Genetic variants associated with beta-cell function and insulin sensitivity potentially influence bile acid metabolites and gestational diabetes mellitus in a Chinese population

Introduction To investigate associations between genetic variants related to beta-cell (BC) dysfunction or insulin resistance (IR) in type 2 diabetes (T2D) and bile acids (BAs), as well as the risk of gestational diabetes mellitus (GDM). Research design and methods We organized a case-control study of 230 women with GDM and 217 without GDM nested in a large prospective cohort of 22 302 Chinese women in Tianjin, China. Two weighted genetic risk scores (GRSs), namely BC-GRS and IR-GRS, were established by combining 39 and 23 single nucleotide polymorphisms known to be associated with BC dysfunction and IR, respectively. Regression and mediation analyses were performed to evaluate the relationship of GRSs with BAs and GDM. Results We found that the BC-GRS was inversely associated with taurodeoxycholic acid (TDCA) after adjustment for confounders (Beta (SE)=-0.177 (0.048); p=2.66x10(-4)). The BC-GRS was also associated with the risk of GDM (OR (95% CI): 1.40 (1.10 to 1.77); p=0.005), but not mediated by TDCA. Compared with individuals in the low tertile of BC-GRS, the OR for GDM was 2.25 (95% CI 1.26 to 4.01) in the high tertile. An interaction effect of IR-GRS with taurochenodeoxycholic acid (TCDCA) on the risk of GDM was evidenced (p=0.005). Women with high IR-GRS and low concentration of TCDCA had a markedly higher OR of 14.39 (95% CI 1.59 to 130.16; p=0.018), compared with those with low IR-GRS and high TCDCA. Conclusions Genetic variants related to BC dysfunction and IR in T2D potentially influence BAs at early pregnancy and the development of GDM. The identification of both modifiable and non-modifiable risk factors may facilitate the identification of high-risk individuals to prevent GDM.