Type 1 diabetes genetic risk score is discriminative of diabetes in non-Europeans: evidence from a study in India

James W Harrison,Giriraj R Chandak,Kalpana S Jog,Seth A Sharp,Michael N Weedon,Seema Bhaskar,Kashyap A Patel,Divya Sri Priyanka Tallapragada,Richard A Oram,Chittaranjan S Yajnik,Alma Baptist

doi:10.1038/s41598-020-65317-1

Abstract

Type 1 diabetes (T1D) is a significant problem in Indians and misclassification of T1D and type 2 diabetes (T2D) is a particular problem in young adults in this population due to the high prevalence of early onset T2D at lower BMI. We have previously shown a genetic risk score (GRS) can be used to discriminate T1D from T2D in Europeans. We aimed to test the ability of a T1D GRS to discriminate T1D from T2D and controls in Indians. We studied subjects from Pune, India of Indo-European ancestry; T1D (n = 262 clinically defined, 200 autoantibody positive), T2D (n = 345) and controls (n = 324). We used the 9 SNP T1D GRS generated in Europeans and assessed its ability to discriminate T1D from T2D and controls in Indians. We compared Indians with Europeans from the Wellcome Trust Case Control Consortium study; T1D (n = 1963), T2D (n = 1924) and controls (n = 2938). The T1D GRS was discriminative of T1D from T2D in Indians but slightly less than in Europeans (ROC AUC 0.84 v 0.87, p < 0.0001). HLA SNPs contributed the majority of the discriminative power in Indians. A T1D GRS using SNPs defined in Europeans is discriminative of T1D from T2D and controls in Indians. As with Europeans, the T1D GRS may be useful for classifying diabetes in Indians.

Highlights

We and others have previously shown that a Type 1 diabetes (T1D) genetic risk score (T1D GRS) comprising of between 9 and 67 SNPs can be a useful tool to aid the discrimination between T1D and type 2 diabetes (T2D) or controls in Europeans[3,4,5,6]
Was higher in people with autoantibody positive T1D (n = 200) than in people with clinical T1D but who were autoantibody negative (n = 62). This suggested that there may be some cases of misclassified T1D in the clinically defined cohort, so we proceeded using only those with clinical T1D and a positive autoantibody for the remainder of the analysis
The power of the 9 SNP GRS to discriminate people with T1D from people with T2D was slightly lower in Indians compared to Europeans (ROC area under the curve (AUC) [95% CI] 0.84 [0.80–0.87] vs 0.87 [0.86–0.88] respectively, P < 0.0001, Fig. 1B)

Summary

Introduction

We and others have previously shown that a T1D genetic risk score (T1D GRS) comprising of between 9 and 67 SNPs can be a useful tool to aid the discrimination between T1D and T2D or controls in Europeans[3,4,5,6]. The majority of the discriminative power of the T1D GRS is in the first 9 SNPs when ranked by effect size[3]. These 9 SNPS include SNPs tagging the high-risk HLA DR3-DQ2.5 (DR3)/DR4-DQ8 (DR4) alleles and the highly protective HLA DR15-DQ6.2 (DR15) allele. In this study we aimed to assess if the T1D GRS developed in Europeans discriminates T1D from T2D and controls in Indians and could aid diabetes classification in this population

Objectives

Methods

Results

Conclusion