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

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Introduction</jats:title> <jats:p>Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with <jats:italic>HLA-DRB1*</jats:italic>04 and <jats:italic>HLA-DRB1</jats:italic>*01; <jats:italic>HLA-DRB1</jats:italic> alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within <jats:italic>HLA-DRB1</jats:italic> best explained <jats:italic>HLA-DRB1</jats:italic> 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 <jats:italic>HLA-DRB1</jats:italic> alleles that we identified in our meta-analysis.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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 <jats:italic>HLA-DRB1</jats:italic>*04 population carrier frequency and latitude to GCA incidence reported in different countries.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>In our UK data (225 cases and 1378 controls), <jats:italic>HLA-DRB1*</jats:italic>04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, <jats:italic>P</jats:italic> = 1.5×10<jats:sup>−11</jats:sup>), but <jats:italic>HLA-DRB1*</jats:italic>01 was protective (adjusted OR = 0.55, <jats:italic>P</jats:italic> = 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 <jats:italic>HLA-DRB1</jats:italic>*15 and <jats:italic>HLA-DRB1</jats:italic>*16 (OR = 0.65, <jats:italic>P</jats:italic> = 8.2×10<jats:sup>−6</jats:sup>) and possibly from <jats:italic>HLA-DRB1</jats:italic>*01 (OR = 0.73, <jats:italic>P</jats:italic> = 0.037). GCA incidence (<jats:italic>n</jats:italic> = 17 countries) was associated with population <jats:italic>HLA-DRB1</jats:italic>*04 allele frequency (<jats:italic>P</jats:italic> = 0.008; adjusted R<jats:sup>2</jats:sup> = 0.51 on univariable analysis, adjusted R<jats:sup>2</jats:sup> = 0.62 after also including latitude); latitude also made an independent contribution.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We confirm that <jats:italic>HLA-DRB1</jats:italic>*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 <jats:italic>HLA-DRB1</jats:italic>*04 and with latitude itself. We conclude that variation in population <jats:italic>HLA-DRB1</jats:italic>*04 frequency may partly explain variations in GCA incidence and that <jats:italic>HLA-DRB1</jats:italic>*04 may warrant investigation as a potential prognostic or predictive biomarker.</jats:p> </jats:sec>