A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

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.

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

“…Consistent with their equivalent effect sizes, these variants are in almost complete LD (r 2  = 0.99). However, the rs2476601 variant encodes an Arg620Trp substitution in the Lyp phosphatase associated with risk of multiple autoimmune diseases, including giant cell arteritis 18, 19. Although not consistently observed in candidate gene studies 20, 21, the association of rs2476601 with GPA/MPA is strongly supported by our data, and unlike most of the other significant associations observed, this allele's strength of association did not differ between the subgroups (Table 2).…”

New insights into the pathogenesis of giant cell arteritis

“…In a study performed on GCA patients from Rochester, Minnesota, USA, it has been proposed a DRYF motif at positions 28-31 in the second hypervariable region (HVR2) of MHC class II as a risk factor for GCA development [25]. However, this result has not been confirmed in a recent meta-analysis [26] and in a multicenter immunochip study [27]. Further studies have also demonstrated an association between HLA-DRB1*04 and visual loss [28] and glucocorticoid resistance [29].…”

Giant cell arteritis

“…[13]), interpretation of these studies has been hampered by difficulties in achieving the required large sample sizes for derivation and replication data sets. The first large-scale GCA genetic study, using the ImmunoChip platform, was published in 2013, and confirmed HLA-DRB1*04, followed by PTPN22 rs2476601, as the strongest genetic risk factors for GCA [18]. The study also identified other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.…”