Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

TitleGenetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
Publication TypeJournal Article
Year of Publication2020
AuthorsHahn, J, Fu, Y-P, Brown, MR, Bis, JC, de Vries, PS, Feitosa, MF, Yanek, LR, Weiss, S, Giulianini, F, Smith, AVernon, Guo, X, Bartz, TM, Becker, DM, Becker, LC, Boerwinkle, E, Brody, JA, Chen, Y-DIda, Franco, OH, Grove, M, Harris, TB, Hofman, A, Hwang, S-J, Kral, BG, Launer, LJ, Markus, MRP, Rice, KM, Rich, SS, Ridker, PM, Rivadeneira, F, Rotter, JI, Sotoodehnia, N, Taylor, KD, Uitterlinden, AG, Völker, U, Völzke, H, Yao, J, Chasman, DI, Dörr, M, Gudnason, V, Mathias, RA, Post, W, Psaty, BM, Dehghan, A, O'Donnell, CJ, Morrison, AC
JournalPLoS One
Volume15
Issue11
Paginatione0230035
Date Published2020
ISSN1932-6203
KeywordsAging, Coronary Artery Disease, Cross-Sectional Studies, Europe, European Continental Ancestry Group, Genetic Loci, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies
Abstract

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF)

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

DOI10.1371/journal.pone.0230035
Alternate JournalPLoS One
PubMed ID33186364
PubMed Central IDPMC7665790
Grant ListN01 HC095163 / HC / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
U01 HL072518 / HL / NHLBI NIH HHS / United States
N01 HC095165 / HC / NHLBI NIH HHS / United States
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UM1 CA182913 / CA / NCI NIH HHS / United States
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HHSN268201800001C / HL / NHLBI NIH HHS / United States
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R01 HL120393 / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
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