The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.

Background: One of the most common genetic variants among individuals with cystic fibrosis screen-positive inconclusive diagnosis (CFSPID) is 5T;12TG. Classified as having “varying clinical consequences” (VVCC), it may produce a wide spectrum of CF phenotypes when combined in trans with a pathogenic variant on the other CFTR allele, ranging from asymptomatic cases to CFTR-related disorders (CFTR-RD) or classical cystic fibrosis (CF). The 5T;12TG variant is currently eligible for modulator treatment in the United States. Methods: We conducted a retrospective analysis of CFSPID children born between July 2009 and June 2023 in the Community of Madrid (Spain) who carried at least one 5T;12TG variant in trans with another CFTR variant. Data collected included trends in sweat chloride (SC) values, respiratory and digestive symptoms, lung function by spirometry, microbiological findings in nasopharyngeal aspirates, anthropometric data, and fecal elastase levels. Results: Twenty-one children (52.3% females; median age: 4.66 years [IQR 3.6–6.9]) were included. Eighteen had 5T;12TG in trans with a CF-causing variant (CFc), two had another VVCC variant, and one had a variant of unknown significance (VUS). After a median follow-up of 3.45 years [IQR 1.4–4.3], all the children remained asymptomatic. However, SC values rose to intermediate levels in nine (42.8%) of the children. No isolates of Pseudomonas aeruginosa were identified. Lung function and pancreatic markers remained normal. Conclusions: This is the first Spanish cohort of children with CFSPID and the 5T;12TG allele. Although clinical symptoms did not manifest during childhood, the SC value increased to intermediate values in 42.8% of the cohort, so these may require long-term follow-up to observe conversions to CFTR-RD or CF. The potential initiation of modulator therapy based solely on SC levels or emerging symptoms warrants careful consideration.