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

Am J Hum Genet. 2017 Jan 5;100(1):64-74. doi: 10.1016/j.ajhg.2016.11.013. Epub 2016 Dec 29.

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 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, 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.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alleles*
  • Cohort Studies
  • Europe / ethnology
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation*
  • Genome-Wide Association Study*
  • Giant Cell Arteritis / genetics*
  • Humans
  • Male
  • Neovascularization, Physiologic
  • Plasminogen / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Prolyl Hydroxylases / genetics*
  • Risk

Substances

  • Plasminogen
  • Prolyl Hydroxylases
  • collagen prolyl-4-hydroxylase alpha subunit 2, human