[Impact of tumor necrosis factor superfamily member 4 gene polymorphisms on the risk of Crohn's disease and clinical efficacy of ustekinumab].
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OBJECTIVE: To explore the impact of tumor necrosis factor superfamily member 4 (TNFSF4) gene polymorphisms on the risk and clinicopathological features of Crohn's disease (CD), as well as the clinical efficacy of ustekinumab (UST). METHODS: A total of 296 patients with CD diagnosed at the Department of Gastroenterology, The Second Affiliated Hospital of Wenzhou Medical University between January 2018 and August 2025, and 532 healthy controls were selected. Genotypes of TNFSF4 (rs3850641 and rs45454293) were detected using multiplex polymerase chain reaction-ligase detection reaction technique. According to the Montreal Classification Criteria of Crohn's disease, the patients were divided into subgroups. The degree of clinical activity and intestinal inflammation degree of CD patients were evaluated by the Crohn's disease activity index (CDAI) and Simplified Crohn's disease endoscopic score (SES-CD), respectively. Unconditional Logistic regression model was used to analyze the distribution of TNFSF4 gene polymorphisms between the CD group and health control group, as well as between different subgroups of CD patients. Among them, a total of 247 cases receiving the routine UST therapy were divided into clinical response group (CDAI decreased by ≥ 100 points compared to week 0 or CDAI < 150 points) and clinical non-response group based on the changes in CDAI at week 8. They were also divided into mucosal healing group (SES-CD ≤ 2 points or no mucosal ulcer) and non-mucosal healing group based on the changes in SES-CD at week 34. Univariate Logistic regression was used to analyze the influencing factors for the clinical response and mucosal healing. Furthermore, unconditional Logistic regression was applied to assess the effect of TNFSF4 gene variants on the clinical response and mucosal healing. Generalized estimating equations were employed to analyze the effect of TNFSF4 gene polymorphisms on the longitudinal changes of efficacy outcomes. Bonferroni correction was applied for multiple comparisons. RESULTS: The variant genotype (AG+GG) and variant allele (G) of rs3850641 in the CD group were more frequent than those in the control group (38.18% vs. 29.32%, P = 0.011, adjusted P = 0.022; 21.45% vs. 16.45%, P = 0.015, adjusted P = 0.030). The same conclusion was also drawn for the variant genotype (CT+TT) and variant allele (T) of rs45454293 (35.81% vs. 27.26%, P = 0.012, adjusted P = 0.024; 19.59% vs. 14.76%, P = 0.014, adjusted P = 0.028). Although the homozygous variant genotype (TT) of rs45454293 was more frequent among patients with stricturing or penetrating CD compared with those with non-stricturing, non-penetrating CD (5.93% vs. 1.24%, P = 0.041), the adjusted P value was over 0.05 after Bonferroni multiple correction. At week 8 of the UST therapy, the homozygous variant genotype (GG) of rs3850641 in the response group was less prevalent compared with the non-response group (1.69% vs. 11.59%, P = 0.004, adjusted P = 0.008). Similar result was obtained for the homozygous variant genotype (TT) of rs45454293 (1.69% vs. 10.14%, P = 0.008, adjusted P = 0.016). At week 34, the homozygous variant genotype (GG) of rs3850641 in the mucosal healing group was less common compared with the mucosal non-healing group (1.27% vs. 10.11%, P = 0.015, adjusted P = 0.030). CONCLUSION: The rs3850641 and rs45454293 variants may not only increase the risk of CD, but also reduce the early clinical response rate of the UST therapy. The rs3850641 variant may also lower the late mucosal healing rate of the UST therapy.