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 ] 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 1.012; 95% CI 1.007-1.015; P < 0.001), solute carrier family 30 member 8 (SLC30A8; OR 1.001; 95% CI 1.000-1.007; P < 0.040), B-cell lymphoma/leukemia 11A (BCL11A; OR 1.009; 95% CI 1.007-1.016; P < 0.001), prospero homeobox 1 (PROX1; OR 1.005; 95% CI 1.003-1.011; P < 0.001) and a disintegrin and metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9; OR 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 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.