title: Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women.
abstract: OBJECTIVE
  Is there an association between polycystic ovary syndrome (PCOS) and the sex hormone-binding globulin (SHBG) rs1799941, rs6257, rs6259 and rs727428 variants in a large series of Mediterranean women?
  
  
  CONCLUSIONS
  The rs727428 and rs6259 variants are associated with PCOS in Mediterranean women.
  
  
  BACKGROUND
  The level of SHBG, the primary plasma transport protein for sex steroids, which regulates the bioavailability of these hormones to target tissues, is reduced in patients with PCOS. Single-nucleotide polymorphisms in the SHBG gene influence circulating SHBG levels in American patients with PCOS and may predict the development of type 2 diabetes.
  
  
  METHODS
  This was a genetic case-control association study including 1004 premenopausal Mediterranean women.
  
  
  METHODS
  In an Academic setting, we genotyped a clinical cohort consisting of 281 patients with PCOS and 142 women without any evidence of androgen excess, and a population-based cohort comprised of 581 unselected female blood donors from Spain and Italy. The latter included 31 patients with PCOS and 550 controls, of whom 298 had no evidence of any androgen excess disorder and were considered hyper-normal controls.
  
  
  RESULTS
  Mutant alleles of the rs727428 variant were more frequent in patients with PCOS compared with controls and with hyper-normal controls. This association was independent of obesity. Carrying mutant alleles of rs727428 was found to be associated with a 1.29 odds ratio (OR) for PCOS, whereas carrying mutant alleles of rs6259 associated with a 0.68 OR for PCOS. The rs1799941 and rs6257 variants were not associated with PCOS. None of the SHBG variants influenced serum SHBG concentrations.
  
  
  CONCLUSIONS
  The associations found here were relatively weak and, arising from a case-control study, do not necessarily indicate a causative role of the SHBG variants in the development of PCOS. Also, we studied different patients and controls from different sources, making some of the interpretations difficult. Finally, the rs1799941 variant was not in Hardy-Weinberg equilibrium in the small group of patients with PCOS recruited from the general population, yet this variant was not associated with PCOS.
  
  
  CONCLUSIONS
  SHBG variants that influenced circulating SHBG levels in American patients with PCOS are also associated with this syndrome in Mediterranean women, pointing to SHBG as a candidate gene for PCOS.
  
  
  BACKGROUND
  This study was supported by grants PI080944 and PI110357 from Instituto de Investigación Carlos III, Spanish Ministry of Economy and Competitiveness. CIBERDEM is also an initiative of Instituto de Investigación Carlos III. The Authors have no competing interests to declare.
authors.affiliation: Diabetes, Obesity and Human Reproduction Research Group,  Hospital Universitario Ramón y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, Madrid E-28034,  Spain.
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Martínez-García
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambineri
authors.forename: Macarena
authors.initials: M
authors.lastname: Alpañés
authors.forename: Raúl
authors.initials: R
authors.lastname: Sanchón
authors.forename: Renato
authors.initials: R
authors.lastname: Pasquali
authors.forename: Héctor F
authors.initials: HF
authors.lastname: Escobar-Morreale
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007558:Italy; D008055:Lipids / Q000097:blood; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017697:Premenopause; D012738:Sex Hormone-Binding Globulin / Q000235:genetics*; D013030:Spain
chemical_list: D008055:Lipids; D012738:Sex Hormone-Binding Globulin