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

Early-onset cardiovascular and renal diseases have a strong genetic component. In the present study, exome-wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early-onset myocardial infarction (MI), hypertension, or chronic kidney disease (CKD) in Japanese individuals. A total of 8,093 individuals aged ≤65 years was enrolled in the study. The EWASs for MI, hypertension, and CKD were performed in 6,926 subjects (1,152 cases, 5,774 controls), 8,080 subjects (3,444 cases, 4,636 controls), and 2,556 subjects (1,051 cases, 1,505 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 associations 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. 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 associated with MI (P<0.0005), hypertension (P<0.0011), or CKD (P<0.0011), respectively. On examination of the results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, 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) were identified as novel loci significantly associated with MI, hypertension, and 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. Therefore, 13 novel loci (MOB3C-TMOD4, COL6A3, ADGRL3-CXCL8-MARCH1, OR52E4, TCHP- GIT2, CCDC63, 12q24.1, OAS3, PLCB2-VPS33B, ZNF77, COL6A5, NFKBIL1-NCR3, MUC17) were identified that confer susceptibility to early-onset MI, hypertension, or CKD. The determination of genotypes for the SNPs at these loci may provide informative for assessment of the genetic risk for MI, hypertension, or CKD.