Proteome-Wide Mendelian Randomization in Ankylosing Spondylitis

Objectives While numerous proteins have been linked to ankylosing spondylitis (AS), the causal nature of these associations remains unconfirmed. This study employed a Mendelian randomization (MR) approach to evaluate whether circulating plasma protein levels, derived from large-scale international dataset, are causally associated with AS risk. Methods The study analyzed genetic summary data from 1,462 AS patients and 164,682 controls, all of whom had undergone genome-wide association scans, as identified from the FinnGen consortium. Large-scale plasma protein quantitative trait locus (pQTL) data were sourced from the UK Biobank Proteomics Project (UKB-PPP; 2,923 unique proteins), the INTERVAL study (2,995 unique proteins), and the Icelandic study (4,719 proteins).[1] Potential protein candidates were identified based on SNP associations with proteins (p < 5×10^-8), followed by linkage disequilibrium (LD) clumping to identify independent pQTLs for each protein (r^2 < 0.001), and defining SNPs when the leading SNP was located within 500kb of the transcription site of the protein-coding gene. A 2-sample MR analysis was then conducted, using the Wald ratio for genes with 1 SNP and inverse variance weighting (IVW) for those genes with multiple SNPs. Sensitivity analyses, including tests for pleiotropy and heterogeneity, were performed to ensure robustness of the causal estimates. Results A total of 21 unique proteins were identified as being associated with the risk of AS. In the UKB-PPP dataset, 3 proteins were linked to an increased risk of AS (DXO, LTA, AGER), while 6 proteins associated with a decreased risk (TRIM40, LTB, AIF1, HLA-E, MICB_MICA, CFB). The INTERVAL dataset identified 5 proteins correlated with an elevated risk of AS (IL-23R, TNXB, CFB, MICB, ERAP1) and AGER protein was linked to a reduced risk. From a 2021 dataset,[1] MR identified 8 proteins significantly associated with AS (HLA-DQA2, ERAP1, MICB, BTN3A3, TAPBP, C2, CFB, TNXB and 7 proteins with decreased risk NCR3, HSPA1L, MICA, VARS, APOM, AIF1, AGER). The top 6 Reactome pathways identified from pathway enrichment analysis included Immune system, cytokine signaling, adaptive immune system, adaptive immune system, innate immune system and signaling by interleukins (1 ×10^-6). Conclusion This proteome-wide MR study identified 21 unique proteins associated with AS risk, offering novel insights into the disease’s pathogenesis. These prioritized proteins also present potential druggable targets, warranting further investigation to explore novel therapeutic opportunities. References [1.] Ferkingstad E. Nat Genet 2021;53:1712-21.