Patients With Gestational Diabetes May Have 2 Categories of Genetic Risk Factors

The genetic etiology for gestational diabetes (GD) is only partially shared with the genetic risk for type 2 diabetes (T2D), according to research published in an article in Nature Genetics. Investigators of a recent Finland-based cohort study found that GD may be genomically correlated with T2D, but there is also a genetic risk factor that is independent of the risk for T2D—that is, patients have an additional risk based gestational disease contributors alone.

“Our current results suggest plausible mechanisms related to maternal adaptive physiological responses to pregnancy,” wrote authors in the article.

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Due to the lack of literature assessing genetic predisposition for GD, investigators conducted the largest genome-wide association study (GWAS) of GD. The study includes 12,332 cases and 131,109 parous female controls who were part of the FinnGen study, which evaluated a cohort of women from Finland.

Investigators first discovered that there are 13 distinct associated chromosomal regions associated with GD. The team performed replication studies to reaffirm findings, and later performed fine-mapping of the loci to characterize them.

Next, the team evaluated the shared genetic etiology of GD with T2D by analyzing genome-wide significant signals; they observed that the loci in patients with GD had a heterogenous relationship to that associated with T2D (P < 0.001). Specifically, in the FinnGenn cohort there were 5 GD-associated loci which were not significantly associated with the loci observed in patients with T2D (P < 5 × 10−8).

“At the genomic level, GD and T2D were genetically correlated (rg = 0.71, s.e. = 0.06, P = 6.8 × 10−37), which is significantly greater than 0 (P = 6.8 × 10−37) but less than 1 (P = 1.2 × 10−7),” study authors wrote in the article.

Results also showed that GD was associated with some glycemic traits, like fasting glucose (FG) or hemoglobin A1c (HbA1C), although it was not associated with fasting insulin level. And after further tests, investigators concluded that genetic risk of GD is based on 2 categories, one being a shared genetic risk with T2D and the other being an independent genetic risk associated with gestation.

“The comparison of effect sizes between GD and T2D does not support the existence of a single, consistent relationship between GD and T2D across loci, but instead proposes 2 distinct classes of significant variants,” authors write.

The major limitation of this study was in evaluating a homogenous cohort of Finnish women. This could limit generalizability of findings, especially given that this population has some rare alleles that are not common around the world.

Pregnancy itself might be a risk factor for GD because women have more circulating gestational hormones which impact homeostatic glycemic pathways in the pancreas and brain. Further, the insulin sensitivity in their peripheral tissues is negatively affected. Investigators suggest that new areas of research need to evaluate the molecular cause of GD risk.

“This work underscores the benefits of focusing resources on pregnancy disorders as pregnancy is a natural perturbation that offers leverage to discover loci with new physiologic mechanisms of glycemic or homeostatic control,” authors wrote in the article.

Reference

Elliot A, Walters RK, Pirinen M, et al. Distinct and shared genetic architectures of gestational diabetes mellitus and type 2 diabetes. Nat Genet. 2024;doi: 10.1038/s41588-023-01607-4