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


METHODS
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.


CONCLUSIONS
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.
Hahn
Susanne
S
Endokrinologikum Ruhr, Center for endocrine and metabolic diseases, Alter Markt 4, 44866 Bochum, Germany. susanne.hahn@endokrinologikum.com
Frey
Ulrich H
UH
Siffert
Winfried
W
Tan
Susanne
S
Mann
Klaus
K
Janssen
Onno E
OE
D000728:Androgens / Q000097:blood; D001835:Body Weight; D002864:Chromogranins; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008687:Metformin / Q000627:therapeutic use; D009765:Obesity / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000235:genetics*; D011110:Polymorphism, Genetic
D000728:Androgens; D002864:Chromogranins; D008687:Metformin; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs