title: Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess.
abstract: 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.
  
  
  METHODS
  Prospective case-control study.
  
  
  METHODS
  University reproductive endocrinology laboratory and outpatient clinic.
  
  
  METHODS
  Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 95).
  
  
  METHODS
  Blood and DNA sampling before hormonal therapy.
  
  
  METHODS
  Polycystic ovary syndrome patient and healthy control genotypes, with the CYP21 and IRS1 variants.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA. selma.witchel@chp.edu
authors.forename: Selma F
authors.initials: SF
authors.lastname: Witchel
authors.forename: Melissa
authors.initials: M
authors.lastname: Kahsar-Miller
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Aston
authors.forename: Carlie
authors.initials: C
authors.lastname: White
authors.forename: Ricardo
authors.initials: R
authors.lastname: Azziz
mesh_terms: D000311:Adrenal Glands / Q000503:physiopathology; D016022:Case-Control Studies; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D017588:Hyperandrogenism / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000453:epidemiology / Q000235:genetics*; D015995:Prevalence; D011446:Prospective Studies; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D019314:Dehydroepiandrosterone Sulfate; D013255:Steroid 21-Hydroxylase