on August 30, 2007
Published online before print August 30, 2007, doi: 10.1161/STROKEAHA.107.486225
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Submitted on February 23, 2007
From the Center for Molecular Medicine and Genetics (S.W., S.L., H.K., G.T.), Department of Surgery (H.K.), Department of Neurology (G.T.), Department of Obstetrics and Gynecology (S.L.), and Applied Genomics Technology Center (S.L.), Wayne State University, Detroit, Mich; the Department of Epidemiology and Biostatistics (K.A.B.G., A.R.P., Q.L., M.S.), Case Western Reserve University, Cleveland, Ohio; The Urals State Medical Academy (E.R.L., V.P.S.), Yekaterinburg, Russia; the Institute of Biochemistry and Genetics (E.K., R.K.), Ufa Research Center, Russian Academy of Sciences, Ufa, Russia; the Department of Neurosurgery (A.R., K.H., J.E.J.), Kuopio University Hospital, Kuopio, Finland; and the Department of Neurosurgery (M.N.), Helsinki University Central Hospital, Helsinki, Finland. * To whom correspondence should be addressed. E-mail: gerard.tromp{at}sanger.med.wayne.edu.
Background and Purpose—Genomewide DNA linkage analysis identified a susceptibility locus for intracranial aneurysm (IA) on chromosome 19q13 in the Finnish population, a region including the kallikrein gene cluster. We investigated the association of single nucleotide polymorphisms (SNPs) in the kallikrein gene cluster with IA in the Finnish population. Methods—We genotyped 18 haplotype-tagging SNPs spanning a 244 kbp region in the kallikrein gene cluster for 266 Finnish IA cases and 290 Finnish control subjects. In a second phase, we genotyped 2 SNPs (rs1722561 and rs1701946) in an additional set of 102 Finnish IA cases and 102 Finnish control subjects; and in a third phase, we genotyped these 2 SNPs in 156 Russian IA cases and 186 Russian control subjects. Both single-marker and haplotype-based tests of association were performed. Results—In phase I, SNPs rs1722561 and rs1701946 were significantly associated with IA in the Finnish population for single locus models (rs1722561: P=0.0395; rs1701946: P=0.0253). A 2-SNP haplotype block (rs1722561–rs1701946) identified in phase I was also associated with IA in the expanded Finnish (phase II) data set (asymptotic P=0.012; empirical P=0.019). In the Finnish and Russian combined data set (phase III) with 524 cases and 578 control subjects, the same 2 SNPs (OR: 1.35, 95% CI: 1.14, 1.60; P=0.0005 for rs1722561 and OR: 1.32, 95% CI: 1.12, 1.57; P=0.0011 for rs1701946) were significantly associated with IA. These SNPs are located in the intronic region of KLK8, although linkage disequilibrium could extend from rs268912–rs2250066, a Conclusions—Polymorphisms within the kallikrein gene cluster are associated with IA suggesting that the kallikreins are important candidate genes for IA.
Revised on April 2, 2007
Accepted on April 17, 2007
Association of Kallikrein Gene Polymorphisms With Intracranial Aneurysms
Shantel Weinsheimer PhD;
76-kbp region that includes KLK5–KLK10.
Key words: cerebrovascular disease • genetic association • genetics • polymorphism • subarachnoid hemorrhage
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