Abstract
Background Glucocorticoid monotherapy remains the principal treatment for giant cell arteritis (GCA), yet concurrent toxicity and adverse effects highlight the need for targeted therapies and improved risk stratification. Previous work suggests that evidence of genetic association can improve success rates in clinical trials and identify biomarkers for risk assessment, particularly when combined with other ‘omics data, such as proteomics. However, relatively little is currently known about the genetic basis of GCA.
Methods Polygenic risk scores (PRS) were developed for 169 human plasma proteins and tested for association with GCA susceptibility (cases N=729, controls N=2,619). Associated PRS were replicated in an independent cohort (cases N=1,129, controls N=2,654) and their respective proteins were evaluated for causality using Mendelian randomization (MR). Finally, relationships between proteins with GCA-associated PRS were assessed using protein-protein interaction (PPI) network analysis
Results The Apolipoprotein L1 (APOL1) PRS had a statistically significant GCA association with a protective effect (P-value[P]=1 x 10-4), which replicated in an independent dataset (P=8.69 x 10- 4), and MR analysis supported a causal relationship (beta=-0.093; SE=0.02; P=4.42 x 10-9). PPI network analysis of proteins with GCA-associated PRS revealed enrichment for “negative regulation of fibrinolysis” and “negative regulation of blood coagulation” pathways.
Conclusions This work emphasizes a potentially protective role of APOL1 and therefore reverse cholesterol transport in the pathogenesis of GCA. These findings also implicate fibrinolytic and coagulation cascades in GCA susceptibility, highlighting pathways that may be of interest for future pharmaceutical targeting.
Non-standard Abbreviations and Acronyms GCA, giant cell arteritis; MHC, major histocompatibility complex; GWAS, genome-wide association study; SNPs, single nucleotide polymorphisms; PRS, polygenic risk score; pQTL, protein quantitative trait loci; MR, Mendelian randomization; QC, quality control; WTCCC, Wellcome Trust Case Control Consortium; PCA, principal component analysis; IV, instrumental variables; IVW, inverse-variance weighted; PheWAS, phenome-wide association study; GO, gene ontology; FUMA, Functional Mapping and Annotation of Genome-Wide Association Studies; MAGMA, Multi-marker Analysis of GenoMic Annotation; RCT, reverse cholesterol transport.
What is new?
An apoliporotein-L1 polygenic risk score was associated with giant cell arteritis susceptibility, and replicated in an independent dataset.
Evidence for causality of a protective effect of apolipoprotein-L1 in giant cell arteritis susceptibility was identified using Mendelian randomization.
Proteins with giant cell arteritis-associated polygenic risk scores were enriched in coagulation-related, fibrinolytic and immune response pathways.
What are the clinical implications?
Findings from this study indicate a protective role of apolipoprotein-L1 in giant cell arteritis susceptibility, highlighting a potential involvement of reverse cholesterol transport and lipid metabolism in disease pathogenesis.
Fibrinolytic and coagulation cascades were also implicated in the disease in addition to innate immune response pathways, redrawing attention to the role of thromboinflammation and the need to re-evaluate anti-platelet and anticoagulant therapies, particularly for those with impending visual loss and cranial ischaemic complications.
Competing Interest Statement
The authors have no conflicts of interest for the work presented in this manuscript.
Funding Statement
This work was supported in part by the MRC ?Treatment According to Response in Giant cEll arTeritis? (TARGET) Partnership award, MRC DiMeN award, NIHR Leeds Biomedical Research Centre. The MRC TARGET Partnership award supported the salaries of AWM. AWM and MI were supported by the NIHR Leeds Biomedical Research Centre, AWM was supported by the NIHR Leeds MedTech and In Vitro Diagnostic Co-operative, NC was supported by an MRC DiMeN PhD studentship and MZ was supported by the HELICAL European Union Horizon 2020 International Training Network. AWM is additionally supported through an NIHR Senior Investigator award. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
A favourable ethical opinion for the UK GCA Consortium (UK GCA) study was granted by the Yorkshire and the Humber Leeds West Research Ethics Committee (05/Q1108/28).
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Footnotes
7 See Appendix 1 for members of the UK GCA Consortium
Apolipoprotein-L1 association with giant cell arteritis
Data Availability
Data access requests should be directed to the corresponding author. We are unable to share UK Biobank data but have included the variable names so that the study can be reproduced. Generated PRS are available on request.