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(Circulation. 2006;113:2002-2010.)
© 2006 American Heart Association, Inc.

Stroke

Search on Chromosome 17 Centromere Reveals TNFRSF13B as a Susceptibility Gene for Intracranial Aneurysm

A Preliminary Study

Kayoko Inoue, MD, MPH, PhD; Youhei Mineharu, MD; Sumiko Inoue, PhD; Shigeki Yamada, MD, PhD; Fumihiko Matsuda, PhD; Kazuhiko Nozaki, MD, PhD; Katsunobu Takenaka, MD, PhD; Nobuo Hashimoto, MD, PhD; Akio Koizumi, MD, PhD

From the Department of Health and Environmental Sciences (K.I., Y.M., S.I., A.K.), Department of Neurosurgery (Y.M., S.Y., K.N., N.H.), Center for Genomic Medicine (F.M.); Kyoto University Graduate School of Medicine, Kyoto, Japan; and the Department of Neurosurgery, Takayama Red Cross Hospital (K.T.), Gifu, Japan.

Correspondence to Akio Koizumi, MD, PhD, Professor, Department of Health and Environmental Sciences, Graduate School of Medicine Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. E-mail koizumi{at}pbh.med.kyoto-u.ac.jp

Received July 29, 2005; revision received February 24, 2006; accepted February 28, 2006.

Background— Our previous studies have shown a significant linkage of intracranial aneurysms (IAs) to chromosome 17.

Methods and Results— Nine genes (TNFRSF13B, M-RIP, COPS3, RAI1, SREBF1, GRAP, MAPK7, MFAP4, and AKAP10) were selected from 108 genes that are located between D17S1857 and D17S1871 by excluding 99 genes that were pseudogenes, hypothetical genes, or well-characterized genes but not likely associated with IA. Direct sequencing of all coding and regulatory regions in 58 cases (29 pedigree probands and 29 unrelated nonpedigree cases) was performed. Deleterious changes were found only in TNFRSF13B, K154X, and c.585 to 586insA in exon4. The association of IA with TNFRSF13B was further studied in 304 unrelated cases and 332 control subjects. Rare nonsynonymous changes, a splicing acceptor site change and a frame shift, were found in unrelated cases (2.3%; 14 of 608) more frequently than in control subjects (0.8%; 5 of 664; P=0.035). The association study using single-nucleotide polymorphisms in an unrelated case-control cohort revealed a protective haplotype (odds ratio 0.69, 95% confidence interval 0.52 to 0.92, P=0.012) compared with the major haplotype after adjustment for covariates.

Conclusions— We propose that TNFRSF13B is one of the susceptibility genes for IA.

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