Exploration of the circulating human secretome through protein quantitative trait analysis...
Published Date: 21st January 2024
Publication Authors: Dawson G
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.
Chaddock, NJM et al Dawnson, G (Collaborator). (2024). 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. medRxiv. epub 21 Jan(.), p... [Online]. Available at: https://doi.org/10.1101/2024.01.19.24301534 [Accessed 4 April 2024].
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