Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study

Abstract

Background: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci.

Methods: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings.

Findings: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10^-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10^-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10^-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10^-13).

Interpretation: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis.

Funding: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Figure 1

Gene prioritisation for loci associated with giant cell arteritis Colours indicate the SNPs or genes associated with giant cell arteritis that overlap with the considered functional annotations. Different colours indicate different categories of annotations. The items evaluated comprise information about the genomic location of the genetic variants, their correlation with gene and protein expression, evidence of chromatin interaction, and their V2G score from Open Target Genetics (appendix p 15). The last column shows if the prioritised causal genes are targets for approved drugs, according to our drug repurposing analysis. The drug target item was not considered for gene prioritisation. pQTL=protein quantitative trait loci. eQTL=expression quantitative trait loci. SNP=single nucleotide polymorphism. V2G=Variant-to-Gene. *The gene is in high-confidence protein–protein interaction with an identified drug target.

Figure 2

Genetic risk distribution Predictive ability of the polygenic risk score model, including 11 SNPs (HLA and non-HLA). (A) Density plot of the distribution of genetic risk between patients with giant cell arteritis and controls. Dashed lines represent the percentile thresholds used to calculate the OR of each division. (B) ORs associated with the group at high risk of giant cell arteritis when segregating the test sample by the same percentile thresholds. Error bars depict 95% CIs. OR=odds ratio.