A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

Abstract

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10, OR = 1.28; and rs128738, p = 4.60 × 10, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.

New insights into the pathogenesis of giant cell arteritis

“…More recently, Carmona et al published a GWAS demonstrating that PLG and P4HA2 are risk genes at the genome-wide level of significance. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, processes involved in the pathogenic mechanisms underlying GCA [32]. Coit P et al recently performed a DNA-methylation study in temporal arteries from patients with GCA and controls [33].…”

Varicella Zoster Virus–Specific T Cell Responses in Untreated Giant Cell Arteritis: Comment on the Article by England et al

“…T cells are important in the pathogenesis of GCA . Genetic association studies and strict tissue tropism suggest that it is an antigen‐driven disease . The antigen could be either a self antigen or a pathogen‐derived antigen that is expressed only in the large arteries.…”

Diagnosis and management of giant cell arteritis: an Asia‐Pacific perspective

“…Similarly, the PTPN22 rs2476601 variant is essentially a northern European Caucasian allele with a north–south decline in frequency across Europe. More recently, genes involved in vascular remodeling and angiogenesis processes (PLG and P4HA2) have been identified as risk factors for GCA, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.…”