Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic association study, meta-analysis and geo-epidemiological investigation.

INTRODUCTION: Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with HLA-DRB1*04 and HLA-DRB1*01; HLA-DRB1 alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within HLA-DRB1 best explained HLA-DRB1 allele susceptibility and protective effects in GCA, seen in UK data combined in meta-analysis with previously published data, and (2) to determine whether the incidence of GCA in different countries is associated with the population prevalence of the HLA-DRB1 alleles that we identified in our meta-analysis. METHODS: GCA patients from the UK GCA Consortium were genotyped by using single-strand oligonucleotide polymerization, allele-specific polymerase chain reaction, and direct sequencing. Meta-analysis was used to compare and combine our results with published data, and public databases were used to identify amino acid residues that may explain observed susceptibility/protective effects. Finally, we determined the relationship of HLA-DRB1*04 population carrier frequency and latitude to GCA incidence reported in different countries. RESULTS: In our UK data (225 cases and 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, P = 1.5×10(-11)), but HLA-DRB1*01 was protective (adjusted OR = 0.55, P = 0.0046). In meta-analysis combined with 14 published studies (an additional 691 cases and 4038 controls), protective effects were seen from HLA-DR2, which comprises HLA-DRB1*15 and HLA-DRB1*16 (OR = 0.65, P = 8.2×10(-6)) and possibly from HLA-DRB1*01 (OR = 0.73, P = 0.037). GCA incidence (n = 17 countries) was associated with population HLA-DRB1*04 allele frequency (P = 0.008; adjusted R(2) = 0.51 on univariable analysis, adjusted R(2) = 0.62 after also including latitude); latitude also made an independent contribution. CONCLUSIONS: We confirm that HLA-DRB1*04 is a GCA susceptibility allele. The susceptibility data are best explained by amino acid risk residues V, H, and H at positions 11, 13, and 33, contrary to previous suggestions of amino acids in the second hypervariable region. Worldwide, GCA incidence was independently associated both with population frequency of HLA-DRB1*04 and with latitude itself. We conclude that variation in population HLA-DRB1*04 frequency may partly explain variations in GCA incidence and that HLA-DRB1*04 may warrant investigation as a potential prognostic or predictive biomarker.

The shared epitope hypothesis in rheumatoid arthritis: evaluation of alternative classification criteria in a large UK Caucasian cohort.

OBJECTIVE: Many classification systems for the HLA-DRB1 allelic association with rheumatoid arthritis (RA) have been reported, but few have been validated in additional populations. We sought to evaluate 3 different DRB1 allele classification systems in a large cohort of Caucasian RA patients and control subjects in the UK. METHODS: HLA-DRB1 typing was undertaken in 1,325 Caucasian RA patients and 462 healthy Caucasian controls who were residents of the UK. Logistic regression analyses were performed to investigate the different classification systems. RESULTS: We confirmed the association between the susceptibility alleles S2 and S3P, as proposed by Tezenas du Montcel, and the presence of RA in UK Caucasians. A significant hierarchy of risk was observed within the S3P allele group. There was no evidence of a significant association between DRB1*1001 and RA. Our data did not support the hypothesis that an isoleucine at position 67 conferred protection against RA, other than in contrast to the susceptibility alleles. However, the presence of an aspartic acid at amino acid 70 did appear to confer some degree of protection. CONCLUSION: We were unable to fully substantiate any of the 3 recent revisions of the shared epitope hypothesis in this large cohort of Caucasian RA patients and control subjects in the UK. This reinforces the importance of evaluating disease susceptibility alleles in different Caucasian populations as well as in other ethnic groups. In particular, it will be important to clarify the precise DRB1 association in a given population before DRB1 genotyping is incorporated into clinical diagnostic or treatment algorithms.