UC Irvine

Prediabetes is a chronic metabolic condition characterized by impaired glucose regulation and represents an early stage in the progression toward type 2 diabetes. Both genetic susceptibility and lifestyle factors – including diet, physical activity, and smoking – contribute to abnormal glycemia. Although type 2 diabetes has been extensively studied, less is known about the genetic and environmental determinants of prediabetes. Importantly, prediabetes presents a critical window for intervention, as maintenance or reversion to normal glycemia remains possible. This study investigates whether prediabetes has distinct genetic determinants compared to type 2 diabetes and whether smoking modifies these associations, providing opportunities to identify individuals at risk earlier in disease development. Multinomial (polytomous) regression models evaluated genetic associations for 22 candidate SNPs with prediabetes or type 2 diabetes, as well as SNP-smoking interactions, using the multi-ethnic GENNID (Genetics of Non-Insulin Dependent Diabetes) family-based dataset. Overall, this study identified evidence of nominally significant genetic associations with both prediabetes and type 2 diabetes, but these associations varied across ancestry groups and did not support the hypothesis that prediabetes has distinct genetic determinants compared to type 2 diabetes. SNP-smoking interaction analyses provided evidence of effect modification for select SNP-glycemic status associations of nominal significance. These findings suggest that genetic contributions to dysglycemia in GENNID may be heterogeneous across ancestry and glycemic outcome, underscoring the importance of studying prediabetes directly.