Women's reproductive risk and genetic predisposition in type 2 diabetes: A prospective cohort study

Objective: To assess synergistic effects of reproductive factors and gene-reproductive interaction on type 2 diabetes (T2D) risk, also the extent to which the genetic risk of T2D can be affected by reproductive risk. Methods: 84,254 women with genetic data and reproductive factors were enrolled between 2006 and 2010 in the UK Biobank. The reproductive risk score (RRS) was conducted based on 17 reproductive items, and genetic risk score (GRS) was based on 149 genetic variants. Results: There were 2300 (2.8 %) T2D cases during an average follow-up of 4.49 years. We found a significant increase in T2D risk across RRS categories (Ptrend < 0.001). Compared with low reproductive risk, high-mediate (adjusted hazard ratio [aHR] 1.38, 95 % CI 1.20-1.58) and high (aHR 1.84, 95 % CI 1.54-2.19) reproductive risk could increase the risk of T2D. We further observed a significant additive interaction between reproductive risk and genetic predisposition. In the situation of high genetic predisposition, women with low reproductive risk had lower risk of T2D than those with high reproductive risk (aHR 0.47, 95 % CI 0.30-0.76), with an absolute risk reduction of 2.98 %. Conclusions: Our novo developed RRS identified high reproductive risk is associated with elevated risk of women's T2D, which can be magnified by gene-reproductive interaction.