The T393C Polymorphism of the Gαs Gene (<i>GNAS1</i>) Is a Novel Prognostic Marker in Bladder Cancer

Frey, Ulrich H.; Eisenhardt, Andreas; Lümmen, G.; Rübben, H.; Jöckel, Karl‐Heinz; Schmid, Kurt Werner; Siffert, Winfried

doi:10.1158/1055-9965.epi-04-0720

Cited by 73 publications

(95 citation statements)

References 43 publications

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“…The T393C polymorphism is silent, not changing the amino acid of the affected codon in exon 5 of the GNAS1 gene. However, we have previously shown that the GNAS1 polymorphism is associated with altered Gas mRNA expression in different tissues (35). We found that the TOC substitution at position 393 changes the mRNA folding structures (37).…”

Section: Discussionmentioning

confidence: 77%

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

Hahn¹,

Frey²,

Siffert³

et al. 2006

eur j endocrinol

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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.

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Section: Discussionmentioning

confidence: 77%

“…Tukey's HSD test is one of the several methods of ensuring that the chance of finding a significant difference in any comparison (under a null model) is maintained at the alevel of the test and therefore preserves 'family-wise type I error'. Since the T393C polymorphism shows a genedose effect (35)…”

Section: Discussionmentioning

confidence: 99%

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

Hahn¹,

Frey²,

Siffert³

et al. 2006

eur j endocrinol

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“…26 Increased Gas expression may cause increased cAMP concentrations, 29 comparable to activating mutations of GNAS1, which also increase IL-6 levels. 30 IL-6 is a major mediator of osteoclast formation and bone resorption in aseptic loosening.…”

Section: Discussionmentioning

confidence: 99%

“…Definitely, it has been shown in different tissues, that Gas mRNA expression is increased in TT genotypes. 26 Yang et al 27 reported that the T393C polymorphism is not linked to an other, possibly functional polymorphism in linkage disequilibrium, and Frey et al 28 showed in an in silico analysis that the altered mRNA expression is most likely caused by altered mRNA stability. The T393C SNP and the associated alteration of Gas expression could influence bone and macrophage physiology as well as IL-6 expression levels and, therefore, may also alter the time to aseptic loosening.…”

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confidence: 99%

Gender‐dependent association of the GNAS1 T393C polymorphism with early aseptic loosening after total hip arthroplasty

Bachmann

Hanenkamp

Kornacki

et al. 2008

Journal Orthopaedic Research

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The G-protein Gas is involved in the physiology and pathophysiology of bone. Especially, Gas is a key regulator of interleukin-6, which is a potent promoter of aseptic loosening. We hypothesized that the common single nucleotide polymorphism GNAS1 T393C could also affect time to aseptic loosening. Caucasian patients were genotyped for the GNAS1 T393C polymorphism. Time and median time to aseptic loosening were analyzed for dependency on GNAS1 genotypes. Time and median time were not significantly associated with genotypes. Additional analysis corrected for gender revealed, that the TT genotype was associated with significantly longer time (p ¼ 0.048) as well as median time ( p ¼ 0.022) to aseptic loosening in female patients. In contrast to the findings in females, male TT genotype carriers had significantly shorter time ( p ¼ 0.018) and median time ( p ¼ 0.023) to aseptic loosening. Compared with TT genotype carriers heterozygous patients had a 6.25-fold lower risk with a hazard ratio of 0.160 ( p ¼ 0.016) and male patients carrying the CC genotype had an 11-fold lower risk with a hazard ratio of 0.088 ( p ¼ 0.006) in multivariate analysis. The present study suggests a significant gender-dependent role of the T393C polymorphism in aseptic loosening. The apparently contradictory results in women and men and the finding that the GNAS1 T393C genotype is an independent factor for time to aseptic loosening in male patients assigned this polymorphism as an interesting target for further investigations in bone diseases. ß

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“…Gas signaling is of particular interest in the study of endophenotypes of schizophrenia, because increased activity of this protein has been noted in the striatum and leukocytes of patients with schizophrenia (Memo et al, 1983;Avissar et al, 2001). Further, a polymorphism, which results in increased mRNA expression of Gas (Frey et al, 2005), has recently been genetically linked to schizophrenia (Minoretti et al, 2006). Interestingly, transgenic mice expressing a constitutively active isoform of Gas (Gas*) show decreased PPI (Gould et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Gas (Gas*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Gas* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Gas* increases cAMP levels in the striatum. Suprisingly, however, Gas* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Gas* on PPI because Rp-cAMPS decreases PPI in C57BL/ 6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gas* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Gas*. We conclude that expression of Gas* within forebrain neurons causes PPI deficits because of a PKAdependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

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The T393C Polymorphism of the Gαs Gene (GNAS1) Is a Novel Prognostic Marker in Bladder Cancer

Cited by 73 publications

References 43 publications

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

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

Gender‐dependent association of the GNAS1 T393C polymorphism with early aseptic loosening after total hip arthroplasty

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

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