The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome

Abstract

Objective: Variants in the Gs protein a subunit gene (GNAS1) are known to be involved in the pathogenesis of several endocrine and metabolic disorders. To understand genetic determinants of androgen excess, insulin resistance, and obesity in polycystic ovary syndrome (PCOS), we investigated the effect of the common GNAS1 T393C polymorphism on the phenotype of German PCOS women. Design: Two hundred and seventy-eight PCOS women and 820 Caucasian controls were genotyped for the common T393C polymorphism in GNAS1. To this end, genomic DNA was amplified by PCR with specific oligonucleotides and genotypes were determined using the restriction enzyme FokI. In addition, we evaluated whether the T393C polymorphism had an influence on the response to 6 months metformin treatment in a subgroup of 105 PCOS women. Methods: Anthropometric variables, metabolic parameters including indices of insulin resistance measured by oral glucose tolerance testing, and endocrine biochemical as well as clinical parameters were measured in all PCOS subjects. Results: GNAS1 genotype distributions were not significantly different between PCOS women and controls. In PCOS women, no significant differences in endocrine clinical and biochemical variables were found between the genotypes. However, the C-allele carrier group had significantly higher mean body weight, body mass index, leptin levels, and higher indices of insulin resistance compared with women with GNAS1 TT-genotype. Metformin treatment significantly improved hyperandrogenism, menstrual cyclicity, body weight, and insulin resistance independent of GNAS1 genotype. The major determinant of weight loss was body weight before treatment. Conclusion: The T393C polymorphism is not associated with PCOS in Caucasian women, but may represent a genetic marker for increased susceptibility for obesity in this cohort.

Extra-long Gαs Variant XLαs Protein Escapes Activation-induced Subcellular Redistribution and Is Able to Provide Sustained Signaling

“…6). Thus, XL␣s extended the duration of the cAMP response induced by the typically short acting agonist M-PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Although this finding was consistent with the absence of XL␣s internalization upon activation, a similar effect was not observed when the same cells were stimulated by isoproterenol.…”

“…We addressed this hypothesis by using a Förster resonance energy transfer (FRET)-based reporter that permits real time recording of cAMP production in live cells (46). As an agonist, we chose a PTH analog, M-PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), which has been shown to induce a short lived cAMP response (41). As expected, a rapid change in the FRET signal was observed upon the addition of 100 nM M-PTH (1-14) onto HEK293 cells expressing the PTHR alone or in combination with XL␣s and G␤ 1 ␥ 2 (Fig.…”

A functional GNAQ promoter haplotype is associated with altered Gq expression and with insulin resistance and obesity in women with polycystic ovary syndrome

“…DNA from patients with PCOS (n = 265, age range 18-45 years) was provided by the Department of Endocrinology, University Hospital Essen. Study details are described elsewhere [13,22,24]. The control group consisted of 293 healthy, age-matched women, who were likewise recruited at the Department of Transfusion Medicine, University Hospital Essen [23].…”

“…Influences on insulin and glucose metabolism in PCOS are likely multifactorial and are exerted by both environmental [16] and genetic factors [17,18]. Identified modifier genes encode for products involved in steroid biosynthesis like CYP11, CYP17, CYP19, androgen receptor but also in the secretion and action of insulin [19,20] or are associated with insulin resistance and obesity [21,22]. Owing to the involvement of Gq in insulin and glucose metabolism, GNAQ appears a good candidate gene responsible for metabolic alterations in the PCOS.…”

Lack of association between interleukin-1a gene (IL-1a) C (-889) T variant and polycystic ovary syndrome in chinese women

“…Radioimmunity systems were used for the determination of testosterone, LH, FSH, estradiol, and progesterone. In patients with amenorrhea after excluding pregnancy by a commercially available pregnancy test, blood is taken from the antecubital vein on average day after an overnight fast [15,28].…”