title: Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic association study, meta-analysis and geo-epidemiological investigation.
abstract: BACKGROUND
  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.
authors.affiliation: School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK. s.l.mackie@leeds.ac.uk.
authors.forename: Sarah Louise
authors.initials: SL
authors.lastname: Mackie
authors.affiliation: School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK. j.c.taylor@leeds.ac.uk.
authors.forename: John C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK. l.shafi@leeds.ac.uk.
authors.forename: Lubna
authors.initials: L
authors.lastname: Haroon-Rashid
authors.affiliation: School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK. s.g.martin@leeds.ac.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Martin
authors.affiliation: Department of Rheumatology, Southend University Hospital, Prittlewell Chase, Southend, SS0 0RY, Essex, UK. bhaskar.dasgupta@southend.nhs.uk.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Dasgupta
authors.affiliation: Department of Rheumatology, Harrogate and District Foundation NHS Trust, Lancaster Park Road, Harrogate, HG2 7SX, North Yorkshire, UK. andrew.gough@hdft.nhs.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gough
authors.affiliation: Department of Rheumatology, York Teaching Hospital NHS Foundation Trust, Wigginton Road, York, YO31 8HE, North Yorkshire, UK. michael.green@york.nhs.uk.
authors.forename: Michael
authors.initials: M
authors.lastname: Green
authors.affiliation: Department of Rheumatology, Dewsbury and District Hospital, Halifax Road, Dewsbury, WF13 4HS, West Yorkshire, UK. lesley.hordon@midyorks.nhs.uk.
authors.forename: Lesley
authors.initials: L
authors.lastname: Hordon
authors.affiliation: Department of Rheumatology, Pinderfields General Hospital, Aberford Road, Wakefield, WF1 4DG, West Yorkshire, UK. stephen.jarrett@midyorks.nhs.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Jarrett
authors.affiliation: Department of Rheumatology, Chapel Allerton Hospital, Leeds, Leeds, LS7 4SA, West Yorkshire, UK. colin.pease@leedsth.nhs.uk.
authors.forename: Colin T
authors.initials: CT
authors.lastname: Pease
authors.affiliation: School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK. j.h.barrett@leeds.ac.uk.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.affiliation: Department of Rheumatology, Ipswich Hospital NHS Trust, Heath Road, Ipswich, IP4 5PD, Suffolk, UK. richard.watts@ipswichhospital.nhs.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Watts
authors.affiliation: School of Medicine and NIHR-Leeds Biomedical Research Unit, Chapel Allerton Hospital, Leeds, LS7 4SA, West Yorkshire, UK. a.w.morgan@leeds.ac.uk.|Wellcome Trust Brenner Building, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, West Yorkshire, UK. a.w.morgan@leeds.ac.uk.
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
mesh_terms: D000596:Amino Acids; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D013700:Giant Cell Arteritis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D011446:Prospective Studies; D012189:Retrospective Studies; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D000596:Amino Acids; D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen