Genome-wide association study of plasma resistin levels identified rs1423096 and rs10401670 as possible functional variants in the Japanese population.
Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene (RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 whereRETNis located. The top-hit SNP was SNP -358 G>A, followed by rs1423096 C>T, SNP -420 C>G, and rs10401670 C>T (P= 5.39×10-47, 1.81×10-22, 2.09×10-16, and 9.25×10-15, respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3'-region ofRETNand were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.
Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan.
Ryoichi
R
Kawamura
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yasuharu
Y
Tabara
Matsumoto University Graduate School of Health Science, Nagano, Japan.
Akiko
A
Tsukada
Department of Geriatric Medicine & Neurology, Ehime University Graduate School of Medicine, Ehime, Japan.
Michiya
M
Igase
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
Jun
J
Ohashi
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Ryo
R
Yamada
Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan.
Yasunori
Y
Takata
Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
Ryuichi
R
Kawamoto
Department of Community Health Systems Nursing, Ehime University Graduate School of Medicine, Ehime, Japan.
Isao
I
Saito
Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan.
Hiroshi
H
Onuma
Department of Public Health, Juntendo University School of Medicine, Tokyo, Japan; and.
Takeshi
T
Tanigawa
Matsumoto University Graduate School of Health Science, Nagano, Japan.
Kazuya
K
Yamada
Department of Gene Diagnostics and Therapeutics Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Norihiro
N
Kato
Department of Geriatric Medicine & Neurology, Ehime University Graduate School of Medicine, Ehime, Japan.
Yasumasa
Y
Ohyagi
Department of Geriatric Medicine & Neurology, Ehime University Graduate School of Medicine, Ehime, Japan.
Tetsuro
T
Miki
Department of Geriatric Medicine & Neurology, Ehime University Graduate School of Medicine, Ehime, Japan.
Katsuhiko
K
Kohara
Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan; harosawa@m.ehime-u.ac.jp.
Haruhiko
H
Osawa
D000368:Aged; D044466:Asian People / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005260:Female; D017930:Genes, Reporter; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D052243:Resistin / Q000097:blood* / Q000235:genetics*
D009687:Nuclear Proteins; C499624:RETN protein, human; D052243:Resistin; D008156:Luciferases
SNP; genome-wide association study (GWAS), functional analysis; resistin