Identification of susceptibility genes in type 2 diabetes

Identification of the susceptibility genes will offer better understanding of molecular mechanisms underlying T2D pathogenesis, and subsequently may lead to development of novel therapeutic approaches. This thesis mainly concerns the genetic association study of four candidate genes. They are selected from a region in chromosome 10q linked to T2D or based on involvement of the candidates in specific pathways related to T2D.

IDE plays a principal role in the proteolysis of several peptides in addition to insulin. The gene resides in a region of chromosome 10q linked to T2D. Fourteen SNPs in the IDE and IDE-HHEX regions were genotyped in 321 IGT and 403 NGT subjects selected from SDPP. The analyses of diplotypes (haplotypic genotypes) containing three tag SNPs provided evidence of the association with fasting plasma insulin levels, 2h plasma insulin levels, HOMA-IR and BMI in men, and suggested that the polymorphisms in/near the IDE gene contribute to variance in plasma insulin levels and correlated traits. The TCF7L2 gene is also located in the region of chromosome 10q. Five SNPs in the gene were genotyped in 243 T2D patients and 528 NGT subjects, and they were Swedish men. SNPs rs7901695, rs4506565, rs7903146 and rs12255372 are strongly associated with T2D. As to rs7903146, T2D patients carrying genotypes CT or TT had higher fasting plasma glucose levels, lower HOMA-β index and BMI compared to the patients carrying CC genotype. Furthermore, NGT subjects carrying the risk alleles of SNPs rs7901695 and rs4506565 demonstrated a more pronounced increase in fasting plasma glucose levels during the follow-up period. The study consistently indicated that TCF7L2 has a crucial contribution to impaired insulin secretion underlining the development of T2D. In order to evaluate whether Leu7Pro (T1128C) polymorphism in the NPY gene contributes to the development of T2D, genotyping of this SNP in 263 T2D patients, 309 IGT and 469 NGT subjects was performed. This SNP was significantly associated with IGT and T2D among Swedish men but not women. The carriers with TC and CC genotypes in male IGT subjects had significantly higher fasting plasma glucose in comparison with the TT carriers. A previous study using the Goto-Kakizaki rat implicated that AC3 may be a candidate for T2D. The variation screening in the putative promoter was performed and a novel variant -17A/T was identified. Genotyping of 14 SNPs covering the gene, including the novel variant, was performed in male subjects, including 243 T2D and 188 NGT. Interestingly, SNPs rs2033655 C/T and rs1968482 A/G were significantly associated with T2D patients with BMI ≥30 kg/m2. Further genotyping and analysis in 199 male obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity. The present study thus provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without T2D.

In conclusion, this thesis has contributed with information on the role of the IDE, TCF7L2 and NPY genes in the development of T2D and/or control of insulin levels. AC3 may play a role in the development of obesity with and without T2D.

List of scientific papers

I. Gu HF, Efendic S, Nordman S, Ostenson CG, Brismar K, Brookes AJ, Prince JA (2004). Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels. Diabetes. 53(8): 2137-42.
https://pubmed.ncbi.nlm.nih.gov/15277398

II. Nordman S, Ostenson CG, Efendic S, Gu HF (2008). Effects of the Transcription factor 7 like 2 (TCF7L2) genetic polymorphisms in type 2 diabetes among Swedish men. [Submitted]

III. Nordman S, Ding B, Ostenson CG, Kärvestedt L, Brismar K, Efendic S, Gu HF (2005). Leu7Pro polymorphism in the neuropeptide Y (NPY) gene is associated with impaired glucose tolerance and type 2 diabetes in Swedish men. Exp Clin Endocrinol Diabetes. 113(5): 282-7.
https://pubmed.ncbi.nlm.nih.gov/15926114

IV. Nordman S, Abulaiti A, Hilding A, Långberg EC, Humphreys K, Ostenson CG, Efendic S, Gu HF (2007). Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men. Int J Obes. Sep 25: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/17895882