Evidence of Epistatic Interactive Effects of HK1 and GCK Genes on Circulating Hemoglobin A1c Levels in Humans

Hemoglobin A1c (HbA1c), an important diagnostic biomarker for type 2 diabetes (T2D), is also associated with aging, cognitive performance, and mortality. To identify epistatic interactions, we assessed 133 known gene variants associated with HbA1c among 3778 non-diabetic subjects of European ancestry in the Long Life Family Study (LLFS). We applied Bayesian imputation based association mapping (BIMBAM) to identify significant pairwise epistatic interactions among 133 genetic variants. To take into account confounding effects, we adjusted age, sex, field centers, body mass index (BMI), and genetic principal components (PCs). This analysis yielded seven pairs with log10(BF) > 10; of those, six pairs were confirmed using a full-term mixed regression model. Specifically, these included significant interactions of HK1-rs17476364 with variants in GCK (rs2971670, rs4607517) or G6PC2 (rs560887), as well as between HK1-rs16926246 and the same variants (p values for each term ≤ 7.14 × 10−3). All epistatic interactions between HK1 and GCK, and between HK1 and G6PC2 were replicated at p < 0.05 in at least one of two large independent studies (namely, Framingham Offspring Study; Health and Retirement Study). The present study revealed that HK1 and GCK interact to contribute to regulating levels of HbA1c and are likely to be involved in molecular mechanisms underlying healthy aging processes.