Rheumatoid arthritis (RA) is characterized by inflammation in the synovial membrane of diarthrodial joints. The cause of RA is unknown, but both environmental factors and genetic susceptibility appear to be involved. Although RA is consistently shown to have a prevalence of ~1% among populations of European ancestry (1
), there appears to be a relatively low prevalence among black Africans, particularly those living in rural settings, and its prevalence in African Americans is not well described. The reported prevalence of RA in rural regions of Africa has ranged from 0% to 0.68% of the populations under study (2
The HLA encoding the major histocompatibility complex (MHC) is the genetic region with the strongest association with RA in persons of European ancestry (8
). The HLA–DRB1 alleles associated with RA (*0401, *0404, *0405, *0408, *0413, *0101, *0102, *1402, and *1001) encode a common sequence at amino acids 70–75 (QKRAA) in the third hypervariable region of the β
-chain, referred to as the shared epitope (SE) (9
). HLA–DRB1 alleles containing the SE are found in ~50–70% of RA patients of European ancestry (1
). Association of RA with HLA–DRB1 alleles is observed in all racial/ethnic populations studied to date, but there is a paucity of data on Africans and African Americans. The particular SE-containing alleles appear to vary by racial/ethnic group. HLA–DRB1*0401 and *0404 are most common in Northern Europeans and persons of European ancestry living in the US (13
), while *1402 appears to be important in Native Americans (14
). HLA–DRB1*0101 and *1001 have been reported among Israelis, Greeks, and Spaniards with RA (15
). Among Asian populations (Koreans, Japanese, and Chinese), HLA–DRB1*0405 may be the dominant RA-associated allele (18
). HLA–DRB*09 alleles have also been reported to influence susceptibility to RA in Koreans, Chileans, and Japanese, as well as persons of European ancestry living in the UK (18
According to the 1995 National Marrow Donor Program (comprising more than 1.35 million HLA-typed healthy volunteers), there are significant differences in frequencies of HLA–DR4 alleles (as defined by micro-lymphocytotoxicity serologic assays) between persons of European ancestry (mean ± SEM gene frequency 16.8 ± 0.05%) and African Americans (mean ± SEM gene frequency 5.7 ± 0.08%) (24
). Characterization of HLA–DRB1 alleles from 564 consecutively recruited African American volunteers for a hematopoietic stem cell registry was recently reported (25
). In a study by Silman et al, HLA–DRB1*04 alleles were observed in only 1 (1.8%) of 55 persons in a rural Nigerian population (6
Because few studies have focused on African Americans with RA, the role of HLA–DRB1 alleles in that ethnic group is unclear. McDaniel et al (26
) observed that alleles *0401 to *0411 represented 18 (14.8%) of 121 alleles in 66 African American patients with rheumatoid factor (RF)–positive RA, 5 (14.7%) of 34 alleles in 20 patients with RF-negative RA, and 17 (6.9%) of 247 alleles in 130 control subjects. Of 57 African American patients in the Minocycline in RA trial, approximately one-third had at least 1 SE allele (27
). Del Rincón and Escalante (28
) analyzed HLA–DRB1 genotypes of RA patients of different ethnic groups, including 53 African Americans. They observed that *04 alleles were significantly less common among African American patients with RA than among non-Hispanic white patients (odds ratio [OR] 0.19, 95% confidence interval [95% CI] 0.09–0.41). HLA–DRB1*09, *12, *13, and *16 were enriched in African Americans with RA compared with non-Hispanic whites. Given these data, we sought to determine the degree to which HLA–DRB1 alleles associated with RA in persons of European ancestry are associated with RA in African Americans.
Genetic admixture between European and African populations, which was brought to the Americas as part of the slave trade, might be a contributing factor to the possible difference in the prevalence of RA in African Americans compared with Africans. Although the majority of slaves originated from western Africa, a substantial number were from central Africa as well. African Americans have, on average, 20% European ancestry, resulting from admixture that has occurred largely within the past 15 generations (29
). Because of the limited number of generations of admixture, there are extended stretches of DNA containing contiguous European and African ancestry (29
). Estimates of European ancestry can be made by genotyping sets of ancestry-informative markers (AIMs; ethnic difference markers) (29
), defined as single-nucleotide polymorphisms, in which there are much higher minor allele frequencies in one ethnic group compared with the other. Given the differences in frequencies of HLA–DRB1 alleles containing the SE in Africans versus persons of European ancestry, we hypothesized that if there was an association between these alleles and RA in African Americans, there would be selective enrichment of European ancestry among those individuals with the HLA–DRB1 SE.
The most prominent autoantibody in RA is RF, which is directed against the Fc portion of IgG, but antibodies directed against citrullinated peptides have been found to be highly specific for RA (for review, see ref. 30
). We recently reported the diagnostic utility of anti–cyclic citrullinated peptide (anti-CCP) antibodies in African Americans with early RA, using data and sera from the subjects in the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) registry (31
). It has recently been appreciated that in persons of European ancestry, the HLA–DRB1 SE is associated with anti-CCP–positive RA and not with anti-CCP–negative RA (32
). The association of HLA–DRB1 alleles and the presence of anti-CCP antibodies has not been examined in African Americans with RA. The final hypothesis we sought to test was that HLA–DRB1 alleles encoding the SE were associated with anti-CCP antibody–positive RA, but not anti-CCP antibody–negative RA, in African Americans.
In summary, the goals of this study were 1) to determine whether RA in African Americans is associated with the HLA–DRB1 SE, 2) to determine whether the presence of the SE is attributable to a higher degree of global (genome-wide) European admixture, and 3) to determine whether the HLA–DRB1 SE is associated with the subset of anti-CCP antibody–positive RA in African Americans.