study was to determine the magnitude of change in estimated cardiovascular disease risk when multiple same day blood pressure measurements are used in estimating coronary heart disease, heart failure and stroke risks.

METHODS AND RESULTS: Black and White participants, N = 11,129, enrolled in the Atherosclerosis Risk in Communities study (mean age 53.9 ± 5.7 (SD) years) were included. Each participant had three sitting, five supine, and six standing blood pressure measures during one day. Main outcome measures were changes in estimated coronary heart disease, heart failure and stroke risk when using the different blood pressure measures. Mean sitting, standing and supine systolic blood pressure values of the study population were 120.8 ± 18.6, 124.9 ± 20 and 124.7 ± 19.6 mmHg, respectively. The substitution of the second sitting systolic blood pressure with the third sitting systolic blood pressure (taken ∼5 min later) in two separate coronary heart disease risk models reclassified 3.3% to 5.1% of study participants. Similar substitutions for heart failure and stroke risk prediction models led to reclassification of 1.9% and 2.7% of participants respectively. When mean sitting systolic blood pressure was replaced with mean standing systolic blood pressure 5.4% to 11.6% of the participants were reclassified. Maximum upward and downward change in an individual's estimated risk was 31% and 26% respectively.

CONCLUSIONS: Estimated risks of coronary heart disease, heart failure, and stroke for an individual can change significantly within a day due to changes in systolic blood pressure. Given recommendations to use estimated risk for therapeutic decisions, our study has implications for the use of a single systolic blood pressure in cardiovascular risk estimation.

%B Eur J Prev Cardiol %V 23 %P 1529-36 %8 2016 Sep %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/26869459?dopt=Abstract %R 10.1177/2047487316633549 %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 Hum Mol Genet %D 2010 %T Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Hoogeveen, Ron C %A Schnabel, Renate B %A Nambi, Vijay %A Bretler, Monique %A Smith, Nicholas L %A Peters, Annette %A Lu, Chen %A Tracy, Russell P %A Aleksic, Nena %A Heeriga, Jan %A Keaney, John F %A Rice, Kenneth %A Lip, Gregory Y H %A Vasan, Ramachandran S %A Glazer, Nicole L %A Larson, Martin G %A Uitterlinden, André G %A Yamamoto, Jennifer %A Durda, Peter %A Haritunians, Talin %A Psaty, Bruce M %A Boerwinkle, Eric %A Hofman, Albert %A Koenig, Wolfgang %A Jenny, Nancy S %A Witteman, Jacqueline C %A Ballantyne, Christie %A Benjamin, Emelia J %K ABO Blood-Group System %K Blood Platelets %K Enzyme-Linked Immunosorbent Assay %K Fluorescence %K Genome-Wide Association Study %K Humans %K Intercellular Adhesion Molecule-1 %K P-Selectin %K White People %X

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

%B Hum Mol Genet %V 19 %P 1863-72 %8 2010 May 01 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract %R 10.1093/hmg/ddq061