Association between genetic risk variants and glucose intolerance during pregnancy in north Indian women

Abstract

BackgroundGestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women.MethodsFive thousand one hundred pregnant women of gestational age 24–28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women.ResultsIn support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p < 0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM.ConclusionsGDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0380-8) contains supplementary material, which is available to authorized users.

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus

“…The power to detect association of rs11605924 ( CRY2 ) with GDM at a significance level of 0.05 was 0.85. This protective effect was consistent even when WHO 1999 criteria were applied in our previous study on the same population . CRY2 encodes the circadian rhythm gene cryptochrome 2 and is a target for the CLOCK ‐ BMAL1 , which are core components of the endogenous clock.…”

“…In our previous study, we observed that the T2D risk SNP in the TCF7L2 gene did not associate with GDM using either WHO 1999 or WHO 2013 criteria . However, using the Swedish GDM diagnostic criteria (2‐h capillary blood glucose concentration ≥ 10 mmol L −1 ), we see a trend towards an association.…”

Precision medicine in type 2 diabetes

“…A woman with GDM is at increased risk of GDM during subsequent pregnancies as well as increased risk ofT2D . There is also emerging evidence for shared genetic background of GDM and T2D . Similar to T2D, GDM can also be heterogeneous, especially in different ethnic groups .…”

Dephosphorylation of clustered phosphoserine residues in human Grb14 by protein phosphatase 1 and its effect on insulin receptor complex formation

“…Therefore, the disruption of Grb14‐mediated homeostasis may be associated with the progression of several physiological disorders. Genetic analyses during the last decade, including genome‐wide association studies, have demonstrated that the GRB14 gene is associated with cancer, obesity, and metabolic diseases such as noninsulin‐dependent and gestational diabetes mellitus …”

“…Genetic analyses during the last decade, including genome-wide association studies, have demonstrated that the GRB14 gene is associated with cancer, obesity, and metabolic diseases such as noninsulin-dependent and gestational diabetes mellitus. [11][12][13][14][15][16][17][18] The Grb7 family proteins is composed of several modular signaling domains, including N-terminal polyproline sequences, a Rasassociation domain, a pleckstrin homology (PH) domain, and a Cterminal Src homology-2 (SH2) domain. In addition, Grb7 family proteins contain a unique region termed the between PH and SH2 (BPS) domain 8 or phosphorylated IR-interacting region (PIR).…”