Polygenic Risk of Prediabetes, Undiagnosed Diabetes, and Incident Type 2 Diabetes Stratified by Diabetes Risk Factors

Abstract

Objective To investigate whether genetic risk of type 2 diabetes modifies associations between body mass index (BMI) and first degree family history of diabetes with 1) prevalent pre-diabetes or undiagnosed diabetes; and 2) incident confirmed type 2 diabetes. Methods We included 431,658 40-69 year olds at baseline of multi-ethnic ancestry from the UK Biobank. We used a multi-ethnic polygenic risk score for type 2 diabetes (PRS_T2D) developed by Genomics PLC. Pre-diabetes or undiagnosed diabetes was defined as baseline HbA1c ≥ 42 mmol/mol (6.0%) and incident type 2 diabetes was derived from medical records. Results At baseline, 43,472 participants had pre-diabetes or undiagnosed diabetes, and 17,259 developed type 2 diabetes over 15 years follow-up. Dose-response associations were observed for PRS_T2D with each outcome in each category of BMI or first degree family history of diabetes. Those in the highest quintile of PRS_T2D with a normal BMI, were at the similar risk as those in the middle quintile who were overweight. Participants who were in the highest quintile of PRS_T2D and did not have a first degree family history of diabetes were at the similar risk than those with a family history who were in the middle category of PRS_T2D. Conclusions Genetic risk of type 2 diabetes remains strongly associated with risk of pre-diabetes, undiagnosed diabetes and future type 2 diabetes within categories of non-genetic risk factors. This could have important implications for identifying individuals at risk of type 2 diabetes for prevention and early diagnosis programmes.