Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population.
OBJECTIVE
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.


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
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.
Moritani
M
M
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Nomura
K
K
Tanahashi
T
T
Osabe
D
D
Fujita
Y
Y
Shinohara
S
S
Yamaguchi
Y
Y
Keshavarz
P
P
Kudo
E
E
Nakamura
N
N
Yoshikawa
T
T
Ichiishi
E
E
Takata
Y
Y
Yasui
N
N
Shiota
H
H
Kunika
K
K
Inoue
H
H
Itakura
M
M
D000328:Adult; D000368:Aged; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values
D004706:Endodeoxyribonucleases; D004720:Endonucleases; D006442:Glycated Hemoglobin; C523510:EXOG protein, human; C052391:endonuclease G