Objectives: Identifying causal biomarkers of rheumatoid arthritis (RA) to improve treatment and monitor disease progression remains a critical but elusive goal. To search for putatively causal protein biomarkers of RA, we designed an integrative genomic strategy utilizing Mendelian randomization (MR), which allows for causal inference between an exposure and an outcome by incorporating genetic variants associated with an exposure (circulating protein level) and inferring its effect on the outcome (rheumatoid arthritis). Methods: We utilized genetic variants associated with 71 cardiovascular disease-related proteins measured in nearly 7000 Framingham Heart Study participants in conjunction with variants associated with RA in a genome-wide association study (GWAS) from the UK Medical Research Council Integrative Epidemiology Unit (19,234 cases, 61,565 controls) to identify putatively causal proteins for RA. In addition, we applied MR to study circulating rheumatoid factor (RF) levels using GWAS of RF from the UK Biobank (n=30,565) as the outcome. Results: We identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1 standard deviation increment in inverse-rank normalized sRAGE level=0.482; 95% confidence interval 0.374-0.622; p=1.85E-08) and RF levels ({beta} [change in RF level per sRAGE increment]=-1.280; SE=0.434; p=0.003). Conclusions: By integrating GWAS of 71 cardiovascular disease-related proteins, RA, and RF, we identified sRAGE as a putatively causal protein protective for both RA ad RF levels. These results highlight the AGER/RAGE axis as a promising new target for RA treatment.

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