Role of metabolic syndrome and its components as mediators of the genetic effect on type 2 diabetes: A family-based study in China

Background: Metabolic syndrome (MetS) share a genetic basis with type 2 diabetes (T2D). However, whether MetS and its components mediate genetic susceptibility to T2D is not completely understood. Methods: We assessed the effects of MetS and its components on associations T2D and 18 genome-wide association studies-identified variants using a two-stage strategy based on parametric models involving 7110 Chinese participants (2436 were T2D patients) across 2885 families. Multilevel logistic regression was used to account for the intrafamilial correlation. Results: Metabolic syndrome significantly mediated the effect of a melatonin receptor 1B (MTNR1B) polymorphism on T2D risk (OR of average causal mediation effect [OR_ACME] 1.004; 95% confidence interval [CI] 1.001-1.008; P = 0.018). In addition, low high-density lipoprotein cholesterol (HDL-C) levels mediated the genetic effects of MTNR1B (OR_ACME 1.012; 95% CI 1.007-1.015; P < 0.001), solute carrier family 30 member 8 (SLC30A8; OR_ACME 1.001; 95% CI 1.000-1.007; P < 0.040), B-cell lymphoma/leukemia 11A (BCL11A; OR_ACME 1.009; 95% CI 1.007-1.016; P < 0.001), prospero homeobox 1 (PROX1; OR_ACME 1.005; 95% CI 1.003-1.011; P < 0.001) and a disintegrin and metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9; OR_ACME 1.006; 95% CI 1.001-1.009; P = 0.022), whereas increased fasting blood glucose (FBG) significantly mediated the genetic effect of BCL11A (OR_ACME 1.017; 95% CI 1.003-1.021; P = 0.012). Conclusions: This study provides evidence that MetS and two of its components (HDL-C, FBG) may be involved in mediating the genetic predisposition to T2D, which emphasize the importance of maintaining normal HDL-C and FBG levels.