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Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population

Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European populations, genetic variants that contribute toward susceptibility to this condition in Japa...

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Autores principales: Yamada, Yoshiji, Yasukochi, Yoshiki, Kato, Kimihiko, Oguri, Mitsutoshi, Horibe, Hideki, Fujimaki, Tetsuo, Takeuchi, Ichiro, Sakuma, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201041/
https://www.ncbi.nlm.nih.gov/pubmed/30402224
http://dx.doi.org/10.3892/br.2018.1152
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author Yamada, Yoshiji
Yasukochi, Yoshiki
Kato, Kimihiko
Oguri, Mitsutoshi
Horibe, Hideki
Fujimaki, Tetsuo
Takeuchi, Ichiro
Sakuma, Jun
author_facet Yamada, Yoshiji
Yasukochi, Yoshiki
Kato, Kimihiko
Oguri, Mitsutoshi
Horibe, Hideki
Fujimaki, Tetsuo
Takeuchi, Ichiro
Sakuma, Jun
author_sort Yamada, Yoshiji
collection PubMed
description Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European populations, genetic variants that contribute toward susceptibility to this condition in Japanese patients remain to be definitively identified. In the present study, exome-wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. A total of 7,256 individuals aged ≤65 years were enrolled in the present study. EWAS were conducted on 1,482 patients with CAD and 5,774 healthy controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed using Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The association between allele frequencies for 31,465 SNPs that passed quality control and CAD was examined using Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, a false discovery rate (FDR) of <0.05 was applied for statistically significant associations. The association between allele frequencies for 31,465 SNPs and CAD, as determined by Fisher's exact test, demonstrated that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) associated with CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R(2)), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. Following examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY and EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34 and 20q13.2) that were significantly associated with CAD were newly identified in the present study. Gene ontology analysis demonstrated that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously revealed to be associated with CAD or with the 228 genes identified in previous genome-wide association studies. The present study newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese patients.
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spelling pubmed-62010412018-11-06 Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population Yamada, Yoshiji Yasukochi, Yoshiki Kato, Kimihiko Oguri, Mitsutoshi Horibe, Hideki Fujimaki, Tetsuo Takeuchi, Ichiro Sakuma, Jun Biomed Rep Articles Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European populations, genetic variants that contribute toward susceptibility to this condition in Japanese patients remain to be definitively identified. In the present study, exome-wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. A total of 7,256 individuals aged ≤65 years were enrolled in the present study. EWAS were conducted on 1,482 patients with CAD and 5,774 healthy controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed using Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The association between allele frequencies for 31,465 SNPs that passed quality control and CAD was examined using Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, a false discovery rate (FDR) of <0.05 was applied for statistically significant associations. The association between allele frequencies for 31,465 SNPs and CAD, as determined by Fisher's exact test, demonstrated that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) associated with CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R(2)), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. Following examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY and EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34 and 20q13.2) that were significantly associated with CAD were newly identified in the present study. Gene ontology analysis demonstrated that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously revealed to be associated with CAD or with the 228 genes identified in previous genome-wide association studies. The present study newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese patients. D.A. Spandidos 2018-11 2018-09-17 /pmc/articles/PMC6201041/ /pubmed/30402224 http://dx.doi.org/10.3892/br.2018.1152 Text en Copyright: © Yamada et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Yamada, Yoshiji
Yasukochi, Yoshiki
Kato, Kimihiko
Oguri, Mitsutoshi
Horibe, Hideki
Fujimaki, Tetsuo
Takeuchi, Ichiro
Sakuma, Jun
Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
title Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
title_full Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
title_fullStr Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
title_full_unstemmed Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
title_short Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
title_sort identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a japanese population
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201041/
https://www.ncbi.nlm.nih.gov/pubmed/30402224
http://dx.doi.org/10.3892/br.2018.1152
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