Publication Date
2015
Journal Title
Am J Hum Genet
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 x 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DR beta 1 and HLA-DQ alpha 1 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 DR beta 1 13 (p = 4.08 x 10(-43)) and HLA-DQ alpha 1 47 (p = 4.02 x 10(-46)), 56, and 76 (both p = 1.84 x 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 x 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 x 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 x 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.
Volume Number
96
Issue Number
4
Pages
565-580
Document Type
Article
EPub Date
2015/03/31
Status
Faculty
Facility
School of Medicine
Primary Department
Molecular Medicine
Additional Departments
General Internal Medicine
PMID
DOI
10.1016/j.ajhg.2015.02.009