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

ABSTRACT: 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<1.60x10?6), hypertension (P<1.60x10?6), or CKD (P<1.59x10?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.

SUBMITTER: Yamada Y

PROVIDER: S-EPMC6192728 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Yamada Yoshiji Y Kato Kimihiko K Oguri Mitsutoshi M Horibe Hideki H Fujimaki Tetsuo T Yasukochi Yoshiki Y Takeuchi Ichiro I Sakuma Jun J

International journal of molecular medicine 20180904 5

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), ...[more]

PMID: 30226566

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Project description:<p>The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.</p> <p>In the Grand Opportunities Exome Sequencing Program Early MI Project (GO ESP - EOMI), we are sequencing cases with extremely early-onset MI drawn from 8 cohorts. These cohorts include five hospital or community-based studies that ascertained individuals based on MI status. These include PennCATH, Cleveland Clinic Genebank, Massachusetts General Hospital Premature Coronary Artery Disease Study (MGH-PCAD), Heart Attack Risk in Puget Sound (HARPS), and Translational Research Investigating Underlying Disparities in Myocardial Infarction Patients' Health Status (TRIUMPH). Cases were selected based on MI occurring in men aged ≤50 years and women aged ≤60 years. In addition, early-MI cases are being drawn from three population-cohort studies including the Framingham Heart Study, the Women's Health Initiative, and the Atherosclerosis Risk in Communities Study. MI-free controls are being drawn from five population-based cohort studies including the Framingham Heart Study, the Women's Health Initiative, Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and the Jackson Heart Study. Controls were selected based on two factors: (1) highest predicted risk for MI based on Framingham risk score; and (2) absence of prevalent or incident MI despite a high predicted risk.</p>

Project description:The circulating concentrations of triglycerides, high density lipoprotein (HDL)?cholesterol, and low density lipoprotein (LDL)?cholesterol have a substantial genetic component, and the heritability of early?onset dyslipidemia might be expected to be higher compared with late?onset forms. In the present study, exome?wide association studies (EWASs) were performed for early?onset hypertriglyceridemia, hypo?HDL?cholesterolemia, and hyper?LDL?cholesterolemia, with the aim to identify genetic variants that confer susceptibility to these conditions in the Japanese population. A total of 8,073 individuals aged ?65 years were enrolled in the study. The EWASs for hypertriglyceridemia (2,664 cases and 5,294 controls), hypo?HDL?cholesterolemia (974 cases and 7,085 controls), and hyper?LDL?cholesterolemia (2,911 cases and 5,111 controls) were performed with Illumina Human Exome?12 v1.2 DNA Analysis BeadChip or Infinium Exome?24 v1.0 BeadChip arrays. The association of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) to hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, Bonferroni's correction was applied for statistical significance of association. The results demonstrated that 25, 28 and 65 SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that all 25, 28 and 65 of these SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Following examination of the association of the identified SNPs to serum concentrations of triglycerides, HDL?cholesterol, or LDL?cholesterol, linkage disequilibrium of the SNPs, and results of previous genome?wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C?TMOD4, LPGAT1, EHD3, COL6A3, ZNF860?CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo?HDL?cholesterolemia, and three loci (KIAA0319?FAM65B, UBD, LOC105375015) for hyper?LDL?cholesterolemia. The present study thus identified 12 novel loci that may confer susceptibility to early?onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of genetic risk for hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia in the Japanese population.

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

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

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