Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus

Abstract

Aims/hypothesis: Gestational diabetes mellitus (GDM) and type 2 diabetes share a common pathophysiological background, including beta cell dysfunction and insulin resistance. In addition, women with GDM are at increased risk of developing type 2 diabetes later in life. Our aim was to investigate whether, like type 2 diabetes, GDM has a genetic predisposition by studying five common polymorphisms in four candidate genes that have previously been associated with type 2 diabetes. Materials and methods: We studied 1,777 unrelated Scandinavian women (588 with GDM and 1,189 pregnant non-diabetic controls) for polymorphisms in the genes encoding potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), insulin receptor substrate 1 (IRS1 G972R), uncoupling protein 2 (UCP2 −866G→A) and calpain 10 (CAPN10 SNP43 and SNP44). Results: The EE, EK and KK genotype frequencies of the KCNJ11 E23K polymorphism differed significantly between GDM and control women (31.5, 52.7 and 15.8% vs 37.3, 48.8 and 13.9%, respectively; p=0.050). In addition, the frequency of the K allele was increased in women with GDM (odds ratio [OR]=1.17, 95% CI 1.02−1.35; p=0.027), and this effect was greater under a dominant model (KK/EK vs EE) (OR=1.3, 95% CI 1.05−1.60; p=0.016). Analysis of the IRS1 G972R polymorphism showed that RR homozygosity was found exclusively in women with GDM (91.0, 8.3 and 0.7% vs 90.7,9.3 and 0.0% for GG, GR and RR genotypes, respectively; p=0.014). The genotype and allele frequencies of the other polymorphisms studied were not statistically different between the GDM and control women. Conclusions/interpretation: The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women.

A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus

“…Given the influence of the variant on insulin secretion [14,15,17] and our previous findings of associations of KCNJ11 E23K, GCK 30G>A and TCF1 I27L [10,11] variants with gestational diabetes mellitus, this finding supports the central role of impaired beta cell function in the pathogenesis of gestational diabetes mellitus [3].…”

“…Scandinavian) and were recruited from the same place and during the same time period. The characteristics of the majority of participants in the present study have been reported earlier [10]. Detailed phenotypic characteristics, including OGTT data, were available only for a small proportion of the women with gestational diabetes mellitus [31].…”

“…In addition, we and others have demonstrated that gestational diabetes mellitus shares some genetic risk factors with type 2 diabetes [2]. For example, potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), glucokinase (GCK −30G>A) and transcription factor 1, hepatic; LF-B1, hepatic nuclear factor (HNF1), albumin proximal factor (TCF1, also known as hepatocyte nuclear factor 1-α [HNF1A I27L]) polymorphisms, all of which have been associated with type 2 diabetes [7][8][9], also increase the risk of gestational diabetes mellitus with a modest effect size [10,11].…”

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

“…Several studies have examined candidate genes in women with and without GDM. Positive associations were shown for genes encoding glucokinase [11], calpain-10 [12], sulfonylurea receptor 1 [13], potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) [14], β 3 adrenergic receptor [15], plasminogen activator inhibitor 1 [16] and transcription factor 7-like 2 (TCF7L2) [17,18]. Except for the effects of TCF7L2 in Scandinavian women [17], no robust associations of genetic variants with GDM have been demonstrated.…”

Gestasyonel diyabet gelişiminde KCNJ11 geninin rolü

“…Son yıllarda farklı popülasyonlarda KCNJ11 genindeki polimorfizmlerin GDM ile ilişkili olduğuna dair çalış-malar da rapor edilmiştir (32)(33)(34) …”