Common single‐nucleotide polymorphisms combined with a genetic risk score provide new insights regarding the etiology of gestational diabetes mellitus

Abstract

Aims: Few studies have constructed a genetic risk score (GRS) to predict the risk of gestaional diabetes mellitus (GDM). We tested the hypothesis that singlenucleotide polymorphisms (SNPs) confirmed for diabetes and obesity and the GRS are associated with GDM. Methods:We conducted a case-control study comprising 971 GDM cases and 1682 controls from the University of Hong Kong Shenzhen Hospital. A total of 1448 SNPs reported with type 2 diabetes (T2D), type 1 diabetes (T1D), and obesity were selected and the GRS based on SNPs associated with GDM was created. Results:We confirmed that rs10830963 (OR = 1.41,95% CI = 1.25, 1.59) in MTNR1B and rs2206734 (OR = 1.38, 95% CI = 1.22, 1.55) in CDKAL1 were strongly associated with the risk of GDM. Compared with participants with GRS based on T2D SNPs in the low tertile, the ORs of GDM across increasing GRS tertiles were 1.63 (95% CI 1.29, 2.06) and 2.72 (95% CI 2.18, 3.38) in the middle and high tertile, respectively. The positive associations between the GRS and the risk of GDM were also observed in GRS based on obesity/waist-to-hip ratio (WHR)/ body mass index (BMI) SNPs. The resulting GRS for each allele increase was significantly associated with higher glycemic indices and lower HOMA-B values for GRS based on T2D SNPs, but not for GRS based on T1D SNPs and GRS based on obesity/WHR/BMI SNPs. Conclusion:These findings indicate that GDM may share a common genetic background with T2D and obesity and that SNPs associated with insulin secretion defects have a vital role in the development of GDM.

Genetic variants in epoxyeicosatrienoic acid processing and degradation pathways are associated with gestational diabetes mellitus

“…Several genome-wide association studies (GWAS) and candidate gene association studies have been performed to examine the association between genetic variants and the risk of GDM, which can be utilised to identify individuals at high risk for GDM or in the early stage of the disease. Notwithstanding, these studies have largely focused on common variants known to be associated with T2D and glycaemic traits outside of pregnancy based on the hypothesis that a shared genetic architecture exists between GDM and T2D [ 32 , 43 ]. For example, TCF7L2 , GCK , KCNJ11 , CDKAL1 , IGF2BP2 , and MTNR1B are thought to modulate pancreatic islet β-cell function, all of which were associated with GDM (OR 1.15–1.46) [ 44 , 45 ].…”

“…Blood pressure measurements were performed in both arms using a mercury sphygmomanometer after a rest period of at least 5 min, and the arm with the higher reading was tested twice at 3-min intervals to calculate the mean value [ 31 ]. Blood samples collected in the fasting status were used to measure the levels of fasting plasma glucose (FPG), fasting insulin (FINS), glycated haemoglobin A1c (HbA1c), total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C); details of these biochemical measurements have been described previously by Lu W et al [ 32 , 33 ]. Homeostasis model assessment of β-cell function (HOMA-β) and insulin resistance (HOMA-IR) were used to evaluate basal insulin secretion and insulin resistance, respectively, which were calculated using insulin and glucose concentrations as follows: HOMA-β = 20 × FINS (mU/L)/[FPG (mmol/L) − 3.5] and HOMA-IR = FINS (mU/L)/(22.5e − lnFPG (mmol/L) ) [ 34 , 35 ].…”

Genetic Risk Factors and Gene–Lifestyle Interactions in Gestational Diabetes

“…With regards to insulin-resistance-associated T2D-loci, only IRS variants have demonstrated significant association with GDM in GWAS or meta-analyses (Table 1), whereas PPARG has been reported to associate with GDM only in candidate gene studies [52]. Although obesity is a common risk factor for GDM, fat-mass/obesity-associated gene variants that predispose to T2D (e.g., FTO) have been linked to GDM in candidate gene studies [52,65,66] but not yet in GWAS.…”

Interactions of CDKAL1 rs7747752 polymorphism and serum levels of L-carnitine and choline are related to increased risk of gestational diabetes mellitus

“…In European populations, CDKAL1 polymorphisms, i.e., rs7754840 and rs10946398, were not associated with the risk of GDM [ 15 , 16 ]. On the other hand, CDKAL1 polymorphisms were strongly associated with risk of GDM in Chinese and other Asian populations [ 17 , 18 ]. Single nucleotide polymorphism (SNP) rs7747752 is in the intron of CDKAL1 .…”