Association of SH-2 containing inositol 5'-phosphatase 2 gene polymorphisms and hyperglycemia.
OBJECTIVE
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.
Ishida
Satoru
S
Institute for Clinical Research, National Kyushu Cancer Center, Fukuoka, Japan.
Funakoshi
Akihiro
A
Miyasaka
Kyoko
K
Shimokata
Hiroshi
H
Ando
Fujiko
F
Takiguchi
Soichi
S
D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism; D007564:Japan; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D014162:Transfection
D020121:5' Untranslated Regions; D008156:Luciferases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases