P1542Identification of 13 novel susceptibility loci for early-onset myocardial infarction, hypertension, or chronic kidney disease in Japanese

Abstract

Abstract Background Early-onset cardiovascular and renal diseases have a strong genetic component. Purpose To identify genetic variants that confer susceptibility to early-onset myocardial infarction (MI), hypertension, or chronic kidney disease (CKD) in Japanese. We have performed exome-wide association studies (EWASs) in subjects with early-onset forms of these diseases. Methods A total of 8093 individuals aged ≤65 years was enrolled in the study. The EWASs for MI, hypertension, and CKD were conducted with 6926 subjects (1152 cases, 5774 controls), 8080 subjects (3444 cases, 4636 controls), and 2556 subjects (1051 cases, 1505 controls), respectively. Genotyping of single nucleotide polymorphisms (SNPs) was performed with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 31,245, 31,276, or 31,514 SNPs that passed quality control to MI, hypertension, and CKD, respectively, was examined with Fisher's exact test. Bonferroni's correction for statistical significance of association was applied to compensate for multiple comparisons of genotypes with MI, hypertension, or CKD. Results The EWASs of allele frequencies revealed that 25, 11, and 11 SNPs were significantly associated with MI (P<1.60 × 10–6), hypertension (P<1.60 × 10–6), or CKD (P<1.59 × 10–6), respectively. Multivariable logistic regression analysis with adjustment for covariates showed that all 25, 11, and 11 SNPs were significantly related to MI (P<0.0005), hypertension (P<0.0011), or CKD (P<0.0011), respectively. After examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, we newly identified 11 loci (TMOD4, COL6A3, ADGRL3-CXCL8-MARCH1, OR52E4, TCHP-GIT2, CCDC63, 12q24.1, OAS3, PLCB2-VPS33B, GOSR2, ZNF77), six loci (MOB3C-TMOD4, COL6A3, COL6A5, CXCL8-MARCH1, NFKBIL1-6p21.3-NCR3, PLCB2-VPS33B), and seven loci (MOB3C-TMOD4, COL6A3, COL6A5, ADGRL3-CXCL8-MARCH1, MUC17, PLCB2-VPS33B, ZNF77) that were significantly associated with MI, hypertension, or CKD, respectively. Furthermore, six genes (TMOD4, COL6A3, CXCL8, MARCH1, PLCB2, VPS33B) were significantly associated with MI, hypertension, and CKD; two genes (ADGRL3, ZNF77) with MI and CKD; and two genes (COL6A5, MOB3C) with hypertension and CKD. Network analysis showed that the 13, 10, or 11 genes associated with MI, hypertension, or CKD, respectively, in the present study had direct or indirect interactions with the corresponding sets of 50 genes previously shown to be associated with MI, hypertension, or CKD. Conclusion We newly identified 13 loci (MOB3C-TMOD4, COL6A3, ADGRL3-CXCL8-MARCH1, OR52E4, TCHP-GIT2, CCDC63, 12q24.1, OAS3, PLCB2-VPS33B, ZNF77, COL6A5, NFKBIL1-NCR3, MUC17) that confer susceptibility to early-onset MI, hypertension, or CKD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for MI, hypertension, or CKD in Japanese.