Impact of Candidate Genes on Obesity and Type 2 Diabetes

Abstract: Obesity and type 2 diabetes (T2D) have strong genetic components. Identification of susceptibility genes in both diseases will give better knowledge of their pathomechanisms and future therapies. In this thesis, the candidate gene approach was used to find genetic variations associated with obesity and T2D in a Swedish population, including controls with normal glucose tolerance (NGT), subjects with impaired glucose tolerance (IGT), patients with T2D and obese subjects. The candidate genes were selected based on previous studies and on their role in biological pathways relevant for determination of body composition and glucose homeostasis. Receptor protein tyrosine phosphatase sigma (RPTP?) (paper I) has a function in cellular receptor signaling and is highly expressed in insulin target tissues. We have previously shown that RPTP? is over-expressed in pancreatic islets and liver of spontaneously diabetic Goto–Kakizaki (GK) rats. Single nucleotide polymorphisms (SNPs) in the RPTP? gene were genotyped in NGT subjects, IGT subjects, and T2D patients. Three polymorphisms conferred susceptibility to T2D. SNP rs1143699 was associated with an increased risk of T2D in male patients carrying the C/C genotype. SNPs rs4807015 and rs1978237 were associated with an increased risk of T2D in both male and female patients. Zn-?2-glycoprotein 1 (AZGP1) (paper II) is a novel adipokine that may be involved in the regulation of body weight. Through microarray gene expression we found that the AZGP1 gene was down-regulated 3.9-fold in subcutaneous (S.C.) abdominal fat of NGT obese subjects compared to lean. We also showed that AZGP1 is significantly decreased in S.C. abdominal and omental fat but not in S.C. thigh fat. Genotyping of AZGP1 polymorphisms in NGT lean subjects, NGT obese subjects, IGT obese subjects and T2D patients revealed that SNP rs2525554 is associated with obesity. Association with the T-allele was evident for BMI, waist circumference, waist-hip ratio and 2h glucose. Decreased AZGP1 expression in obese subjects was found to correlate with their higher frequency of risk allele T in rs2525554. Alpha 2-adrenergic receptors are involved in insulin secretion and lipolysis. We evaluated association for the adrenergic receptor alpha 2A (ADRA2A) gene (paper III) with obesity and/or T2D in our cohort. Data indicate that two SNPs, rs553668 and rs521674, are associated with disease. rs553668 in men is linked to obesity and rs521674 in women to obesity and possibly T2D. Adenylate cyclase 3 (AC3) (paper IV) is expressed in pancreatic islets, brain, heart, kidney, liver, lung and skeletal muscle. A previous study from our laboratory demonstrated that the AC3 mRNA was overexpressed in the pancreatic islets of the GK rat. In our association study for the AC3 gene it was found that SNPs rs2033655 and rs1968482 are strongly associated with obesity in NGT subjects and T2D patients. A diplotype analysis with the associated polymorphisms predicted a significant association with BMI in obese subjects. The results from the four candidate gene association studies have generated knowledge of their role in obesity and T2D development. RPTP? seems to be involved in T2D whereas AZGP1, ADRA2A and AC3 are most likely linked to obesity. Two studies also revealed gender specific associations. The associated variants need to be investigated further regarding function, gene-gene and gene-environment interactions.