Association of single-nucleotide polymorphisms in the suppressor of cytokine signaling 2 (SOCS2) gene with type 2 diabetes in the Japanese.
Several previous linkage scans in type 2 diabetes (T2D) families indicated a putative susceptibility locus on chromosome 12q15-q22, while the underlying gene for T2D has not yet been identified. We performed a region-wide association analysis on 12q15-q22, using a dense set of >500 single-nucleotide polymorphisms (SNPs), in 1492 unrelated Japanese individuals enrolled in this study. We identified an association between T2D and a haplotype block spanning 13.6 kb of genomic DNA that includes the entire SOCS2 gene. Evolutionary-based haplotype analysis of haplotype-tagging SNPs followed by a "sliding window" haplotypic analysis indicated SNPs that mapped to the 5' region of the SOCS2gene to be associated with T2D with high statistical significance. The SOCS2 gene was expressed ubiquitously in human and murine tissues, including pancreatic beta-cell lines. Adenovirus-mediated expression of the SOCS2 gene in MIN6 cells or isolated rat islets significantly suppressed glucose-stimulated insulin secretion. Our data indicate that SOCS2 may play a role in susceptibility to T2D in the Japanese.
Kato
Hitoshi
H
Molecular Medicine Research Laboratories, Drug Discovery Research, Astellas Pharma, Inc., Tokyo, Japan.
Nomura
Kyoko
K
Osabe
Dai
D
Shinohara
Shuichi
S
Mizumori
Osamu
O
Katashima
Rumi
R
Iwasaki
Shoji
S
Nishimura
Koichi
K
Yoshino
Masayasu
M
Kobori
Masato
M
Ichiishi
Eiichiro
E
Nakamura
Naoto
N
Yoshikawa
Toshikazu
T
Tanahashi
Toshihito
T
Keshavarz
Parvaneh
P
Kunika
Kiyoshi
K
Moritani
Maki
M
Kudo
Eiji
E
Tsugawa
Kazue
K
Takata
Yoichiro
Y
Hamada
Daisuke
D
Yasui
Natsuo
N
Miyamoto
Tatsuro
T
Shiota
Hiroshi
H
Inoue
Hiroshi
H
Itakura
Mitsuo
M
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006239:Haplotypes; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011863:Radioimmunoassay; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*
D007328:Insulin; C106643:SOCS2 protein, human; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D005947:Glucose