Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population |
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| Authors: | M. Moritani K. Nomura T. Tanahashi D. Osabe Y. Fujita S. Shinohara Y. Yamaguchi P. Keshavarz E. Kudo N. Nakamura T. Yoshikawa E. Ichiishi Y. Takata N. Yasui H. Shiota K. Kunika H. Inoue M. Itakura |
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| Affiliation: | (1) Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan;(2) Department of Bioinformatics, Division of Life Science System, Fujitsu Limited, Tokyo, Japan;(3) Department of Human Pathology, Division of Medico-Dental Dynamics and Reconstruction, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan;(4) Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan;(5) New Industry Creation Hatchery Center, Tohoku University, Miyagi, Japan;(6) Department of Orthopedics, Institute of Health Bioscience, The University of Tokushima, Tokushima, Japan;(7) Department of Ophthalmology and Visual Neuroscience, Institute of Health Bioscience, The University of Tokushima, Tokushima, Japan |
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| Abstract: | Aims/hypothesis In order to identify type 2 diabetes disease susceptibility gene(s) in a Japanese population, we applied a region-wide case–control association test to the 20.4 Mb region between D3S1293 and D3S2319 on chromosome 3p24.3-22.1, supported by linkage to type 2 diabetes and its related traits in Japanese and multiple populations. Materials and methods We performed a two-stage association test using 1,762 Japanese persons with 485 gene-centric, evenly spaced, common single nucleotide polymorphism (SNP) markers with minor allele frequency >0.1. For mouse studies, total RNA was extracted from various organs of BKS.Cg-+Lepr db /+Lepr db and control mice, and from MIN6, NIH3T3 and C2C12 cell lines. Results We detected a landmark SNP375 (A/G) (rs2051211, p = 0.000046, odds ratio = 1.33, 95% CI 1.16–1.53) in intron 5 of the endonuclease G-like 1 (ENDOGL1) gene. Systematic dense SNPs approach identified a susceptibility linkage disequilibrium (LD) block of 116.5 kb by |D′|, an LD units map and a critical region of 2.1 kb by r 2 in ENDOGL1. A haplotype-based association test showed that an at-risk haplotype is associated with disease status (p = 0.00001). The expression of ENDOGL1 was rather ubiquitous with relatively abundant expression in the brain and also in a pancreatic islet beta cell line. Mouse Endogl1 expression increased in pancreatic islets of hyperglycaemic BKS.Cg-+Lepr db /+Lepr db mice compared with that in control mice. Conclusions/interpretation Based on the population genetics, fine mapping of LD block and haplotype analysis, we conclude that ENDOGL1 is a candidate disease-susceptibility gene for type 2 diabetes in a Japanese population. Further analysis in a larger sample size is required to substantiate this conclusion. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. |
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| Keywords: | ENDOGL1 gene Evenly-spaced common SNP marker Fine mapping Haplotype analysis LD block Single nucleotide polymorphisms (SNPs) Type 2 diabetes |
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