Rheumatoid arthritis, population differences, genetic risk factors, and the effect of admixture

Rheumatoid arthritis is thought to be more prevalent among individuals of European ancestry.
In this paper, they attempt to explain why African Americans are at greater risk of developing RA than Africans. They find a higher degree of European ancestry among African Americans with the HLA-DRB1 SE alleles. Their conclusion: risk alleles were acquired through admixture with European Americans. With respect to causation, they are careful to say (and show in their figure):

It remains unclear whether these associations are attributable to the HLA-DRB1 alleles per se or to allelic variants in genetic regions in linkage disequilibrium with HLA-DRB1. There are a plethora of genes with immune function in the MHC locus, many of which have been implicated in RA, including HLA-DQA1, HLA-DQB1, tumor necrosis factor, MICB, and BTNL2 ([39-41]).

The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture
Laura B. Hughes et al.
Arthritis Rheum. 2008 Jan 31;58(2):349-358 [Epub ahead of print]

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 approximately 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.