Background/Purpose

Giant cell arteritis (GCA) has been reported by many studies (but not all) to be associated with carriage of HLA-DRB1*04, with variable results relating to other alleles, but formal meta-analysis has never been performed. Our objective was to study the influence of HLA-DRB1 alleles on GCA susceptibility and incidence, combining new UK data with a meta-analysis of the literature.

Methods

GCA patients from the UK GCA Consortium were genotyped using single strand oligonucleotide polymerization, allele-specific polymerase chain reaction and direct sequencing. Control data was provided by the UK RA Genetics (UKRAG) Consortium. Meta-analysis was used to combine our results with previously-published data. Finally we determined the relationship of HLA-DRB1*04 population carrier frequency to the incidence of GCA reported in different countries.

Results

In the new UK data (225 cases, 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (OR=2.69, p=1.5 x10^-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, comprising 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). The incidence of GCA (n=17 countries) was associated with HLA-DRB1*04 allele frequency in the population (p=0.008; adjusted R²=0.51 on univariable analysis, adjusted R²=0.62 after also including latitude).

Conclusion

This meta-analysis confirms HLA-DRB1*04 as a GCA susceptibility allele but fails to show a susceptibility effect of HLA-DRB1*01, despite sharing amino acids in common in the third hypervariable region. Variations in population frequency of HLA-DRB1*04 might help explain worldwide variations in GCA incidence; latitude appears to make an independent contribution to GCA risk.