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

BackgroundGlucocorticoid 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. MethodsPolygenic 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 ResultsThe 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. ConclusionsThis 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 AcronymsGCA, 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. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIAn apoliporotein-L1 polygenic risk score was associated with giant cell arteritis susceptibility, and replicated in an independent dataset. C_LIO_LIEvidence for causality of a protective effect of apolipoprotein-L1 in giant cell arteritis susceptibility was identified using Mendelian randomization. C_LIO_LIProteins with giant cell arteritis-associated polygenic risk scores were enriched in coagulation-related, fibrinolytic and immune response pathways. C_LI What are the clinical implications?O_LIFindings 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. C_LIO_LIFibrinolytic 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. C_LI