Exploration of the circulating human secretome through protein quantitative trait analysis identifies an association between circulating levels of apolipoprotein L1 and risk of giant cell arteritis

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. ### 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). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes 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.