Molecular scanning of the human sorbin and SH3-domain-containing-1 (SORBS1) gene: positive association of the T228A polymorphism with obesity and type 2 diabetes

In the mouse, the SH3P12 or the c-Cbl-associated protein (CAP) has been sho wn as an important signaling molecule in insulin-stimulated glucose uptake. The human homolog for the sorbin and SH3-domain-containing-1 gene, termed SORBS1, might play a role in human disorders with insulin resistance. To ex plore the genetic role of SORBS1 in human obesity and type 2 diabetes, we i nvestigated the nucleotide polymorphisms in the SORBS1 gene with molecular scanning. After scanning for a total of 13 136 bp in each of 40 chromosomes , we have identified 14 single nucleotide polymorphisms (SNPs) in the human SORBS1 gene. Among them, two SNPs affected amino acid coding (R74W and T22 8A), four occurred within exons but did not affect amino acid coding, and t he remaining eight occurred within introns, which were located outside of t he consensus region of the splicing mechanism. Further studies in 202 non-o bese, 113 obese and 455 subjects with type 2 diabetes revealed that the A-a llele of the T228A polymorphism in exon 7 exerted a protective role for bot h obesity [relative risk 0.466; 95% confidence interval (95% CI) 0.265-0.82 1] and diabetes (relative risk 0.668; 95% CI 0.472-0.945). Neither allele o f the R74W polymorphism was associated with either obesity or diabetes. In conclusion, our results suggest that the A228 allele of the T228A polymorph ism of the SORBS1 gene is a protective factor for both obesity and diabetes , and also imply that the SORBS1 gene plays an important role in the pathog enesis of human disorders with insulin resistance.