[Association of Toll-like receptor 5 gene polymorphism with the clinical efficacy of ustekinumab in patients with Crohn's disease].

Objectives

To investigate the association of Toll-like receptor 5 (TLR5) gene polymorphisms with the clinical efficacy of ustekinumab (UST) in the treatment of Crohn's disease (CD) patients.

Methods

The patients with active CD who received UST treatment were retrospectively recruited from the Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University between January 2022 and April 2025. The loci rs5744168 and rs5744174 in TLR5 gene were genotyped by multiplex polymerase chain reaction-ligase detection reaction technique. The clinical response of CD patients was evaluated by Harvey-Bradshaw index (HBI) at week 8 of follow-up. The patients were divided into the response group (a decline of HBI≥ 3 points compared with week 0) and the non-response group. The mucosal healing was assessed by the Simplified Endoscopic Score for Crohn's disease (SES-CD) at week 32 of UST treatment. The patients were divided into the mucosal healing group (SES-CD≤2 points or absence of mucosal ulcerations) and the mucosal non-healing group. The distribution differences of TLR5 gene polymorphism were compared between the response group and the non-response group, as well as between the mucosal healing group and the mucosal non-healing group. The genotypes or alleles with distribution differences were included into unconditional logistic regression models to investigate the association between the gene polymorphisms of TLR5 and the clinical efficacy of UST treatment in CD patients.

Results

A total of 198 CD patients were included (133 males, 65 females), with age of (32±12) years. There were 117 cases in the response group and 81 cases in the non-response group at week 8 of UST treatment. The homozygous variant genotype (GG) [1.7% (2/117) vs 11.1% (9/81), corrected P=0.024] and variant allele (G) [15.8% (37/234) vs 27.8% (45/162), corrected P=0.008] of locus rs5744174 in the response group were less frequent than those in the non-response group. The homozygous variant genotype (GG) (OR=0.17, 95%CI: 0.04-0.83, P=0.029) and variant allele (G) (OR=0.51, 95%CI: 0.31-0.85, P=0.010) of locus rs5744174 were shown to be associated with the clinical response at week 8. There were 79 cases in the mucosal healing group and 119 cases in the mucosal non-healing group at week 32 of UST treatment. The frequency of variant genotype (GA+AA) [15.2% (12/79) vs 1.7% (2/119), corrected P<0.001] and the frequency of variant allele (A) [9.5% (15/158) vs 0.8% (2/238), corrected P<0.001] of locus rs5744168 in mucosal healing group were higher than those in the mucosal non-healing group. The variant genotype (GA+AA) (OR=8.94, 95%CI: 1.88-42.50, P=0.006) and variant allele (A) (OR=9.54, 95%CI: 2.09-43.66, P=0.004) of locus rs5744168 were found to be related with the mucosal healing at week 32.

Conclusions

Among the patients with active CD receiving UST treatment, the variation of locus rs5744174 in TLR5 gene may be associated with a reduced clinical response rate at week 8. However, the variation of locus rs5744168 may be linked to an increased mucosal healing rate at week 32.