Association of single nucleotide polymorphisms with insulin secretion, insulin sensitivity, and diabetes in women with a history of gestational diabetes mellitus

Prasad, Rashmi B.; Kristensen, Karl; Katsarou, Anastasia; Shaat, Nael

doi:10.1186/s12920-021-01123-6

Cited by 10 publications

(5 citation statements)

References 48 publications

(55 reference statements)

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“…The first of these is rs3934729 located near ADCY5 , a gene shared by T2DM adj BMI, FG adj BMI and PCOS and overlapping a suggestively significant T2DM adj BMI–PCOS local genetic correlation region chr3:11019665-13070799. Variation in ADCY5 increases fasting glucose levels and type 2 diabetes risk through altered expression in beta cells and impaired glucose signalling [ 33 ] and has been found to decrease the disposition index (an indicator of insulin secretion capacity) in women with gestational diabetes after adjusting for BMI [ 34 ]. Variation in ADCY5 has also been shown to affect ovarian morphological-related traits in bovines [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome

et al. 2022

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Aims/hypothesis The link underlying abnormal glucose metabolism, type 2 diabetes and polycystic ovary syndrome (PCOS) that is independent of BMI remains unclear in observational studies. We aimed to clarify this association using a genome-wide cross-trait approach. Methods Summary statistics from the hitherto largest genome-wide association studies conducted for type 2 diabetes, type 2 diabetes mellitus adjusted for BMI (T2DMadjBMI), fasting glucose, fasting insulin, 2h glucose after an oral glucose challenge (all adjusted for BMI), HbA1c and PCOS, all in populations of European ancestry, were used. We quantified overall and local genetic correlations, identified pleiotropic loci and expression–trait associations, and made causal inferences across traits. Results A positive overall genetic correlation between type 2 diabetes and PCOS was observed, largely influenced by BMI (rg=0.31, p=1.63×10–8) but also independent of BMI (T2DMadjBMI–PCOS: rg=0.12, p=0.03). Sixteen pleiotropic loci affecting type 2 diabetes, glycaemic traits and PCOS were identified, suggesting mechanisms of association that are independent of BMI. Two shared expression–trait associations were found for type 2 diabetes/T2DMadjBMI and PCOS targeting tissues of the cardiovascular, exocrine/endocrine and digestive systems. A putative causal effect of fasting insulin adjusted for BMI and type 2 diabetes on PCOS was demonstrated. Conclusions/interpretation We found a genetic link underlying type 2 diabetes, glycaemic traits and PCOS, driven by both biological pleiotropy and causal mediation, some of which is independent of BMI. Our findings highlight the importance of controlling fasting insulin levels to mitigate the risk of PCOS, as well as screening for and long-term monitoring of type 2 diabetes in all women with PCOS, irrespective of BMI. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome

et al. 2022

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“…Studies indicate that gene variants may be associated with disease susceptibility by gene-gene interaction or affecting complex traits, such as mRNA/protein/methylation levels, biochemical indicators, etc. (14,15). Liu C et al found that ACE2 variants can significantly affect blood pressure (SBP or DBP) and blood lipid (TG, TC, HDL-C, or LDL-C) and regulate the onset of T2DM and its complications (33).…”

Section: Discussionmentioning

confidence: 99%

“…Studies indicate that gene variants may be associated with disease susceptibility by gene–gene interaction or affecting complex traits, such as mRNA/protein/methylation levels, biochemical indicators, etc. ( 14 , 15 ). Liu C et al.…”

Section: Discussionmentioning

confidence: 99%

“…SNPs may act as quantitative trait loci (QTLs) and be associated with complex disease phenotypes by affecting the mRNA/protein levels, methylation rate, and physiological and biochemical indicators, etc. (13)(14)(15). For instance, studies show that the genetic variant rs10830963 of the MTNR1B gene is associated with the pathogenesis of T2DM by affecting the expression of MTNR1B (16), and the rs10830963G allele could significantly increase the odds of antenatal insulin therapy of GDM in pregnancy (17).…”

Section: Introductionmentioning

confidence: 99%

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Association of ACE2 gene functional variants with gestational diabetes mellitus risk in a southern Chinese population

et al. 2022

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ObjectiveTo explore the relationship between angiotensin-converting enzyme 2 (ACE2) genetic variants and gestational diabetes mellitus (GDM) in a southern Chinese population.MethodsPotential 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.ResultsAfter 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 (Pinteraction = .043) and FPG (Pinteraction = .021) and rs2074192 interacted with HDL-c (Pinteraction = .029) and LDL-c (Pinteraction = .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.ConclusionACE2 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.

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“…Prasad et al have shown that the IRS1 rs2943641 C allele is associated with increased insulin resistance (HOMA-IR). Their study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity, and consequently to the development of diabetes [ 32 ]. In our study, the IRS1 TT genotype was associated with higher fasting glucose levels in women with GDM.…”

Section: Discussionmentioning

confidence: 99%

COBLL1 and IRS1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes

et al. 2022

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Gestational diabetes mellitus (GDM) is carbohydrate intolerance in pregnant women leading to various complications. Currently, there is a search for factors predisposing to GDM. Among them are genetic polymorphisms of genes involved in insulin secretion as well as carbohydrate metabolism. Due to the similar pathogenesis of GDM to type 2 diabetes (T2DM), genetic polymorphisms associated with T2DM are considered. The aim of this study was to examine the associations between the COBLL1 rs7607980 T > C and IRS1 rs2943641 T > C gene polymorphisms and the risk of GDM as well as selected clinical parameters in women with GDM. Additionally, we examined the expression of these genes in the placenta of women with and without GDM in correlation with selected clinical parameters. This study included 328 pregnant women with normal glucose tolerance (NGT) and 251 pregnant women with GDM diagnosed on the basis of a 75 g oral glucose tolerance test (OGTT) at 24–28 weeks gestation. There were no statistically significant differences in the distribution of IRS1 rs2943641 gene polymorphisms between women with GDM and pregnant women with NGT. In the GDM group, we observed a decreased frequency of COBLL1 rs7607980 CC homozygous women (CC vs. TC+TT, p = 0.048); however, there was no statistically significant difference in the frequency of alleles between women with GDM and the control group. There were no statistically significant associations between COBLL1 rs7607980 gene polymorphism and clinical parameters in women with GDM. In GDM women with the IRS1 rs2943641 TT genotype, fasting glucose levels were significantly higher than in women with CC and TC genotypes. There was no statistically significant difference in the expression of COBLL1 and IRS1 genes in the placenta between women with GDM and healthy women. There were no statistically significant correlations between COBLL1 gene expression in the placenta and clinical parameters. The expression of IRS1 correlated significantly with an increase in BMI during pregnancy. The results of this study suggest that COBLL1 rs7607980 and IRS1 rs2943641 gene polymorphisms are not significant risk factors for GDM in our population. The IRS1 TT genotype may be associated with higher fasting glucose levels in women with GDM. Expression of the IRS1 gene in the placenta positively correlates with an increase in BMI during pregnancy in women with GDM.

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Association of single nucleotide polymorphisms with insulin secretion, insulin sensitivity, and diabetes in women with a history of gestational diabetes mellitus

Cited by 10 publications

References 48 publications

A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome

A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome

Association of ACE2 gene functional variants with gestational diabetes mellitus risk in a southern Chinese population

COBLL1 and IRS1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes

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