Association of Genetic Loci for Human Plasma Proteins with Response to Treatment in People with Rheumatoid Arthritis

We used locus-specific genotypic scores for human plasma proteins (pQTLs), gene expression (eQTLs), and gene methylation (mQTLs) to detect effects of these intermediate variables on response to Tumor Necrosis Factor inhibitors (TNFi) in over 3,000 people with Rheumatoid Arthritis (RA).  Change in erythrocyte sedimentation rate (ΔESR) and in Swollen 28-Joint Count (ΔSJC) were used to quantify TNFi response. Associations were adjusted for false discovery rate. Significant loci were further explored by Mendelian randomisation (MR) and colocalization analyses. One cis pQTL score on chromosome 10 for the ENTPD1 protein and five trans pQTL scores on chromosome 3 for the ARHGAP30, APOM, EHMT2, BGN, and FURIN proteins were associated with TNFi response. Validation using SWATH-MS protein expression data in 180 people confirmed that APOM expression was significantly associated with TNFi response. Signals on chromosome 3 occurred within butyrylcholinesterase (BCHE) locus. The eQTL and mQTL cis scores for the BCHE gene were associated with TNFi response (P < 0.05) and the genetic signals colocalized with the trans pQTLs suggesting common causal variants. MR analysis using two independent instruments for the butyrylcholinesterase enzyme indicated a positive causal effect on TNFi response (β = 0.13, P = 0.033). We have detected a strong genetic signal for TNFi response at the BCHE locus and provided evidence of a weak causal effect of the butyrylcholinesterase enzyme. BCHE has not been previously associated with TNFi response. The apparent pleiotropy in this locus, indicated by five trans pQTLs makes it difficult to identify the most likely causal pathway.