title: No link between X chromosome inactivation pattern and simple goiter in females: evidence from a twin study.
abstract: BACKGROUND
  Simple goiter (SG) comprises diffuse (DG) and nodular (NG) benign nonautoimmune nontoxic goiter. In nonendemic goiter areas, the ratio of females to males may exceed 5:1, indicating that gender and/or sex hormones may play a role in the etiology of SG in these areas. Theoretically, as shown for autoimmune thyroid disease, X chromosome inactivation (XCI) and resultant tissue chimerism could offer a novel explanation for the female preponderance of SG. To examine whether skewed XCI is associated with SG, we first compared XCI in 71 twin individuals with SG with that in 142 unrelated healthy control twin individuals, and then performed a within-pair comparison of XCI in 48 twin pairs discordant for SG.
  
  
  METHODS
  DNA was extracted from peripheral blood cells. XCI analysis was performed by predigestion of DNA using the methylation-sensitive enzyme Hpall, followed by polymerase chain reaction of the polymorphic CAG repeat of the androgen receptor gene. A polymerase chain reaction product is obtained from the inactive X chromosome only. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X chromosome. Twin zygosity was established by DNA fingerprinting.
  
  
  RESULTS
  The frequency of skewed XCI in female twins with SG, DG, and NG was 11% (8/71), 13% (6/46), and 8% (2/25), respectively, which was not significantly different from the prevalences in the corresponding control populations, 14% (20/142, p = 0.56), 14% (13/92, p = 1.00), and 14% (7/50, p = 0.71), respectively. Essentially, similar results were obtained when comparing the prevalence of skewed XCI in twin pairs discordant for SG (48 pairs), DG (30 pairs), and NG (18 pairs).
  
  
  CONCLUSIONS
  In a sample of Danish female twins, we did not find evidence for involvement of skewed XCI in the etiology or the female preponderance of SG.
authors.affiliation: Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark. thomas.brix@ouh.regionsyddanmark.dk
authors.forename: Thomas Heiberg
authors.initials: TH
authors.lastname: Brix
authors.forename: Pia Skov
authors.initials: PS
authors.lastname: Hansen
authors.forename: Gun Peggy S
authors.initials: GP
authors.lastname: Knudsen
authors.forename: Marianne K
authors.initials: MK
authors.lastname: Kringen
authors.forename: Kirsten Ohm
authors.initials: KO
authors.lastname: Kyvik
authors.forename: Karen Helene
authors.initials: KH
authors.lastname: Orstavik
authors.forename: Laszlo
authors.initials: L
authors.lastname: Hegedüs
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006042:Goiter / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D049951:X Chromosome Inactivation