The melatonin receptor 1B (MTNR1B) polymorphism rs10830963 C>G has been reported to be associated with the risk of gestational diabetes mellitus (GDM) with inconsistent results. To clarify the effect of the polymorphism on the risk of GDM, a meta-analysis therefore was performed.Pooled OR with it's corresponding 95%CI was used to estimate the strength of the association.Totally 14 eligible studies with a number of 5,033 GDM patients and 5,614 controls were included in this meta-analysis. Results indicated that the variant G allele was significantly associated with an increased GDM risk (CG vs. CC: OR = 1.25, 95% CI = 1.11-1.40, P < 0.001; GG vs. CC: OR = 1.78, 95% CI = 1.45-2.19, P < 0.001; G vs. C: OR = 1.33, 95% CI = 1.21-1.47, P < 0.001). In the stratified analysis by ethnicity, similar results were found in Asians (CG vs. CC: OR = 1.15, 95%CI = 1.02-1.28, P = 0.020; GG vs. CC: OR = 1.52, 95% CI = 1.23-1.89, P < 0.001; G vs. C: OR = 1.23, 95% CI = 1.10-1.37, P < 0.001) and in Caucasians (CG vs. CC: OR = 1.40, 95% CI = 1.16-1.70, P < 0.001; GG vs. CC: OR = 2.21, 95% CI =1.54-3.17, P < 0.001; G vs. C: OR = 1.47, 95% CI = 1.24-1.73, P < 0.001). FPRP and TSA analyses confirmed findings support that the rs10830963 G allele increases the risk of GDM, and further functional experimental studies are warranted to explore and clarify the potential mechanism.

The aetiological mechanism of gestational diabetes mellitus (GDM) has still not been fully understood. The aim of this study was to explore the associations between functional genetic variants screened from a genome-wide association study (GWAS) and GDM risk among 554 GDM patients and 641 healthy controls in China. Functional analysis of single nucleotide polymorphisms (SNPs) positively associated with GDM was further performed. Univariate regression and multivariate logistic regression analyses were used to screen clinical risk factors, and a predictive nomogram model was established. After adjusting for age and prepregnancy BMI, rs9283638 was significantly associated with GDM susceptibility (P < 0.05). Moreover, an obvious interaction between rs9283638 and clinical variables was detected (P_interaction < 0.05). Functional analysis confirmed that rs9283638 can regulate not only target gene transcription factor binding, but it also regulates the mRNA levels of SAMD7 (P < 0.05). The nomogram model constructed with the factors of age, FPG, 1hPG, 2hPG, HbA1c, TG and rs9283638 revealed an area under the ROC curve of 0.920 (95% CI 0.902–0.939). Decision curve analysis (DCA) suggested that the model had greater net clinical benefit. Conclusively, genetic variants can alter women's susceptibility to GDM by affecting the transcription of target genes. The predictive nomogram model constructed based on genetic and clinical variables can effectively distinguish individuals with different GDM risk factors.

To clarify the effect of retinoid X receptor-a/g (RXR-α/γ) genes functional genetic variants (RXR-α rs4842194 G>A, RXR-γ rs100537 A>G and rs2134095 T>C) on the risk of gestational diabetes mellitus (GDM), a case-control study with 573 GDM patients and 740 pregnant women with normal glucose tolerance was performed in Guangxi area of China. An odds ratio (OR) with its corresponding 95%CI was used to assess the strengths of the association between genetic variation and GDM. After adjustment of age and pre-BMI, the logistic regression analysis showed that the rs2134095 was significantly associated with GDM risk (CC vs. TT/TC: adjusted OR=0.71, 95%CI=0.56~0.90) in all subjects, and this result remained highly significant after Bonferroni’s correction for multiple testing (P=0.004). The stratified analysis showed that rs2134095 was significantly associated with the risk of GDM among age>30 years (adjusted OR=0.61, 95%CI=0.39~0.97), BMI>22 kg/m² (adjusted OR=0.46, 95%CI= 0.30~0.70), SBP>120mmHg (adjusted OR=1.96, 95%CI= 1.14~3.36), HbA1c 3.12 mmol/L(adjusted OR= 1.47, 95%CI= 1.08~2.00) subjects, under the recessive genetic model. We also found that rs2134095 interacted with age (P_interaction=0.039), pre-BMI (P_interaction=0.040) and TG (P_interaction=0.025) influencing individual's genetic susceptibility to GDM. The rs2134095 T>C is significantly associated with the risk of GDM by effect of a single locus and / or complex joint gene-gene and gene-environment interactions. Larger sample-size and different population studies are required to confirm the findings.

Objectives: The CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1) contributes to islet β-cell function and insulin secretion by inhibiting the activation of CDK5. The current studies on the relationship between CDKAL1 polymorphisms rs7756992 A>G and rs7754840 C>G and the risk of gestational diabetes mellitus (GDM) have drawn contradictory conclusions.Materials and Methods: A meta-analysis with a fixed- or random-effects model was conducted to estimate the correlation between studied CDKAL1 polymorphisms and GDM risk with the summary odds ratio (OR) and 95% confidence interval (CI). In addition, trial sequential analysis (TSA) and false-positive report probability (FPRP) analysis were performed to confirm the study findings.Results: A total of 13,306 subjects were included in the present study. Meta-analysis results showed that the variant heterozygous and homozygous genotypes of the two polymorphisms were associated with increased GDM risk in comparison with the wild-type AA genotype (AG vs. AA: OR = 1.23, 95% CI = 1.08, 1.41, p = 0.002; GG vs. AA: OR = 1.47, 95% CI = 1.05, 2.05, p = 0.024 for rs7756992; and CG vs. GG: OR = 1.36, 95% CI = 1.13, 1.65, p = 0.002; CC vs. GG: OR = 1.76, 95% CI = 1.37, 2.26, p < 0.001 for rs7754840). The TSA confirmed a significant association between rs7754840 and the susceptibility to GDM because the cumulative Z-curve crossed both the conventional cutoff value and the TSA boundaries under the heterozygote and homozygote models.Conclusions: This study supported the finding that rs7756992 and rs7754840 are associated with susceptibility to GDM. However, further functional studies are warranted to clarify the mechanism.

Objective: To explore the relationship between angiotensin-converting enzyme 2 (ACE2) genetic variants and gestational diabetes mellitus (GDM) in a southern Chinese population.Methods: Potential functional variants (rs2106809, rs6632677, and rs2074192) of ACE2 were selected and genotyped in 566 GDM patients and 710 normal pregnaõncies in Guilin, China. The odds ratio (OR) and its corresponding 95% confidence interval (CI) were used to evaluate the association between genetic variant and GDM risk, and then the false positive report probability, multifactor dimensional reduction (MDR), and bioinformatics tools were used to confirm the significant association in the study.Results: After adjusting for age and prepregnancy body mass index, logistic regression analysis showed that ACE2 rs6632677 was significantly associated with a decreased risk of GDM (CC vs. GG: adjusted OR = 0.09, 95% CI: 0.01 – 0.71, P = .023; GC/CC vs. GG: adjusted OR = 0.68, 95% CI = 0.46 – 0.99, P = .048; and CC vs. GG/GC: adjusted OR = 0.09, 95% CI = 0.01 – 0.72, P = .024), whereas rs2074192 was associated with increased GDM risk (TT vs. CC/CT: adjusted OR = 1.38, 95% CI = 1.08 – 1.75, P = .009). Furthermore, we found that rs6632677 interacted with SBP (P_interaction = .043) and FPG (P_interaction = .021) and rs2074192 interacted with HDL-c (P_interaction = .029) and LDL-c (P_interaction = .035) to influence the GDM risk of the individual. In the MDR analysis, the rs6632677 was the best one-locus model, and the three-loci model was the best interaction model to predict GDM risk. In addition, functional analysis confirmed that rs2074192 may regulate the splicing process of ACE2 gene.Conclusion: ACE2 gene variants are significantly associated with the risk of GDM via gene–gene and gene–environment combinations. The rs2074192 C > T affects the splicing of the ACE2 gene, which may be a potential mechanism leading to the changed susceptibility of an individual female during pregnancy to GDM.

Context Gestational diabetes mellitus (GDM) is a pregnancy-complicated disease that poses a risk to maternal and infant health. However, the etiology of the disease has been not yet elucidated. Objective To detect the genetic susceptibility and construct a nomogram model with significantly associated polymorphisms and key clinical indicators for early prediction of GDM. Methods Eleven functional single nucleotide polymorphisms (SNPs) screened by genome-wide association study were genotyped in 554 GDM cases and 641 healthy controls. Functional analysis of GDM positively associated SNPs, multivariate mendelian randomization (MVMR), and a GDM early predictive nomogram model construction were performed. Result rs1965211, rs3760675, and rs7814359 were significantly associated with genetic susceptibility to GDM after adjusting age and prepregnancy body mass index (pre-BMI). It seems that GDM-associated SNPs have effects on regulating target gene transcription factor binding, posttranscriptional splicing, and translation product structure. Besides, rs3760675 can be expression quantitative trait loci and increase the XAB2 mRNA expression level (P = .047). The MVMR analysis showed that the increase of clinical variables of BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) had significant causal effects on GDM (BMI-OR_MVMR = 1.52, HbA1c-OR_MVMR = 1.32, FPG-OR_MVMR = 1.78), P < .05. A nomogram model constructed with pre-BMI, FPG, HbA1c, and genotypes of rs1965211, rs3760675, and rs7814359 showed an area under the receiver operating characteristic curve of 0.824. Conclusion Functional polymorphisms can change women's susceptibility to GDM and the predictive nomogram model based on genetic and environmental factors can effectively distinguish individuals with different GDM risks in early stages of pregnancy.