title: Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age.
abstract: OBJECTIVE
  To estimate familial aggregation of rheumatoid arthritis (RA) in 3 large population-representative samples and to test if familial aggregation is affected by rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) status, type of relative, sex, and age at onset of RA.
  
  
  METHODS
  A register-based nested case-control study was performed in the Swedish total population. Data on patients with RA were ascertained through the nationwide Swedish Patient Register (n = 88,639), the clinical Swedish Rheumatology Quality Register (n = 11,519), and the Epidemiological Investigation of Rheumatoid Arthritis case-control study (n = 2,871). Data on first- and second-degree relatives were obtained through the Swedish Multigeneration Register. Familial risks were calculated using conditional logistic regression.
  
  
  RESULTS
  Consistent across data sources, the familial odds ratio for RA was ∼3 in first-degree relatives of RA patients and 2 in second-degree relatives. Familial risks were similar among siblings, parents, and offspring. Familial aggregation was not modified by sex, but was higher in RA patients with early-onset disease and in RF/ACPA-positive RA patients. The observed familial risks were consistent with a heritability of ∼50% for ACPA-positive RA and ∼20% for ACPA-negative RA.
  
  
  CONCLUSIONS
  The pattern of risks suggests that familial factors influence RA in men and women equally and that these factors are of less importance for late-onset RA. Familial factors are more important for seropositive RA, but there is significant familial overlap between seropositive RA and seronegative RA. Even if the familial risk is assumed to be completely due to genetics, the observed risks suggest that heritability of RA is lower than previously reported, in particular for ACPA-negative RA.
authors.affiliation: Karolinska Institutet, Solna, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Frisell
authors.forename: Marie
authors.initials: M
authors.lastname: Holmqvist
authors.forename: Henrik
authors.initials: H
authors.lastname: Källberg
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Johan
authors.initials: J
authors.lastname: Askling
mesh_terms: D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D012042:Registries / Q000706:statistics & numerical data; D012217:Rheumatoid Factor / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D012307:Risk Factors; D017678:Sex Distribution; D013548:Sweden / Q000453:epidemiology
chemical_list: D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor