title: Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype.
abstract: BACKGROUND
  Both genetic and environmental factors contribute to susceptibility to Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as disease manifestations.
  
  
  OBJECTIVE
  The objective of the study was to define how endogenous/environmental factors contribute to variation in phenotype.
  
  
  METHODS
  This was a multicenter cohort study. PATIENTS/OUTCOME MEASURES: We prospectively collected clinical/biochemical data as part of the protocol for a United Kingdom DNA collection for GD and HT. We investigated, in 2805 Caucasian subjects, whether age at diagnosis, gender, family history (FH), smoking history, and presence of goiter influenced disease manifestations.
  
  
  RESULTS
  For 2405 subjects with GD, the presence of goiter was independently associated with disease severity (serum free T4 at diagnosis) (P < 0.001). Free T4 (P < 0.05) and current smoking (P < 0.001) were both independent predictors of the presence of ophthalmopathy. Approximately half of those with GD (47.4% of females, 40.0% of males) and HT (n = 400) (56.4% of females, 51.7% of males) reported a FH of thyroid dysfunction. In GD, a FH of hyperthyroidism in any relative was more frequent than hypothyroidism (30.1 vs. 24.4% in affected females, P < 0.001). In HT, a FH of hypothyroidism was more common than hyperthyroidism (42.1 vs. 22.8% in affected females, P < 0.001). For GD (P < 0.001) and HT (P < 0.05), a FH was more common in maternal than paternal relatives. The reporting of a parent with thyroid dysfunction (hyper or hypo) was associated with lower median age at diagnosis of both GD (mother with hyperthyroidism, P < 0.001) and HT (father with hypothyroidism, P < 0.05). In GD and HT, there was an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis (P < 0.01).
  
  
  CONCLUSIONS
  Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.
authors.affiliation: Division of Medical Sciences, The Medical School, University of Birmingham, Edgbaston, Second Floor, Birmingham B15 2TT, United Kingdom.
authors.forename: N
authors.initials: N
authors.lastname: Manji
authors.forename: J D
authors.initials: JD
authors.lastname: Carr-Smith
authors.forename: K
authors.initials: K
authors.lastname: Boelaert
authors.forename: A
authors.initials: A
authors.lastname: Allahabadia
authors.forename: M
authors.initials: M
authors.lastname: Armitage
authors.forename: V K
authors.initials: VK
authors.lastname: Chatterjee
authors.forename: J H
authors.initials: JH
authors.lastname: Lazarus
authors.forename: S H S
authors.initials: SH
authors.lastname: Pearce
authors.forename: B
authors.initials: B
authors.lastname: Vaidya
authors.forename: S C
authors.initials: SC
authors.lastname: Gough
authors.forename: J A
authors.initials: JA
authors.lastname: Franklyn
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006042:Goiter / Q000150:complications / Q000453:epidemiology; D006111:Graves Disease / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D049970:Graves Ophthalmopathy / Q000453:epidemiology / Q000209:etiology; D050031:Hashimoto Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects*