Women With Gestational Diabetes Mellitus May Have 2 Categories of Genetic Risk Factors

The genetic etiology for gestational diabetes mellitus (GDM) is only partially shared with the genetic risk for type 2 diabetes (T2D), according to authors of a study published in Nature Genetics. Investigators of a recent Finland-based cohort study found that GDM may be genomically correlated with T2D, but there is also a genetic risk factor for GDM that is independent of the risk for T2D.

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

Currently, there is a lack of literature assessing one’s genetic predisposition for GDM, so investigators conducted a large genome-wide association study (GWAS) of GDM to learn more about the condition. Investigators conducted the study by evaluating data collected on women in the FinnGen study. The FinnGen study included 131,109 parous female controls from Finland. There were 12,332 cases of GDM in the cohort (women were diagnosed during pregnancy).

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

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Next, the team evaluated the shared genetic etiology of GDM and T2D by analyzing genome-wide significant signals, and they observed that many of the loci in patients with GDM were heterogenous to T2D (P < 0.001).

“At the genomic level, GDM and T2D were genetically correlated (r_g= 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.

Results also showed that GDM was associated with glycemic traits, like fasting glucose (FG) or hemoglobin A1_c (HbA1C), although it was not associated with fasting insulin level. After further tests, investigators concluded that genetic risk of GDM is based on 2 categories, 1 being a shared genetic risk with T2D and the other being an independent genetic risk associated with gestation.

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

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.

The reason that pregnancy can be a risk factor for GDM is because women have more circulating gestational hormones which impact homeostatic glycemic pathways in the pancreas and brain. Further, gestation impacts insulin sensitivity in their peripheral tissues. New areas of research need to evaluate the molecular cause of GDM 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,” study authors wrote.

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