title: The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Alabama at Birmingham 35294-2182, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Hughes
authors.forename: Dahliann
authors.initials: D
authors.lastname: Morrison
authors.forename: James M
authors.initials: JM
authors.lastname: Kelley
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Padilla
authors.forename: L Kelly
authors.initials: LK
authors.lastname: Vaughan
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Westfall
authors.forename: Harshit
authors.initials: H
authors.lastname: Dwivedi
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Lezlie A
authors.initials: LA
authors.lastname: Parrish
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: Doyt L
authors.initials: DL
authors.lastname: Conn
authors.forename: Beth L
authors.initials: BL
authors.lastname: Jonas
authors.forename: Leigh F
authors.initials: LF
authors.lastname: Callahan
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Smith
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: George
authors.initials: G
authors.lastname: Howard
authors.forename: Larry W
authors.initials: LW
authors.lastname: Moreland
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.forename: David
authors.initials: D
authors.lastname: Reich
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics* / Q000706:statistics & numerical data; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000208:ethnology* / Q000235:genetics* / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000235:genetics / Q000276:immunology; D016036:Seroepidemiologic Studies; D044465:White People / Q000235:genetics* / Q000706:statistics & numerical data
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide