Abstract
Recent studies have revealed the importance of rare variants in myocardial infarction (MI) susceptibility in European populations. Because genetic architectures vary in different populations, we investigated how they contribute to MI susceptibility in Japanese subjects. We performed targeted sequencing of 36 coronary artery disease risk genes, identified by genome-wide association studies, in 9,956 cases and 8,373 controls. Gene-based association tests identified significant enrichment of rare variants in LDLR and PCSK9 in MI cases. We identified 52 (novel 22) LDLR variants predicted to be damaging. Carriers of these variants showed a higher risk of MI (carriers/non-carriers 89/9867 in cases, 17/8356 controls, OR = 4.4, P = 7.2 × 10−10), higher LDL-cholesterol levels and younger age of onset for MI. With respect to PCSK9, E32K carriers showed higher LDL-cholesterol levels and younger age of onset for MI, whereas R93C carriers had lower LDL-cholesterol levels. A significant correlation between LDL-cholesterol levels and onset age of MI was observed in these variant carriers. In good agreement with previous studies in patients with familial hypercholesterolaemia, our study in the Japanese general population showed that rare variants in LDLR and PCSK9 were associated with the onset age of MI by altering LDL-cholesterol levels.
Highlights
Despite advances in therapeutic strategies, myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide[1]
Gene-based association was analysed with the Cohort Allelic Sum Test (CAST)[16] and Sequence Kernel Association Test (SKAT)[17], and we found 7 genes (PCSK9, GUCY1B3, PLG, ICA1L, NBEAL1, TCTN1 and LDLR) that showed P < 0.05 in at least one of the following three variant categories: (1) all non-synonymous variants; (2) damaging, defined by all disruptive variants and missense variants annotated as deleterious by all five protein function prediction algorithms, PolyPhen-2 HumDiv, Polyphen2-HumVar[18], SIFT19, MutationTaster[20] and LRT21 score; and (3) disruptive variants (Supplementary Table S5)
We identified a significant association of rare variants in LDLR and PCSK9 with MI
Summary
Despite advances in therapeutic strategies, myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide[1]. The protective effect of ANGPTL4 low-frequency variant on CAD was reported in a European population[10,11] but was not observed in a Chinese population[12] These uneven distributions of rare variants could be explained by population differences. The significance of GWAS-identified genes in rare and functional variant discovery has been demonstrated in other studies on dyslipidaemia[14,15] Based on these genetic findings, to detect efficiently www.nature.com/scientificreports/. The rare variants associated with CAD, we adopted a strategy for performing targeted sequencing of 36 genes from CAD-associated GWAS loci reported up to the beginning of our present study and conducted an association analysis using 9,956 cases and 8,373 controls in the Japanese population. The aim was to better understand the contribution of rare variants to the susceptibility of MI, followed by proposing a possible preventive strategy for Japanese
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