The Interaction Between HDL-C Level and HNF4A rs4812829 on Incident Type 2 Diabetes Risk in a Chinese Cohort

Background/Objectives: To evaluate the association between HNF4A rs4812829 and type 2 diabetes (T2D) in a rural Chinese population and to investigate its interaction with blood lipids in the association. Methods: A total of 4496 participants free of diabetes at baseline from a family-based cohort in rural China were included. Demographic, lifestyle, and medical history data were collected via standardized questionnaires. Anthropometric and biochemical measurements were performed using standardized protocols and automated assays on fasting blood samples. Mixed-effects Cox proportional hazards models, accounting for familial clustering, were employed to examine the association between HNF4A rs4812829 and incident T2D risk. Additionally, multiplicative interaction terms were used to assess interactions. Results: After a median follow-up of 10.76 years, 895 incident T2D cases were identified. Under an additive genetic model, each additional G allele of rs4812829 was significantly associated with an increased risk of T2D (HR 1.38, 95% CI 1.19-1.59). A significant multiplicative interaction was observed between rs4812829 and HDL-C (p = 0.004). In genotype-stratified analyses, higher HDL-C levels were strongly associated with lower T2D risk among AA homozygotes (HR 0.04, 95% CI 0.003-0.43) and AG heterozygotes (HR 0.30, 95% CI 0.10-0.84), but not among GG homozygotes (HR 1.32, 95% CI 0.35-4.91). Conclusions: This study finds HNF4A intronic variant rs4812829 is significantly associated with the incident T2D risk in a rural Chinese population, and this association exhibits an interaction with HDL-C levels. These findings support further investigation of HNF4A-related lipid pathways and require replication in independent Chinese and multi-ancestry cohorts before genetic and lipid profiles can be considered for T2D risk stratification.