Guy's and St Thomas' NHS Foundation Trust London, United Kingdom
No financial relationships with ineligible companies to disclose
Benjamin Zuckerman1, Alasdair Warwick2, art Schuermans3, Mark Gibson4, Ioasaf Karafotias5, Zijing Yang1, Carine moezinia6, Mark Russell7, Chris Wincup8, James Galloway9 and Sizheng Zhao10, 1King's College London, London, England, United Kingdom, 2University college London, London, United Kingdom, 3KU Leuven, Leuven, Belgium, 4King's College London, Newmarket, United Kingdom, 5King's College London, London, United Kingdom, 6univerity college hospital, London, United Kingdom, 7King's College London, London, United Kingdom, 8King's College Hospital, London, United Kingdom, 9Centre for Rheumatic Diseases, King's College London, London, United Kingdom, 10Centre for Musculoskeletal Research, The University of Manchester, Liverpool, United Kingdom Background/Purpose: The pathophysiology of primary Sjögren’s disease involves the interaction of genetic, epigenetic, and environmental factors. With limited treatment options for severe disease, a detailed understanding the proteomic architecture is necessary. Herein, we investigated the associations between circulating proteins on primary Sjögren’s disease using mendelian randomization. Methods: We selected single nucleotide polymorphisms from protein quantitative trait loci using the genome wide association studies from samples profiled in the UK Biobank Pharma Proteomics Project. Genetic association data for proteins were collected from a study with a sample size of 54,306, and from 3,232 individuals with primary Sjögren’s syndrome and 17,481 controls. Forward and reverse mendelian randomization analyses were conducted. The Wald ratio or inverse variance weighted methods estimated causal effects. We applied colocalization and pleiotropy-robust methods as sensitivity analyses for confounding. Results: 1,963 of the selected proteins were valid from which 35 survived the mendelian randomization analyses and multiple comparisons assessment, as well as the sensitivity tests (Table 1). Colocalization analyses highlighted that 15 of these proteins had conditional probabilities for a shared causal variant exceeding 80%, suggesting minimal genetic confounding. Notably, our results suggested that CD40 is implicated in primary Sjögren's disease pathogenesis (odds ratio [OR] 0.80; 95% confidence interval [CI] 0.72-0.88). Reverse mendelian randomization analyses confirmed a causal role for the 15 proteins which survived multiple comparison assessments and identified 28 potential biomarkers for primary Sjögren’s disease (Table 2). Conclusion: We provided genetic evidence further elucidating the complexity of primary Sjögren’s disease pathogenesis. Additionally, we suggested a genetic causal link between CD40 and primary Sjögren's disease - supporting the continued investigation of anti-CD40 therapy, such as iscalimab, as a novel treatment for this condition.
Table 1. The mendelian randomization results for assessing protein quantitative trait loci association with primary Sjögren’s disease.
Table 2. The mendelian randomization results for assessing primary Sjögren’s disease associations with protein quantitative trait loci.
B. Zuckerman: None; A. Warwick: None; a. Schuermans: None; M. Gibson: None; I. Karafotias: None; Z. Yang: None; C. moezinia: None; M. Russell: AbbVie/Abbott, 6, Biogen, 1, Eli Lilly, 6, Galapagos, 6, Menarini, 6, Sandoz, 5, UCB, 6, Viforpharma, 6; C. Wincup: Versus Arthritis, Lupus UK, Astrazeneca and British Society for Rheumatology, 5; J. Galloway: AbbVie, 6, AstraZeneca, 5, Galapagos, 2, 6, Janssen, 2, 5, 6, Lilly, 2, 6, Pfizer, 2, 5, 6, UCB, 6; S. Zhao: None.