Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Giant cell arteritis (GCA) is an immune-mediated polygenic disease characterized by inflammatory lesions in medium- and large-sized arteries. The aim of the present study was to perform the first unbiased genome-wide association study (GWAS) of GCA in order to identify the most relevant genetic factors contributing to disease predisposition.
Methods: We obtained genome-wide genotypes of 2,134 cases of GCA and 9,125 unaffected controls from 10 different populations of European ancestry (Spain, UK, North America, Italy, Germany, France, Norway, Netherlands, Switzerland, and Ireland). After imputation and tight quality filters, a total of 1,844,133 single-nucleotide polymorphisms were analyzed by logistic regression under an additive model using sex and ten first principal components as covariates. The inverse variance weighted method under fixed effects was used to meta-analyze the different studies.
Results: Two independent signals within the HLA class II region were strongly associated with GCA: rs9268905 (P = 1.94E-54, OR = 1.79, 95% CI = 1.67-1.93), located between the HLA-DRA and HLA-DRB1 genes, and rs9275592 (P = 1.14E-40, OR = 2.08, 95% CI = 1.87-2.32), located between HLA-DQA1 and HLA-DQA2. Outside the HLA region, different genetic variants of plasminogen (PLG) and prolyl 4-hydroxylase subunit alpha 2 (P4HA2), which encode proteins with relevant roles in vascular remodeling and neoangiogenesis, were associated at the genome-wide level of significance (top hits: PLG rs4252134, P = 1.23E-10, OR = 1.28, 95% CI = 1.19-1.39; and P4HA2 rs128738, P = 4.60E-09, OR = 1.32, 95% CI = 1.20-1.45). Using publicly available functional annotation data, we observed that the associated signals correlated with eQTLs and histone marks specific for cell types and tissues involved in GCA pathology.
Conclusion: Consistent with previously published data, our results confirm the HLA class II as the most relevant genetic region for GCA. Additionally, we have identified PLG and P4HA2 as novel GCA risk loci, highlighting the importance of the angiogenesis processes in the development of this form of large vessel vasculitis.
To cite this abstract in AMA style:Carmona FD, Vaglio A, Mackie S, Hernández-Rodríguez J, Monach PA, Castañeda S, Solans R, Morado IC, Narváez FJ, Ramentol-Sintas M, Pease CT, Dasgupta B, Watts R, Khalidi NA, Langford CA, Ytterberg SR, Boiardi L, Beretta L, Govoni M, Emmi G, Bonatti F, Cimmino MA, Witte T, Neumann T, Holle J, Schönau V, Sailler L, Papo T, Haroche J, Mahr A, Mouthon L, Molberg Ø, Diamantopoulos AP, Voskuyl AE, Brouwer E, Daikeler T, Berger C, Molloy ES, O'Neill L, Blockmans D, Lie BA, Mclaren P, Vyse TJ, Wijmenga C, Allanore Y, Koeleman BPC, Barrett JH, Cid MC, Salvarani C, Merkel PA, Morgan AW, González-Gay MA, Martín J. New Insights into the Pathogenesis of Giant Cell Arteritis through a Genome-Wide Association Study [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/new-insights-into-the-pathogenesis-of-giant-cell-arteritis-through-a-genome-wide-association-study/. Accessed October 26, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/new-insights-into-the-pathogenesis-of-giant-cell-arteritis-through-a-genome-wide-association-study/