TNFSF15 Variant Predicts Disease Progression in Chinese Patients with Crohn’s Disease

Background: The genetic variant of tumor necrosis factor superfamily member 15 ( TNFSF15 ) is associated with Crohn's disease (CD) and the development of intestinal fibrosis and stricturing. We aimed to investigate its predictive role in disease progression and the impact of ileal fibrosis-associated protein expression in Chinese patients with CD. Methods: We genotyped the single nucleotide polymorphism rs6478109 within the TNFSF15 gene in 428 CD patients and 450 health controls to assess its association with CD. Genotype-phenotype correlation analyses were performed. Mucosal samples from non-diseased terminal ileum were analyzed for TL1A and fibrosis-associated protein expression using western blot and immunohistochemistry. Results: The G allele frequency of rs6478109 was significantly higher among CD patients compared with health controls (63.3% vs. 46.7%, P < 0.001). Patients with GG genotype were more predisposed to develop the stricturing phenotype, compared with those with AA + AG genotypes with a hazard ratio of 1.426 (95% confidence interval: 1.029-1.977, P = 0.033). This trend was similarly observed in patients utilizing biological agents, with a hazard ratio of 4.396 (95% confidence interval: 1.780-10.854, P = 0.001). Furthermore, increased TL1A, pro-fibrotic proteins, and TGF beta 1/Smad3 pathway activation were observed in non-diseased ileal mucosa of patients with GG genotype compared with those with AA genotype. Conclusions: The TNFSF15 risk genotype GG could promote the expression of pro-fibrotic proteins and may serve as a predictor for stricturing CD.