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.
A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility / Carmona FD; Mackie SL; Martin JE; Taylor JC; Vaglio A; Eyre S; Bossini-Castillo L; Castaneda S; Cid MC; Hernandez-Rodriguez J; Prieto-Gonzalez S; Solans R; Ramentol-Sintas M; Gonzalez-Escribano MF; Ortiz-Fernandez L; Morado IC; Narvaez J; Miranda-Filloy JA; Beretta L; Lunardi C; Cimmino MA; Gianfreda D; Santilli D; Ramirez GA; Soriano A; Muratore F; Pazzola G; Addimanda O; Wijmenga C; Witte T; Schirmer JH; Moosig F; Schonau V; Franke A; Palm O; Molberg O; Diamantopoulos AP; Carette S; Cuthbertson D; Forbess LJ; Hoffman GS; Khalidi NA; Koening CL; Langford CA; McAlear CA; Moreland L; Monach PA; Pagnoux C; Seo P; Spiera R; Sreih AG; Warrington KJ; Ytterberg SR; Gregersen PK; Pease CT; Gough A; Green M; Hordon L; Jarrett S; Watts R; Levy S; Patel Y; Kamath S; Dasgupta B; Worthington J; Koeleman BPC; de Bakker PIW; Barrett JH; Salvarani C; Merkel PA; Gonzalez-Gay MA; Morgan AW; Martin J. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - ELETTRONICO. - 96:(2015), pp. 565-580. [10.1016/j.ajhg.2015.02.009]
A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility
Vaglio A;
2015
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.I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.