Background
In a paper in Nature Immunology, the SCALLOP consortium (Systematic and Combined AnaLysis of Olink Proteins) reported on their findings from a large proteogenomics study into the genetic influences on inflammation-related proteins, providing important insights into the pathogenesis of immune-mediated diseases. GWAS data and plasma protein measurements using the Olink® Target 96 Inflammation panel were obtained from 11 SCALLOP member cohorts, totaling 14,824 samples. Summary protein quantitative trait loci (pQTL) data was generated for each cohort separately and used to input into a multi-cohort meta-analysis and the data was evaluated using Mendelian Randomization (MR) in relation to multiple immunological diseases.
Outcome
The meta-analysis identified 180 significant associations between 108 genomic regions and 70 proteins: 59 (33%) were cis-pQTLs and 121 (67%) trans-pQTLs. These findings included several trans-pQTL “hotspots” associated with multiple proteins (e.g., one genetic variant that was associated with the levels of CXCL9, CXCL10, CXCL11, CD5, CD244 and IL-12B). Overall, 31 pQTLs overlapped with GWAS hits for at least one immune-mediated disease, with 76 unique pQTL protein–disease associations in total. One interesting example was a cis-pQTL for IL-10 that was associated with reduced risk of inflammatory bowel disease (IBD), consistent with the known anti-inflammatory effects of IL-10. Applying MR identified 10 significant causal associations between protein levels and diseases that retained significance after additional filters were applied to account for confounding factors. Several of these links were supported by independent evidence, such as a causal pQTL for IL-12B associated with IBD risk – consistent with the therapeutic benefit of ustekinumab (a monoclonal antibody targeting the p40 subunit of IL-12). Furthermore, CXCL5 was causally associated with ulcerative colitis (UC), a finding supported by elevated gut CXCL5 mRNA levels in patients with UC.
They concluded that their results identify pathways that are already the target of existing drugs, providing confirmation of the utility of the approach used, and also highlight new potential therapeutic targets for several different immune-mediated diseases.
