Published in:
01-06-2007 | Article
Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population
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
Published in:
Diabetologia
|
Issue 6/2007
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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.