Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25

Yusuke Ebana, Kouichi Ozaki, Lian Liu, Hitoshi Hachiya, Kenzo Hirao, Mitsuaki Isobe, Michiaki Kubo, Toshihiro Tanaka, Tetsushi Furukawa

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. Methods We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. Results The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele (p = 0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis-regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles (p < 0.0001, p < 0.005, respectively). Conclusions AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level.

Original languageEnglish
Pages (from-to)366-373
Number of pages8
JournalJournal of cardiology
Volume70
Issue number4
DOIs
Publication statusPublished - 01-10-2017

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Atrial Fibrillation
Genome-Wide Association Study
Alleles
Single Nucleotide Polymorphism
Linkage Disequilibrium
Histone Code
Chromosomes
Genes
Chromatin Immunoprecipitation
Luciferases
Gene Expression

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Ebana, Y., Ozaki, K., Liu, L., Hachiya, H., Hirao, K., Isobe, M., ... Furukawa, T. (2017). Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25. Journal of cardiology, 70(4), 366-373. https://doi.org/10.1016/j.jjcc.2016.11.016
Ebana, Yusuke ; Ozaki, Kouichi ; Liu, Lian ; Hachiya, Hitoshi ; Hirao, Kenzo ; Isobe, Mitsuaki ; Kubo, Michiaki ; Tanaka, Toshihiro ; Furukawa, Tetsushi. / Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25. In: Journal of cardiology. 2017 ; Vol. 70, No. 4. pp. 366-373.
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abstract = "Background Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. Methods We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. Results The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele (p = 0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis-regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles (p < 0.0001, p < 0.005, respectively). Conclusions AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level.",
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Ebana, Y, Ozaki, K, Liu, L, Hachiya, H, Hirao, K, Isobe, M, Kubo, M, Tanaka, T & Furukawa, T 2017, 'Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25', Journal of cardiology, vol. 70, no. 4, pp. 366-373. https://doi.org/10.1016/j.jjcc.2016.11.016

Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25. / Ebana, Yusuke; Ozaki, Kouichi; Liu, Lian; Hachiya, Hitoshi; Hirao, Kenzo; Isobe, Mitsuaki; Kubo, Michiaki; Tanaka, Toshihiro; Furukawa, Tetsushi.

In: Journal of cardiology, Vol. 70, No. 4, 01.10.2017, p. 366-373.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25

AU - Ebana, Yusuke

AU - Ozaki, Kouichi

AU - Liu, Lian

AU - Hachiya, Hitoshi

AU - Hirao, Kenzo

AU - Isobe, Mitsuaki

AU - Kubo, Michiaki

AU - Tanaka, Toshihiro

AU - Furukawa, Tetsushi

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Background Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. Methods We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. Results The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele (p = 0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis-regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles (p < 0.0001, p < 0.005, respectively). Conclusions AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level.

AB - Background Chromosome 4q25 has been repeatedly identified as atrial fibrillation (AF)-sensitive locus in multiple genome-wide association studies (GWAS) and is considered to hold some clues to AF pathogenesis. We aimed to investigate the clinical utilities in Japanese and to unveil the function of the 4q25 locus in affecting transcription of adjacent genes. Methods We conducted AF GWAS in Japanese population (1382 AF cases and 1478 controls) and the replication panel (1666 AF cases and 1229 controls) with detailed clinical information which showed the acceleration of AF onset. Stepwise investigations with linkage disequilibrium analysis, histone code patterns, and reporter assay in the 4q25 locus were performed. Results The AF GWAS confirmed a significant association of rs4611994 and rs1906617 in chromosome 4q25 with AF. In the clinical analysis, AF onset of the individuals with risk allele accelerated 2.5 years compared with those with protective allele (p = 0.00012). Next, in the functional analysis, three single nucleotide polymorphisms (SNPs) in the variant group selected by linkage disequilibrium analysis were identified as candidates for the cis-regulatory element toward adjacent genes in chromatin immunoprecipitation assay. Among them, rs4611994 and rs72900144 regions showed higher effects on the transcriptional activity of luciferase gene in the risk alleles than those in the protective alleles (p < 0.0001, p < 0.005, respectively). Conclusions AF GWAS in Japanese confirmed the association with 4q25 locus and indicated that its SNP affected the acceleration of AF onset. The candidate regions of the causative SNPs, rs4611994 and rs72900144, could alter the adjacent gene expression level.

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