Abstract
We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05× 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08× 10(-43)) and HLA-DQα1 47 (p = 4.02× 10(-46)), 56, and 76 (both p = 1.84× 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73× 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39× 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10× 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.
Highlights
Giant cell arteritis (GCA [MIM 187360]) is a chronic and polygenic immune-mediated disease of unknown etiology that is the most common form of vasculitis in individuals over the age of 50 in Western countries.[1,2] It is characterized by inflammatory damage of large- and medium-sized arteries, the extracranial branches of the carotid artery, which can lead to severe complications such as blindness or cerebrovascular events.[3,4]During the last decade, genetic association studies have described several genes that are associated with predisposition to giant cell arteritis (GCA), including genes of immune/inflammatory pathways and genes of the human leukocyte antigen (HLA) class I and II regions
High association peaks were observed in HLA-DRB1*04, HLA-DQA1*03, and HLADQB1*03 alleles (Table 1), HLA-DRB1*04:04 (p 1⁄4 2.12 3 10À23, Odds ratios (OR) 1⁄4 2.28), HLA-DQA1*03:01 (p 1⁄4 1.38 3 10À35, OR 1⁄4 1.85), and HLA-DQB1*03:02 (p 1⁄4 3.93 3 10À28, OR 1⁄4 1.90)
The peak signal corresponded to a SNP in high linkage disequilibrium (LD; r2 1⁄4 0.43, D’ 1⁄4 1.00) with a group of SNPs and amino acids of HLA-DRB1 in complete LD with one another that have a stronger effect size, including a His in position 13 (p 1⁄4 5.12 3 10À38, OR 1⁄4 1.92) located in the binding groove of the molecule.[35]
Summary
Giant cell arteritis (GCA [MIM 187360]) is a chronic and polygenic immune-mediated disease of unknown etiology that is the most common form of vasculitis in individuals over the age of 50 in Western countries.[1,2] It is characterized by inflammatory damage of large- and medium-sized arteries, the extracranial branches of the carotid artery, which can lead to severe complications such as blindness or cerebrovascular events.[3,4]During the last decade, genetic association studies have described several genes that are associated with predisposition to GCA, including genes of immune/inflammatory pathways and genes of the human leukocyte antigen (HLA) class I and II regions. The Immunochip allows a dense analysis of 196,524 SNPs, rare variants, and insertion/deletion (indel) polymorphisms, located within 186 known susceptibility loci for autoimmune and inflammatory disorders.[6] The use of the Immunochip has substantially increased the number of established genetic risk factors for multiple immune-mediated diseases, including Takayasu arteritis (another large-vessel vasculitis [MIM 207600]),[7] celiac disease (MIM 212750),[8] rheumatoid arthritis (RA [MIM 180300]),[9] autoimmune thyroid disease (MIM 275000 and 140300),[10] psoriasis (MIM 177900),[11] primary biliary cirrhosis (MIM 109720),[12,13] juvenile idiopathic arthritis (MIM 604302),[14] primary sclerosing cholangitis (MIM 613806),[15] narcolepsy (MIM 161400),[16] ankylosing spondylitis (MIM 106300),[17] atopic dermatitis (MIM 603165),[18] and systemic sclerosis (SSc [MIM 181750]).[19] The use of the same platform in all the above studies has facilitated the identification of common aetiopathogenic pathways among those disorders.[20]
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