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(Stroke. 2009;40:1245.)
© 2009 American Heart Association, Inc.

Original Contributions

Lack of Association Between Variations of PDE4D and Ischemic Stroke in the Japanese Population

Tomonaga Matsushita, MD; Michiaki Kubo, MD, PhD; Koji Yonemoto, PhD; Toshiharu Ninomiya, MD, PhD; Kyota Ashikawa; Bailing Liang; Jun Hata, MD, PhD; Yasufumi Doi, MD, PhD; Takanari Kitazono, MD, PhD; Setsuro Ibayashi, MD, PhD; Mitsuo Iida, MD, PhD; Yutaka Kiyohara, MD, PhD Yusuke Nakamura, MD, PhD

From the Laboratory for Genotyping Development (T.M., M.K., K.A., B.L.), Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Kanagawa, Japan; the Departments of Clinical Sciences (T.M., M.K., T.K., S.I., M.I.) and Environmental Medicine (M.K., K.Y., T.N., J.H., Y.D., Y.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and the Laboratory for Molecular Medicine (Y.N.), Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Correspondence to Michiaki Kubo, MD, PhD, Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan. E-mail mkubo{at}src.riken.jp

Background and Purpose— After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted. However, the validity of the association has remained controversial because of the heterogeneity of both genetic markers and phenotypes.

Methods— We investigated the association between variations of PDE4D and ischemic stroke by 3 methods: single-marker, haplotype, and tag-single nucleotide polymorphism (SNP) analyses. In the single-marker analysis, we evaluated the association using 2 large case–control samples (1112 cases and 1112 control subjects in a sample obtained from Kyushu, Japan, and 1711 cases and 1786 control subjects in BioBank Japan) and a prospective cohort with 14 years of follow-up. These samples were analyzed both separately and pooled. Haplotype and tag-SNP analyses were performed using the 2 case–control samples together.

Results— In single-marker association tests, we found no significant association in the same direction among the 6 SNP reported in the initial study and ischemic stroke subtypes. Haplotype analysis revealed no significant association between the region around the 5'-end of the gene and combined atherothrombotic and cardioembolic infarction. Rs7730070, a SNP located around the 3'-end of PDE4D, showed the lowest nominal probability value by tag-SNP analysis but was not significant after adjustment for multiple testing (adjusted probability value =0.36).

Conclusions— These results suggest that variations in PDE4D are not associated with ischemic stroke risk in the Japanese population.

Key Words: cerebral infarct • genetics • PDE4D