G2Cdb::Human Disease report

Disease id
D00000150
Name
Polycystic ovary syndrome
Nervous system disease
no

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002164 IRS1
insulin receptor substrate 1
Y (15705377) Single nucleotide polymorphism (SNP) Y
G00001473 GNAS
GNAS complex locus
Y (17062894) Single nucleotide polymorphism (SNP) N

References

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

    Hahn S, Frey UH, Siffert W, Tan S, Mann K and Janssen OE

    Endokrinologikum Ruhr, Center for endocrine and metabolic diseases, Alter Markt 4, 44866 Bochum, Germany. susanne.hahn@endokrinologikum.com

    Objective: Variants in the Gs protein alpha 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.

    European journal of endocrinology 2006;155;5;763-70

  • Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess.

    Witchel SF, Kahsar-Miller M, Aston CE, White C and Azziz R

    Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA. selma.witchel@chp.edu

    Objective: To determine whether frequencies of the mutations in the 21-hydroxylase (CYP21) gene and the G972R variant of the insulin receptor substrate-1 (IRS1) gene are increased in women with polycystic ovary syndrome (PCOS) and adrenal androgen (AA) excess.

    Design: Prospective case-control study.

    Setting: University reproductive endocrinology laboratory and outpatient clinic.

    Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 95).

    Blood and DNA sampling before hormonal therapy.

    Polycystic ovary syndrome patient and healthy control genotypes, with the CYP21 and IRS1 variants.

    Fifty-four PCOS patients with (DHEAS >3000 ng/mL) and 55 without (DHEAS <2500 ng/mL) AA excess, respectively, were studied. Of 109 patients studied, 16 (14.7%) were found to be heterozygous carriers of mutations in the CYP21 gene. Of these 16, 10 (62.5%) had excessive AA secretion (i.e., excess DHEAS levels). Fifteen patients (13.8%) were found to be heterozygous carriers of the IRS1 variant; 9 (60.0%) of these 15 had excessive AA secretion. There were no significant differences in the allele frequency of CYP21 mutations or the IRS1 variant between PCOS patients with and without AA excess, and controls. None of the subjects were found to be homozygous carriers of CYP21 mutations or the IRS1 variant. Combined heterozygosity for CYP21 mutations and the IRS1 variant was limited to women with PCOS and excessive AA (n = 3).

    The G972R variant of the IRS1 gene might represent a modifier locus among women who are heterozygous carriers of CYP21 mutations, potentially increasing their risk of developing AA excess in PCOS. Nonetheless, this IRS1 variant and CYP21 mutations seem to play a limited role in the development of PCOS in the population studied.

    Funded by: NICHD NIH HHS: R01-HD29364, R29-HD34808

    Fertility and sterility 2005;83;2;371-5

Literature (2)

Pubmed - human_disease

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

    Hahn S, Frey UH, Siffert W, Tan S, Mann K and Janssen OE

    Endokrinologikum Ruhr, Center for endocrine and metabolic diseases, Alter Markt 4, 44866 Bochum, Germany. susanne.hahn@endokrinologikum.com

    Objective: Variants in the Gs protein alpha 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.

    European journal of endocrinology 2006;155;5;763-70

Pubmed - other

  • Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess.

    Witchel SF, Kahsar-Miller M, Aston CE, White C and Azziz R

    Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA. selma.witchel@chp.edu

    Objective: To determine whether frequencies of the mutations in the 21-hydroxylase (CYP21) gene and the G972R variant of the insulin receptor substrate-1 (IRS1) gene are increased in women with polycystic ovary syndrome (PCOS) and adrenal androgen (AA) excess.

    Design: Prospective case-control study.

    Setting: University reproductive endocrinology laboratory and outpatient clinic.

    Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 95).

    Blood and DNA sampling before hormonal therapy.

    Polycystic ovary syndrome patient and healthy control genotypes, with the CYP21 and IRS1 variants.

    Fifty-four PCOS patients with (DHEAS >3000 ng/mL) and 55 without (DHEAS <2500 ng/mL) AA excess, respectively, were studied. Of 109 patients studied, 16 (14.7%) were found to be heterozygous carriers of mutations in the CYP21 gene. Of these 16, 10 (62.5%) had excessive AA secretion (i.e., excess DHEAS levels). Fifteen patients (13.8%) were found to be heterozygous carriers of the IRS1 variant; 9 (60.0%) of these 15 had excessive AA secretion. There were no significant differences in the allele frequency of CYP21 mutations or the IRS1 variant between PCOS patients with and without AA excess, and controls. None of the subjects were found to be homozygous carriers of CYP21 mutations or the IRS1 variant. Combined heterozygosity for CYP21 mutations and the IRS1 variant was limited to women with PCOS and excessive AA (n = 3).

    The G972R variant of the IRS1 gene might represent a modifier locus among women who are heterozygous carriers of CYP21 mutations, potentially increasing their risk of developing AA excess in PCOS. Nonetheless, this IRS1 variant and CYP21 mutations seem to play a limited role in the development of PCOS in the population studied.

    Funded by: NICHD NIH HHS: R01-HD29364, R29-HD34808

    Fertility and sterility 2005;83;2;371-5

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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