Association of SH-2 Containing Inositol 5'-phosphatase 2 Gene Polymorphisms and Hyperglycemia

Objectives: SH-2 containing inositol 5'-phosphatase 2 (SHIP2) is a family of inositol 5'-phosphatases, which possess the 5'-phosphatase activity that hydrolyzes phosphatidylinositol-3, 4, 5-trisphosphate to phosphatidylinositol-3, 4-bisphosphate and is suspected to negatively regulates the metabolic signaling of insulin. To clarify the possible involvement of SHIP2 in physiological abnormalities, we examined the human SHIP2 gene polymorphism in a Japanese cohort.

Methods: We searched single-nucleotide polymorphisms (SNPs) on the human SHIP2 gene promoter and 5'-untranslated region (5'-UTR) and investigated their relationship with impaired fasting glycemia (IFG) in a Japanese cohort. Next, the effect of the SNPs on promoter activity was examined in HeLa and HL60 cells.

Results: Among the several SNPs detected on the human SHIP2 gene promoter and 5'-UTR, 3 SNPs (-405 C/A, +57 G/A, and +334 C/T) formed the haplotypes CGC and AAT and were found at a relatively high frequency in the Japanese population. The frequency of genotypes (+334 CT and TT) was significantly higher in the group with IFG than in the normal group (P < 0.0001, odds ratio = 2.23, 95% confidence interval = 1.50-3.32). This association was not affected by age and gender. Furthermore, one haplotype (+57 A, +334 T) which was inserted into a luciferase reporter plasmid and existed more frequently in the IFG group than in the normal group exhibited increased promoter activity in the culture cells compared with the other haplotype (+57 G, +334 C).

Conclusions: The SNPs in the SHIP2 gene promoter and the 5'-UTR may account partly for the IFG and may be a marker for the risk of diabetes.