Abstract and Introduction
Abstract
Context: Early diagnosis of type 2 diabetes is crucial to reduce severe comorbidities and complications. Current screening recommendations for type 2 diabetes include traditional risk factors, primarily body mass index (BMI) and family history, however genetics also plays a key role in type 2 diabetes risk. It is important to understand whether genetic predisposition to type 2 diabetes modifies the effect of these traditional factors on type 2 diabetes risk.
Objective: This work aimed to investigate whether genetic risk of type 2 diabetes modifies associations between BMI and first-degree family history of diabetes with 1) prevalent prediabetes or undiagnosed diabetes; and 2) incident confirmed type 2 diabetes.
Methods: We included 431 658 individuals aged 40 to 69 years at baseline of multiethnic ancestry from the UK Biobank. We used a multiethnic polygenic risk score for type 2 diabetes (PRST2D) developed by Genomics PLC. Prediabetes or undiagnosed diabetes was defined as baseline glycated hemoglobin greater than or equal to 42 mmol/mol (6.0%), and incident type 2 diabetes was derived from medical records.
Results: At baseline, 43 472 participants had prediabetes or undiagnosed diabetes, and 17 259 developed type 2 diabetes over 15 years follow-up. Dose-response associations were observed for PRST2D with each outcome in each category of BMI or first-degree family history of diabetes. Those in the highest quintile of PRST2D with a normal BMI were at a similar risk as those in the middle quintile who were overweight. Participants who were in the highest quintile of PRST2D and did not have a first-degree family history of diabetes were at a similar risk as those with a family history who were in the middle category of PRST2D.
Conclusion: Genetic risk of type 2 diabetes remains strongly associated with risk of prediabetes, undiagnosed diabetes, and future type 2 diabetes within categories of nongenetic risk factors. This could have important implications for identifying individuals at risk of type 2 diabetes for prevention and early diagnosis programs.
Introduction
Diabetes prevalence has grown substantially in recent decades.[1,2] In 2021, an estimated 10.5% of the global population was living with diabetes, 90% of whom had type 2 diabetes.[1,2] This trend is set to continue and is partially attributable to an increase in the prevalence of overweight and obesity, with a high body mass index (BMI) being the strongest risk factor for type 2 diabetes.[1–4]
Genetic variation also plays a key role, with type 2 diabetes estimated to be between 30% and 70% heritable.[5] Recent genome-wide association studies have identified hundreds of genetic variants implicated in type 2 diabetes risk.[6,7] These variants can be summarized in a polygenic risk score (PRS) that provides an overall measure of an individual's inherited predisposition to type 2 diabetes.[8] Consequently, there is growing interest in incorporating genetics into prediction tools to identify high-risk individuals for type 2 diabetes to target for preventive care.[9] Early diagnosis is particularly important, as individuals with undiagnosed type 2 diabetes or prediabetes are at greater risk of developing severe complications and comorbidities.[2,10,11] However, PRSs are a relatively recent development and are not currently used in clinical settings or included in screening recommendations.[12] In 2021, the US Preventive Services Task Force (USPSTF) recommended that overweight or obese adults aged 35 to 70 years be screened for prediabetes or type 2 diabetes by clinicians.[12] The USPSTF also recommended that those with a family history of diabetes be considered for screening at younger ages.[12] Given these recommendations and the increasing interest in using PRSs in clinical settings, it is important to understand whether type 2 diabetes PRSs modify the association between BMI or first-degree family history of diabetes and 1) prediabetes or undiagnosed diabetes and 2) future risk of type 2 diabetes. We investigated this in a population-based cohort of approximately 431 000 initially middle-aged participants of multiethnic ancestry from the UK Biobank (UKB) with genotyping data, glycated hemoglobin (HbA1c) to determine prediabetes and undiagnosed diabetes at baseline, and follow-up over 15 years to capture incident type 2 diabetes diagnoses.
J Endo Soc. 2023;7(4) © 2023 Endocrine Society