Genetic association of primary non-response to Anti-TNFα therapy in patients with Inflammatory Bowel Disease

Abstract OBJECTIVE Primary non-response (PNR) to anti-tumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR. DESIGN Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide Association Study (PheWAS). RESULTS We identified rs34767465 as associated with PNR to anti-TNF-α therapy (OR:2.07, 95%CI:1.46-2.94, p=2.43×10−7, [Replication OR:1.8, 95%CI:1.04-3.16, p=0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNF-α secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy related pathway genes suggesting autophagy mediated TNF-α secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [p=2.3×10−4], pigmentary iris degeneration [p=5.1×10−4], diverticulum of esophagus [p=6.3×10−4]). CONCLUSION We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD. Significance of this study What is already known on this subject? Tumor necrosis factor (TNF) α is one of the major pro-inflammatory cytokines in the underlying pathogenesis of mucosal inflammation in inflammatory bowel disease (IBD), and has been the primary therapeutic target for IBD. Anti-TNFα biologic drugs have been shown to induce clinical response in 60-75% of the patients, and long-term maintenance of remission in a large number of patients that respond to the drug. However, approximately 30-40% of the patients fail to respond to anti-TNF α biologics (primary non-responders; PNR). What are the new findings? This is the first genome-wide association study to identify the genetic loci, rs34767465 associated with 2-fold increased risk of PNR to anti-TNFα therapy. rs34767465 is an expressed quantitative trait locus for FAM114A2, and leads to decreased expression of the gene in blood and LCLs. Knockdown of FAM114A2 in THP-1 cells-derived macrophages increase TNFα secretion through mechanism related to autophagy. Phenome-wide association study reveals association of rs34767465 with comorbid conditions like derangement of joints, pigmentary iris degeneration and diverticulum of esophagus, that are observed in IBD patients How might it impact on clinical practice in the foreseeable future? rs34767465 may help guide physicians’ drug choice and therapeutic drug monitoring to prevent PNR to anti-TNFα therapy and IBD associated comorbidities.