title: Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25.
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.
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ebana
authors.affiliation: Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Ozaki
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Lian
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hachiya
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirao
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Human Genetics and Disease Diversity, Graduate School of Medicine and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: t_furukawa.bip@mri.tmd.ac.jp.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
keywords: Atrial fibrillation; Chromosome 4q25; Genome-wide association study; Histone modification; Pulmonary vein isolation