GRB10 Gene and Type 2 Diabetes in Whites

GRB10 encodes for an inhibitor of insulin receptor signaling [1] and is therefore a candidate for type 2 diabetes (T2D). In a preliminary study, the minor allele (MA) of GRB10 rs4947710 was associated with a reduced T2D risk in Whites from Italy, whereas a trend in the opposite direction, albeit not significant, was observed in Whites from the US [2], making the overall observation uncertain. A different GRB10 single nucleotide polymorphism (SNP) (rs2237457) has been recently associated with T2D among Amish but not in other populations [3], suggesting the possibility of allelic heterogeneity. To further investigate the role of GRB10 variability in modulating susceptibility to T2D in Whites, we genotyped rs4947710 and rs2237457 in a total of 3,433 diabetic cases (1899 males/1534 females; age=61.4±9.2 yrs; BMI=31.5±6.1 Kg/m²) and 2,660 non-diabetic controls (1153 males/1507 females; age=45.5±16.0 yrs; BMI=27.8±6.1 Kg/m²) of European origin included in the “GENetics of T2D in Italy and United States (GENIUS) Consortium”. The clinical characteristics of these subjects have been previously reported in details [4]. All samples, which included those from the previous smaller study (2), were genotyped by TaqMan allelic discrimination assay. The average agreement rate of duplicate samples was >99%. Failure rate of genotyping was <3.0%. Both rs4947710 (MA frequency=0.073) and rs2247457 (MA frequency=0.39) were in Hardy Weinberg equilibrium in controls and cases. Since no genetic heterogeneity across the four centers of recruitment was evident (p values for heterogeneity = 0.11 and 0.16 for rs4947710 and rs2247457, respectively), data were analyzed after pooling the four data sets together and adjusting for center of recruitment, age and sex. No significant association with T2D was observed with either rs4947710 (allelic OR, 95% CI=1.11, 0.92-1.33, adjusted p=0.30) or rs2247457 (OR, 95%CI=0.98, 0.89-1.09, adjusted p=0.73). These results are in agreement with those from the DIAGRAM data set [5], which did not show a significant association between T2D and either rs4947710 (OR, 95% CI =1.08, 0.99-1.17; p=0.1) or rs2237457 (OR, 95% CI=1.06, 0.99-1.13; p=0.1). In conclusion, GRB10 rs2237457 and rs4947710 do not seem to play a significant role in modulating susceptibility for T2D in individuals of European ancestry.