Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease

Abstract

Objectives Primary nonresponse (PNR) to antitumor 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. Patients and methodsPatients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genomewide 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 cellbased assays. Pleiotropic effects were investigated by Phenome-wide association study (PheWAS). ResultsWe identified rs34767465 as associated with PNR to anti-TNFα therapy (odds ratio: 2.07, 95% CI, 1.46-2.94, P = 2.43 × 10 −7 , [replication odds ratio: 1.8, 95% CI, 1.04-3.16, P = 0.03]). rs34767465 is a multipletissue 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. TNFα secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagyrelated pathway genes suggesting autophagy-mediated TNFα secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [P = 3.7 × 10 −4 ], pigmentary iris degeneration [P = 5.9 × 10 −4 ], diverticulum of esophagus [P = 7 × 10 −4 ]). ConclusionsWe 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.

Apoptosis and inflammatory genes variants in primary non-response to anti-TNF therapy in Crohn’s disease patients

“…These studies are a new direction in the optimization of biological treatment. However, they require confirmation by subsequent researchers [40]. Anti-TNFα therapy is effective not only in IBD but also in rheumatological and dermatological diseases.…”

“…This allele affects the reduced expression of FAM114A2 , both at the mRNA level and at the concentration of this protein. The consequence of this is the impairment of the autophagy pathway and the increase of TNFα secretion [40]. Autophagy disorders play a significant role in the pathogenesis of CD.…”

“…These studies are a new direction in the optimization of biological treatment. However, they require confirmation by subsequent researchers [40].…”

Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis

“…Clinical studies on TNFi further supported the role of TNF-α in the pathogenesis of ankylosing spondylitis [ 33 , 34 ]. Intriguingly, in addition to the impact of inherited predisposition on the anti-TNF-α treatment response [ 35 ], the correlation of TNF-α with gut microbiota has also been revealed. For instance, some patients with ulcerative colitis were not sensitive to TNFi and exhibited significantly different baseline gut microbiota compared with patients who were sensitive to TNFi [ 36 ], and the TNF-α level of the host can also influence the gut microbiota composition [ 37 ].…”