Polygenic Risk Score Associated with Gestational Diabetes Mellitus in an AmericanIndian Population

Gestational diabetes mellitus (GDM) is a state of hyperglycemia during pregnancy, increasing the risk of birth complications, and subsequent type 2 diabetes mellitus in the mother and offspring. Risk factors such as diet, obesity, and family history have demonstrated strong association with GDM, but no clear pathophysiology has been ascertained.

An analysis was conducted on 38 women with and 296 without GDM, within a case/control study of pre-eclampsia. The genetic variants examined were selected from among a published polygenic risk score of 10 variants (PRS-10). Genetic models were evaluated for each variant by multivariate logistic regression methods adjusted for age, body mass index, and pre-eclampsia. Since the genotypes for three of the PRS-10 were not available, a risk score comprising the total risk alleles among seven of the variants (PRS-7) was evaluated among those with all genotypes available.

Multivariate logistic regression showed significant, independent, positive associations between body mass index (BMI) and age. The posited PRS-7 showed a trend (OR 1.56, 95% CI 0.92-2.56, p = 0.070), and sensitivity analysis comprising three variants (PRS-3) was significantly associated with GDM (OR 2.43, 95% CI 1.17-5.06, p = 0.017). In univariate analysis, rs1421085 was associated with GDM (OR 0.50, 95% CI 0.26-0.95, p = 0.034), but not after adjustment for covariates, and paradoxically not for the expected risk allele. None of the other six variants showed an individual association with GDM. The previously published meta-analysis of PRS-10 showed a degree of heterogeneity (p_Q= 0.03) among the three cohorts analyzed, suggesting that variant effects may differ according to the genetic background, which points to the importance of examining the generalizability of any posited polygenic risk scores.

In conclusion, we provide additional support for and further refine the results of a previously published polygenic risk score for GDM in an ethically unrelated population.