HLA haplotype diversity, islet autoantibody status and discriminative ability of type 1 diabetes genetic risk score in Indians

Aims: We have reported that a 9SNPs type 1 diabetes (T1D) Genetic Risk Score (GRS) developed from European data had a lower power in Indians to distinguish T1D from type 2 diabetes (T2D). We explore the performance of an improved (67SNPs) T1DGRS and also the potential reasons for lower discriminative ability to classify types of diabetes in Indians. Methods: We studied the discriminative ability of a 67SNPs European T1DGRS in 611 clinically diagnosed T1D and 1153 T2D patients, and 321 non-diabetic controls, using receiver operating characteristic (ROC) area under the curve (AUC). We also compared the frequency and effect sizes of HLA risk haplotypes between Indians and Europeans. Results: The T1DGRS was discriminative of T1D from T2D and controls. However, the ability is lower in Indians than Europeans (AUC, Europeans 0.92, Indians all T1D 0.83, AA-positive 0.86). The T1DGRS was higher in AA-positive than in AA-negative persons [13.01 (12.79–13.23) vs. 12.09 (11.64–12.56)], p < 0.0001. The association of common HLA-DQA1 ~ HLA-DQB1 haplotypes was broadly similar; however, important differences were noted in the frequency, direction and magnitude of effect for some haplotypes between Indians and Europeans. Conclusions: We confirm broad applicability of European 67SNPs T1DGRS to Indian T1D persons. However, differences in HLA allele frequencies, magnitude and directional differences reduced the predictive value. Our results stress the need to generate ancestry-specific GRS, which we plan to do in the near future.