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

Area of Science:

• Genetics
• Immunology
• Rheumatology

Background:

• Giant cell arteritis (GCA) is the most prevalent vasculitis in individuals over 50 in Western countries.
• Understanding the genetic factors influencing GCA susceptibility is crucial for disease management.

Purpose of the Study:

• To identify genetic variants associated with GCA susceptibility through a large-scale genome-wide association study.
• To explore the functional relevance of identified risk genes in GCA pathogenesis.

Main Methods:

• Genome-wide association screening of 1,844,133 genetic variants in 2,134 GCA cases and 9,125 controls of European ancestry.
• Imputation analysis to increase variant density and statistical power.
• Analysis of association peaks overlapping with regulatory elements.

Main Results:

• Confirmed HLA class II as the strongest associated region for GCA risk (e.g., rs9268905, P=1.94×10⁻⁵⁴).
• Identified PLG (rs4252134, P=1.23×10⁻¹⁰) and P4HA2 (rs128738, P=4.60×10⁻⁹) as novel GCA risk genes.
• Observed overlap of association peaks with regulatory elements relevant to GCA pathophysiology.

Conclusions:

• Genetic factors, particularly within HLA class II, PLG, and P4HA2, significantly influence GCA susceptibility.
• PLG and P4HA2 involvement in vascular remodeling and angiogenesis highlights their importance in GCA pathogenesis.
• These findings provide a deeper understanding of GCA's genetic architecture and potential therapeutic targets.