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Extended report
Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk
  1. Elizabeth W Karlson1,
  2. Lori B Chibnik1,
  3. Peter Kraft2,3,
  4. Jing Cui1,
  5. Brendan T Keenan1,
  6. Bo Ding4,
  7. Souyma Raychaudhuri1,
  8. Lars Klareskog5,
  9. Lars Alfredsson4,
  10. Robert M Plenge1
  1. 1Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA
  2. 2Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  3. 3Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  4. 4Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  5. 5Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska Hospital, Stockholm, Sweden
  1. Correspondence to Elizabeth W Karlson, 75 Francis Street, Boston, MA 02115, USA; ekarlson{at}


Background Recent discoveries of risk alleles have made it possible to define genetic risk profiles for patients with rheumatoid arthritis (RA). This study examined whether a cumulative score based on 22 validated genetic risk alleles for seropositive RA would identify high-risk, asymptomatic individuals who might benefit from preventive interventions.

Methods Eight human leucocyte antigen (HLA) alleles and 14 single-nucleotide polymorphisms representing 13 validated RA risk loci were genotyped among 289 white seropositive cases and 481 controls from the US Nurses' Health Studies (NHS) and 629 white cyclic-citrullinated peptide antibody-positive cases and 623 controls from the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA). A weighted genetic risk score (GRS) was created, in which the weight for each risk allele is the log of the published odds ratio (OR). Logistic regression was used to study associations with incident RA. Area under the curve (AUC) statistics were compared from a clinical-only model and clinical plus genetic model in each cohort.

Results Patients with GRS >1.25 SD of the mean had a significantly higher OR of seropositive RA in both NHS (OR=2.9, 95%CI 1.8 to 4.6) and EIRA (OR 3.4, 95% CI 2.3 to 5.0) referent to the population average. In NHS, the AUC for a clinical model was 0.57 and for a clinical plus genetic model was 0.66, and in EIRA was 0.63 and 0.75, respectively.

Conclusion The combination of 22 risk alleles into a weighted GRS significantly stratifies individuals for RA risk beyond clinical risk factors alone. Given the low incidence of RA, the clinical utility of a weighted GRS is limited in the general population.

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  • Funding The NHS is supported by NIH grants R01 AR49880, CA87969, CA49449, CA67262, CA50385, P60 AR047782, K24 AR0524-01. RMP is supported by grants from NIAMS-NIH (R01-AR056768 and R01 AR057108) and the William Randolph Hearst Fund of Harvard University, and also holds a career award for medical scientists from the Burroughs Wellcome Fund. The EIRA study was supported by grants from the Swedish Medical Research Council, from the Swedish Council for Working life and Social Research, from King Gustaf V’s 80-year foundation, from the Swedish Rheumatism Foundation, from Stockholm County Council and from the insurance company AFA.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Partners HealthCare Inc Institutional Review Board and Karolinska Institutet Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.