Association of polar amino acids at position 26 of the HLA-DQB1 first domain with the anticentromere autoantibody response in systemic sclerosis (scleroderma).
HLA class II alleles (detected by DNA typing) were determined in 116 Caucasians with systemic sclerosis positive and negative for anticentromere autoantibodies (ACA). Significantly increased frequencies of HLA-DR5(DRw11) (P = 0.009) and the Dw13(DRB1*0403, *0407) subtypes of DR4 (probability corrected, Pc = 0.005) were seen in ACA positive patients, and HLA-DR1 and DRw8 were also increased. These findings appeared to reflect linkage disequilibrium of DR5(DRw11) and many DR4(Dw13) haplotypes with HLA-DQw7 and DR1 with DQw5. In fact, the presence of a DQB1 allele having a polar glycine or tyrosine at position 26 of the DQB1 first domain versus a hydrophobic leucine accounted for 100% of ACA positive Caucasian systemic sclerosis patients compared to 69% of the ACA negative SS patients (P = 0.0008) and 71% of Caucasian controls (P = 0.0003) as well as all 7 ACA patients of non-Caucasian background. Furthermore, the genotype frequency of DQB1 alleles lacking leucine at position 26 was 73% in ACA positive SS patients, compared to 42% of ACA negative patients (P = 1.2 x 10(-5)) and 38% of controls (P = 5.8 x 10(-7)). These data, then, suggest that the second hypervariable region of the HLA-DQB1 chain may form the candidate epitope associated with the ACA response.
Reveille
J D
JD
Department of Internal Medicine, University of Texas Medical School, Houston 77225.
Owerbach
D
D
Goldstein
R
R
Moreda
R
R
Isern
R A
RA
Arnett
F C
FC
D000483:Alleles; D001323:Autoantibodies / Q000032:analysis*; D001483:Base Sequence; D002503:Centromere / Q000276:immunology*; D005787:Gene Frequency; D006683:HLA-DQ Antigens / Q000032:analysis / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000032:analysis / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D012595:Scleroderma, Systemic / Q000276:immunology*
D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens