The HLA-DRB1 shared epitope is associated with susceptibility, to rheumatoid arthritis in African Americans through European genetic admixture

• Authors: Laura B. Hughes, University of Alabama Birmingham; Dahliann Morrison; James M. Kelley, University of Alabama Birmingham; Miguel A. Padilla, University of Alabama Birmingham; L. Kelly Vaughan, University of Alabama Birmingham; Andrew O. Westfall, University of Alabama Birmingham; Harshit Dwivedi, University of Alabama Birmingham; Ted R. Mikuls, University of Nebraska Medical Center; V. Michael Holers, University of Colorado Health Sciences Center; Lezlie A. Parrish, University of Colorado Health Sciences Center; Graciela S. Alarcn, University of Alabama Birmingham; Doyt L Conn, Emory University; Beth L. Jonas, University of North Carolina; Leigh F. Callahan, University of North Carolina; Edwin Smith, Emory University; Gary S. Gilkeson, Medical University of South Carolina; George Howard, University of Alabama Birmingham; Larry W. Moreland, University of Alabama Birmingham; Nick Patterson, Massachusetts Institute of Technology; David Reich, Massachusetts Institute of Technology; S. Louis Bridges, Jr., University of Alabama Birmingham
• Journal Title: Arthritis and Rheumatism
• Volume: Volume 58, Number 2
• Publisher: Wiley | 2008-02-01, Pages 349-358
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/art.23166
• Subjects: Health Sciences, Medicine and Surgery; Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Rheumatology; DISEASE SEVERITY; HAPLOTYPE FREQUENCIES; POPULATION; ALLELES; JAPANESE; LOCUS; POLYMORPHISMS; PREVALENCE; HYPOTHESIS; SEQUENCES

Abstract

Objective: To determine whether shared epitope (SE)-containing HLA-DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population. Methods: In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti-cyclic citrullinated peptide (anti-CCP) antibodies and HLA-DRB1 genotyping, a panel of > 1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry. Results: The frequency of SE-containing HLA-DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA-DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody-positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody-negative RA (P = 0.01, by chi-square test). Conclusion: HLA-DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which ∼50-70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.