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
Article first published online: 28 OCT 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 11, pages 2773–2782, November 2013
How to Cite
Frisell, T., Holmqvist, M., Källberg, H., Klareskog, L., Alfredsson, L. and Askling, J. (2013), 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. Arthritis & Rheumatism, 65: 2773–2782. doi: 10.1002/art.38097
- Issue published online: 28 OCT 2013
- Article first published online: 28 OCT 2013
- Accepted manuscript online: 29 JUL 2013 09:25AM EST
- Manuscript Accepted: 16 JUL 2013
- Manuscript Received: 18 MAR 2013
- Swedish Medical Research Council to the Epidemiological Investigation of Rheumatoid Arthritis study
- Swedish Foundation for Strategic Research
- Combine public–private research program
- Swedish Research Council
- European Union Innovative Medicines Initiative (BTCure)
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.
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.
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.
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.