Confirmation of an association of single-nucleotide polymorphism rs1333040 on 9p21 with familial and sporadic intracranial aneurysms in Japanese patients.
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.
Hashikata
Hirokuni
H
Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
Liu
Wanyang
W
Inoue
Kayoko
K
Mineharu
Yohei
Y
Yamada
Shigeki
S
Nanayakkara
Shanika
S
Matsuura
Norio
N
Hitomi
Toshiaki
T
Takagi
Yasushi
Y
Hashimoto
Nobuo
N
Miyamoto
Susumu
S
Koizumi
Akio
A
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
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16