Abstract
ObjectiveWe aimed to explore the associations between common genetic risk variants with gestational diabetes mellitus (GDM) risk in Russian women and to assess their utility in the identification of GDM cases.MethodsWe conducted a case-control study including 1,142 pregnant women (688 GDM cases and 454 controls) enrolled at Almazov National Medical Research Centre. The International Association of Diabetes and Pregnancy Study Groups criteria were used to diagnose GDM. A total of 11 single- nucleotide polymorphisms (SNPs), including those in HKDC1 (rs10762264), GCK (rs1799884), MTNR1B (rs10830963 and rs1387153), TCF7L2 (rs7903146 and rs12255372), KCNJ11 (rs5219), IGF2BP2 (rs4402960), IRS1 (rs1801278), FTO (rs9939609), and CDKAL1 (rs7754840) were genotyped using Taqman assays. A logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs). A simple-count genetic risk score (GRS) was calculated using 6 SNPs. The area under the receiver operating characteristic curve (c-statistic) was calculated for the logistic regression model predicting the risk of GDM using clinical covariates, SNPs that had shown a significant association with GDM in our study, GRS, and their combinations.ResultsTwo variants in MTNR1B (rs1387153 and rs10830963) demonstrated a significant association with an increased risk of GDM. The association remained significant after adjustment for age, pre-gestational BMI, arterial hypertension, GDM in history, impaired glucose tolerance, polycystic ovary syndrome, family history of diabetes, and parity (P = 0.001 and P < 0.001, respectively). After being conditioned by each other, the effect of rs1387153 on GDM predisposition weakened while the effect of rs10830963 remained significant (P = 0.004). The risk of GDM was predicted by clinical variables (c-statistic 0.712, 95 % CI: 0.675 – 0.749), and the accuracy of prediction was modestly improved by adding GRS to the model (0.719, 95 % CI 0.682 – 0.755), and more by adding only rs10830963 (0.729, 95 % CI 0.693 – 0.764).ConclusionAmong 11 SNPs associated with T2D and/or GDM in other populations, we confirmed significant association with GDM for two variants in MTNR1B in Russian women. However, these variants showed limited value in the identification of GDM cases.
Highlights
Gestational diabetes mellitus (GDM) is a highly prevalent condition affecting 9.3-25.5% of pregnant women [1]
The pathogenesis of GDM is similar to T2DM, as both conditions are characterized by insulin resistance and a compensatory increase in insulin secretion that is unable to meet requirements [5]
There was a higher frequency of impaired glucose tolerance (IGT), arterial hypertension, GDM in history and family history of type 2 diabetes mellitus in GDM group compared to control group
Summary
Gestational diabetes mellitus (GDM) is a highly prevalent condition affecting 9.3-25.5% of pregnant women [1]. GDM is associated with considerable adverse pregnancy outcomes, including birth trauma [2], increased caesarean delivery rate, as well as the future development of type 2 diabetes (T2D) both in the mother and in the offspring [3, 4]. The pathogenesis of GDM is similar to T2DM, as both conditions are characterized by insulin resistance and a compensatory increase in insulin secretion that is unable to meet requirements [5]. There are over 160 genetic loci that have been associated with T2DM in non-pregnant population [8] and a limited number of them have been evaluated in pregnant women [9]. By the time of planning of this study there were two published meta-analyses confirming association of the following variants with GDM: melatonin receptor 1B (MTNR1B), glucokinase (GCK), transcription factor 7-like 2 (TCF7L2), potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11), regulatory subunit associated protein 1-like 1 (CDKAL1), insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and insulin receptor substrate 1 (IRS1) [10, 11]
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