Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes.
Recent reports have suggested that WNT signaling is an important regulator for adipogenesis or insulin secretion and might be involved in the pathogenesis of type 2 diabetes. To investigate possible roles of the WNT genes in conferring susceptibility to type 2 diabetes, we examined the association of the genes that encode members of the WNT family with type 2 diabetes in the Japanese population. First, 40 single-nucleotide polymorphism (SNP) loci within 11 WNT genes were analyzed in 188 subjects with type 2 diabetes (case-1) and 564 controls (control-1). Among them, six SNP loci exhibited a significant difference (P<.05) in the allele and/or genotype distributions between case and control subjects. These SNP loci were further analyzed in another set of case (case-2; n=733) and control (control-2; n=375) subjects to confirm their statistical significance. As a result, one SNP locus in the WNT5B gene was strongly associated with type 2 diabetes ( chi 2=15.6; P=.00008; odds ratio=1.74; 95% confidence interval 1.32-2.29). Expression of the WNT5B gene was detectable in several tissues, including adipose, pancreas, and liver. Subsequent in vitro experiments identified the fact that expression of the Wnt5b gene was increased at an early phase of adipocyte differentiation in mouse 3T3-L1 cells. Furthermore, overexpression of the Wnt5b gene in preadipocytes resulted in the promotion of adipogenesis and the enhancement of adipocytokine-gene expression. These results indicate that the WNT5B gene may contribute to conferring susceptibility to type 2 diabetes and may be involved in the pathogenesis of this disease through the regulation of adipocyte function.
Kanazawa
Akio
A
Laboratory for Diabetic Nephropathy, SNP Research Center, The Institute of Physical and Chemical Research, Kanagawa, Japan.
Tsukada
Syuuichi
S
Sekine
Akihiro
A
Tsunoda
Tatsuhiko
T
Takahashi
Atsushi
A
Kashiwagi
Atsunori
A
Tanaka
Yasushi
Y
Babazono
Tetsuya
T
Matsuda
Masafumi
M
Kaku
Kohei
K
Iwamoto
Yasuhiko
Y
Kawamori
Ryuzo
R
Kikkawa
Ryuichi
R
Nakamura
Yusuke
Y
Maeda
Shiro
S
D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D010179:Pancreas / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D051153:Wnt Proteins
D017931:DNA Primers; D011518:Proto-Oncogene Proteins; C435831:WNT5B protein, human; D051153:Wnt Proteins