A Type 1 diabetes genetic risk score can aid discrimination between Type 1 and Type 2 diabetes in young adults

Abstract

Objectives

With rising obesity, it is becoming increasingly difficult to distinguish between Type 1 (T1D) and Type 2 diabetes (T2D) in young adults. There has been substantial recent progress in identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also predict severe insulin deficiency in young adults with diabetes.

Research Design and Methods

We developed genetic risk scores (GRS) from published T1D and T2D-associated variants. We first tested whether the scores could distinguish clinically-defined T1D and T2D from the Wellcome Trust Case Control Consortium (WTCCC, n=3,887). We then assessed if the T1D-GRS correctly classified young adults (diagnosed 20-40 years, the age group with the most diagnostic difficulty in clinical practice; n=223) who progressed to severe insulin deficiency <3 years from diagnosis.

Results

In the WTCCC a T1D-GRS based on 30 T1D-associated risk variants was highly discriminative of T1D and T2D (AUC=0.88 [95%CI: 0.87-0.89], P<0.0001), the T2D-GRS added little discrimination (AUC=0.89). A T1D-GRS >0.280 (>50 ^th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D-GRS score <0.234 (<5 ^th centile T1D) is indicative of T2D (53% sensitivity, 95% specificity). Most discriminative ability was obtained from just 9 SNPs (AUC=0.87).

In young adults with diabetes T1D-GRS alone predicted progression to insulin deficiency (AUC=0.87 [95%CI:0.82-0.92], P<0.0001). T1D-GRS, autoantibody status and clinical features were independent and additive predictors of severe insulin deficiency (combined AUC=0.96 [95%CI:0.94-0.99], P<0.0001).

Conclusions

A T1D-GRS can accurately identify young adults with diabetes who will require insulin treatment. This will be an important addition to correctly classifying individuals with diabetes when clinical features and autoimmune markers are equivocal.