Published Online
on April 17, 2006

A more recent version of this article appeared on April 25, 2006

This Article Full Text (PDF) Data Supplement All Versions of this Article: 113/16/2002    most recent CIRCULATIONAHA.105.579326v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inoue, K. Articles by Koizumi, A. Search for Related Content PubMed PubMed Citation Articles by Inoue, K. Articles by Koizumi, A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene UniSTS Genetics Home Reference Related Collections Genetics of Stroke

Submitted on July 29, 2005
Revised on February 24, 2006
Accepted on February 28, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: koizumi{at}pbh.med.kyoto-u.ac.jp.

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.

Key words: aneurysm • cerebrovascular disorders • genes • immune system

This article has been cited by other articles:

				Y. Mineharu, W. Liu, K. Inoue, N. Matsuura, S. Inoue, K. Takenaka, H. Ikeda, K. Houkin, Y. Takagi, K. Kikuta, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3 Neurology, June 10, 2008; 70(24_Part_2): 2357 - 2363. [Abstract] [Full Text] [PDF]

				Y. M. Ruigrok and G. J.E. Rinkel Genetics of Intracranial Aneurysms Stroke, March 1, 2008; 39(3): 1049 - 1055. [Abstract] [Full Text] [PDF]

				S. Weinsheimer, G. M. Lenk, M. van der Voet, S. Land, A. Ronkainen, I. Alafuzoff, H. Kuivaniemi, and G. Tromp Integration of expression profiles and genetic mapping data to identify candidate genes in intracranial aneurysm Physiol Genomics, December 19, 2007; 32(1): 45 - 57. [Abstract] [Full Text] [PDF]

				D. A. Tregouet and V. Garelle A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies Bioinformatics, April 15, 2007; 23(8): 1038 - 1039. [Abstract] [Full Text] [PDF]

				Y. Mineharu, K. Inoue, S. Inoue, S. Yamada, K. Nozaki, N. Hashimoto, and A. Koizumi Model-Based Linkage Analyses Confirm Chromosome 19q13.3 as a Susceptibility Locus for Intracranial Aneurysm Stroke, April 1, 2007; 38(4): 1174 - 1178. [Abstract] [Full Text] [PDF]

				M. Dichgans and R. A. Hegele Update on the Genetics of Stroke and Cerebrovascular Disease 2006 Stroke, February 1, 2007; 38(2): 216 - 218. [Full Text] [PDF]

				Y Mineharu, K Takenaka, H Yamakawa, K Inoue, H Ikeda, K-I Kikuta, Y Takagi, K Nozaki, N Hashimoto, and A Koizumi Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting J. Neurol. Neurosurg. Psychiatry, September 1, 2006; 77(9): 1025 - 1029. [Abstract] [Full Text] [PDF]