Interaction between HNF4A polymorphisms and physical activity in relation to type 2 diabetes-related traits: Results from the Quebec Family Study

Aims To test for associations between type 2 diabetes mellitus (T2DM)-related traits and polymorphisms (SNPs) in the hepatocyte nuclear factor 4-α gene (HNF4A) in the Quebec Family Study cohort, and determine whether these associations are modulated by physical activity (PA). Methods Two HNF4A SNPs (rs1885088 G>A; rs745975 C>T), previously reported to be associated with T2DM, were studied in 528 non-diabetic subjects who underwent a 75g oral glucose tolerance test (OGTT). Glucose, insulin and C-peptide plasma levels, measured in the fasting state and during the OGTT, were used in the analysis. The amount (hours per week) of PA was assessed by questionnaire. Results The HNF4A rs1885088 SNP was not independently associated with T2DM-related traits, whereas the rs745975 was associated with fasting insulin, HOMA-IR and 2-h glucose levels (p <0.05 for all). Genotype by PA interactions were found for glucose homeostasis (p <0.0001) and insulin secretion (p ≤0.03). When subjects were stratified by PA level (according to the median value), we found that high level of PA (>2h/week) was associated with smaller glucose area under the curve (AUC) and 2-h glucose levels in rs1885088 A/A homozygotes and with lower fasting C-peptide and insulin AUC in rs745975 T/T homozygotes. Conclusion These results indicate that the associations of HNF4A rs1885088 with glucose tolerance and rs745975 with insulin secretion are modulated by PA. Our finding therefore suggests that the effect of HNF4A polymorphisms on the risk of T2DM is influenced by PA.