Key result
Low-frequency PLCL1 variant linked to ~80% higher risk of prevalent MI.
Why the study?
Most genomic loci associated with coronary artery disease are common variants in non-coding regions that provide limited information on causal genes and disease etiology, motivating investigation of low-frequency and rare coding variants.
Are specific low-frequency and rare genetic variants associated with the risk of prevalent and incident myocardial infarction and coronary heart disease in individuals of European ancestry?
Meta-Analysis (n=55,736)
Yes
Are specific low-frequency and rare genetic variants associated with the risk of prevalent and incident myocardial infarction and coronary heart disease in individuals of European ancestry?
Odds Ratio: 1.8 (95% CI 1.43–2.27)
p-value: p=7.12 × 10-7
This large-scale genetic meta-analysis identified novel low-frequency variants and genes, including PLCL1, TMPRSS5, LDLRAD1, RC3H2, and ANGPTL4, associated with the risk of myocardial infarction and coronary heart disease.
Rare coding variants may inform CAD etiology; leaves open causal gene discovery and new prevention strategies.
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 better understand etiological pathways that might lead to discovery of new treatments or prevention strategies, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome while also exploring associations with common variants. 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. 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 ). Three common variants, rs9349379 in PHACTR1 , and rs1333048 and rs4977574 in the 9p21 region, were significantly associated with prevalent CHD. Four common variants (rs4977574, rs10757278, rs1333049, and rs1333048) within the 9p21 locus were significantly associated with incident MI. 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 confirmed previously reported loci influencing heart disease risk, and one single variant and three genes associated with MI and CHD were newly identified and warrant future investigation.
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Hahn et al. (2020) conducted a meta-analysis in Myocardial infarction and coronary heart disease (n=55,736). Genetic variants (e.g., rs988583 in PLCL1) vs. Reference alleles was evaluated on Prevalent myocardial infarction (OR 1.80, 95% CI 1.43, 2.27, p=7.12 × 10-7). A low-frequency intronic variant (rs988583) in the PLCL1 gene was significantly associated with an increased risk of prevalent myocardial infarction (OR 1.80).
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