Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes
Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes
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DOI：
10.1086/425340
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发表时间：
2004-11-01
影响因子：
9.8
通讯作者：
Maeda, S
中科院分区：
文献类型：
--
作者：
Kanazawa, A;Tsukada, S;Maeda, S
最近的报道表明，WNT信号是脂肪生成或胰岛素分泌的重要调节因子，可能参与了2型糖尿病的发病机制。为了研究WNT基因在2型糖尿病易感性中的可能作用，我们在日本人群中检测了编码WNT家族成员的基因与2型糖尿病的关联。首先，对188例2型糖尿病患者(例1)和564例对照组(对照组1)的11个WNT基因中的40个单核苷酸多态(SNP)位点进行了分析。其中6个SNP基因座在病例组和对照组之间的等位基因和/或基因型分布存在显著差异(P<0.05)。在另一组病例(病例2；)和对照(对照2；n=375)受试者中进一步分析这些SNP基因座，以确认它们的统计学意义。结果显示，WNT5B基因的一个SNP位点与2型糖尿病密切相关(X_1(2)=15.6；P=0.00008；优势比=1.74；95%可信区间1.32-2.29)。WNT5B基因在包括脂肪、胰腺和肝脏在内的几个组织中都有表达。随后的体外实验证实，在小鼠3T3-L1细胞的脂肪细胞分化早期，Wnt5b基因的表达增加。此外，Wnt5b基因在前脂肪细胞中的过表达还促进了脂肪的生成，增强了脂肪细胞因子基因的表达。这些结果表明，WNT5B基因可能与2型糖尿病的易感性有关，并可能通过调节脂肪细胞的功能参与2型糖尿病的发病。
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.