title: Genetic variation in the carbonyl reductase 3 gene confers risk of type 2 diabetes and insulin resistance: a potential regulator of adipogenesis.
abstract: Prostaglandins are potent modulators of insulin sensitivity. We systemically evaluated the association of 61 tag single-nucleotide polymorphisms (SNP) in 14 genes involved in prostaglandin metabolism with type 2 diabetes. Among all genotyped SNPs, rs10483032 in the CBR3 (carbonyl reductase 3) gene, which encodes for an enzyme converting prostaglandin E(2) to prostaglandin F2(α), was associated with type 2 diabetes in 760 type 2 diabetic cases and 760 controls (stage-1 study) (P = 2.0 × 10(-4)). The association was validated in 1,615 cases and 1,162 controls (stage-2 study) (P = 0.009). The A allele at rs10483032 was associated with increased risk of type 2 diabetes (odds ratio = 1.29; 95% confidence interval = 1.14-1.47; combined P < 0.0001). The association was externally validated in the Finland-United States Investigation of NIDDM Genetics (FUSION) study (P = 3.7 × 10(-4)). The risk A allele was associated with higher homeostasis model assessment of insulin resistance (HOMA-IR) in 1,012 non-diabetic controls and 1,138 non-diabetic subjects from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. CBR3 gene expression in human abdominal adipose tissue was negatively associated with fasting insulin and HOMA-IR. CBR3 gene expression increased during differentiation of 3T3-L1 preadipocytes into adipocytes. Knockdown of CBR3 in 3T3-L1 preadipocytes enhanced adipogenesis and peroxisome proliferator-activator receptor-γ response element reporter activity. Our results indicated that genetic polymorphism in the CBR3 gene conferred risk of type 2 diabetes and insulin resistance in Chinese. The association was probably mediated through modulation of adipogenesis.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.forename: Pi-Hua
authors.initials: PH
authors.lastname: Liu
authors.forename: Yun-Chih
authors.initials: YC
authors.lastname: Tsai
authors.forename: Yen-Feng
authors.initials: YF
authors.lastname: Chiu
authors.forename: Shyang-Rong
authors.initials: SR
authors.lastname: Shih
authors.forename: Low-Tone
authors.initials: LT
authors.lastname: Ho
authors.forename: Wen-Jane
authors.initials: WJ
authors.lastname: Lee
authors.forename: Chieh-Hua
authors.initials: CH
authors.lastname: Lu
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: J David
authors.initials: JD
authors.lastname: Curb
authors.forename: Wei-Jei
authors.initials: WJ
authors.lastname: Lee
authors.forename: Po-Chu
authors.initials: PC
authors.lastname: Lee
authors.forename: You-Han
authors.initials: YH
authors.lastname: He
authors.forename: Jih-I
authors.initials: JI
authors.lastname: Yeh
authors.forename: Juey-Jen
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Tsai
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000818:Animals; D044466:Asian People; D001786:Blood Glucose / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D001786:Blood Glucose; D000429:Alcohol Oxidoreductases; C531130:CBR3 protein, human