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 TGFβ1/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.