04618nas a2200805 4500008004100000022001400041245019400055210006900249260000900318300001300327490000700340520222500347653001002572653002802582653002802610653001102638653004002649653001702689653003402706653001102740653002602751653003602777653002402813100001602837700001602853700002202869700001902891700002202910700002102932700001902953700001802972700002302990700002603013700001703039700002003056700002103076700002103097700002103118700002303139700002203162700002103184700001703205700002203222700001903244700002003263700001903283700002203302700002603324700002103350700002103371700002003392700002603412700002203438700002203460700002003482700002803502700001703530700001903547700001303566700002303579700001803602700002403620700002303644700001603667700002003683700001903703700003003722700002403752856003603776 2020 eng d a1932-620300aGenetic 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.0 aGenetic loci associated with prevalent and incident myocardial i c2020 ae02300350 v153 a
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) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.
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.
10aAging10aCoronary Artery Disease10aCross-Sectional Studies10aEurope10aEuropean Continental Ancestry Group10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aHahn, Julie1 aFu, Yi-Ping1 aBrown, Michael, R1 aBis, Joshua, C1 ade Vries, Paul, S1 aFeitosa, Mary, F1 aYanek, Lisa, R1 aWeiss, Stefan1 aGiulianini, Franco1 aSmith, Albert, Vernon1 aGuo, Xiuqing1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aChen, Yii-Der Ida1 aFranco, Oscar, H1 aGrove, Megan1 aHarris, Tamara, B1 aHofman, Albert1 aHwang, Shih-Jen1 aKral, Brian, G1 aLauner, Lenore, J1 aMarkus, Marcello, R P1 aRice, Kenneth, M1 aRich, Stephen, S1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aYao, Jie1 aChasman, Daniel, I1 aDörr, Marcus1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aPost, Wendy1 aPsaty, Bruce, M1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aMorrison, Alanna, C uhttps://chs-nhlbi.org/node/8625