title: Confirmation of an association of single-nucleotide polymorphism rs1333040 on 9p21 with familial and sporadic intracranial aneurysms in Japanese patients.
abstract: OBJECTIVE
  Genetic factors are important determinants of intracranial aneurysm (IA). Recently, a multinational, genome-wide association study identified 3 loci associated with IA, located on 2q (rs700651), 8q (rs10958409), and 9p (rs1333040 and rs10757278). The aim of this study was to evaluate these associations.
  
  
  METHODS
  Familial and sporadic cases were investigated. Familial cases, consisting of 96 subjects with IA, and 46 subjects of unknown status from 31 pedigrees were analyzed with the transmission disequilibrium test and linkage analysis. Associations of single-nucleotide polymorphisms (SNPs) with IA were tested in 419 sporadic IA cases and in 408 control subjects. Sequencing of CDKN2A, CDKN2B, and CDKN2BAS revealed additional SNPs, and their associations with IA were also tested.
  
  
  RESULTS
  The transmission disequilibrium test revealed associations of 2 SNPs, rs700651 (P=0.036) and rs1333040 (P=0.002), with familial IA. Analysis of SNPs in sporadic cases revealed an allelic association of rs1333040 with IA (odds ratio=1.28; 95% CI, 1.04-1.57; P=0.02) but failed to show associations of rs10757278 and rs496892 with IA. We sequenced 3 candidate genes; CDKN2A, CDKN2B, and CDKN2BAS. All 6 index cases from IA families had the rs1333040-T allele and SNPs (rs10965215, rs10120688, and rs7341791) in CDKN2BAS. None of these SNPs had linkage disequilibrium with rs1333040 and was associated with IA.
  
  
  CONCLUSIONS
  A region between introns 7 and 15 of CDKN2BAS carrying the rs1333040-T allele may confer risk for IA.
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Hashikata
authors.forename: Wanyang
authors.initials: W
authors.lastname: Liu
authors.forename: Kayoko
authors.initials: K
authors.lastname: Inoue
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mineharu
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yamada
authors.forename: Shanika
authors.initials: S
authors.lastname: Nanayakkara
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takagi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000483:Alleles; D044466:Asian People; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005190:Family; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16