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Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease.

ABSTRACT: Background:The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD. Methods:CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn's Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses. Results:A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4.11e-4; duodenum, p = 0.011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy (p = 0.016); damaging variants were enriched in epigenetic marks from CD8+ (p = 6.01e-4) and CD4+ (p = 0.032) T cells. Conclusions:Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8+ T cells are the main mediators of this response.

SUBMITTER: Chaparro M

PROVIDER: S-EPMC6764039 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease.

Chaparro María M Aterido Adrià A Guerra Iván I Iborra Marisa M Cabriada Jose Luis JL Bujanda Luis L Taxonera Carlos C García-Sánchez Valle V Marín-Jiménez Ignacio I Barreiro-de Acosta Manuel M Vera Isabel I Martín-Arranz Maria Dolores MD Hernández-Breijo Borja B Mesonero Francisco F Sempere Laura L Gomollón Fernando F Hinojosa Joaquín J Bermejo Fernando F Beltrán Belén B Rodríguez-Pescador Ainhoa A Banales Jesús María JM Olivares David D Aguilar-Melero Patricia P Menchén Luis L Ferreiro-Iglesias Rocío R Blazquez Gómez Isabel I Benitez García Beatriz B Guijarro Luis G LG Marin Alicia C AC Bernardo David D Marsal Sara S Julia Antonio A Gisbert Javier P JP

Therapeutic advances in gastroenterology 20190925

<h4>Background</h4>The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD.<h4>Methods</h4>CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn's Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the ...[more]

PMID: 31598133

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Project description:BackgroundAnti-TNF medications are the first-line treatment for Crohn's Disease (CD), despite the fact that a significant portion of the population continues to be ineffectively treated. This research aims to discover accurate intervention targets for the follow-up of anti-TNF non-responders using bioinformatics technology.MethodsGSE16879, GSE111761, and GSE52746 retrieved from the GEO database. Unbiased differentially expressed genes (DEGs) were discovered utilizing the limma and RobustRankAggreg (RRA) tools. Then, we used weighted gene co-expression network analysis (WGCNA) to identify the module most strongly associated with non responders and subjected this module to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis with overlapping genes of the DEGs. GSEA analysis applied to check the results of GO and KEGG. Using the Cytoscape program, the protein-protein interaction (PPI) network was constructed. The software's MCODE addon and CytoHubba addon was used to find the most important modules and the hub genes. Subsequently, we employed reverse transcription-polymerase chain reaction (RT-PCR) to confirm hub gene expression from mucosal biopsy specimens.ResultsThere were a total of 142 genes co-upregulated and 65 genes co-downregulated. According to the WGCNA analysis, 42 genes were duplicated inside the light cyan module. GO and KEGG enrichment analyses of overlapped genes in nonresponders demonstrated an increase in the expression of genes associated with inflammation and immune response, consistent with GSEA results. The PPI network was constructed using 41 protein nodes and 177 edges. After validation, 8 of the top 10 genes were verified to be differentially expressed.ConclusionOur investigation is the first to integrate three CD databases after the anti-TNF medication treatment. We identified IL1B, CCL4, CXCL1, CXCL10, CCL3, CSF3, TREM1, and IL1RN as potential therapeutic targets for patients whose anti-TNF treatment failed.

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Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease.

Publications

Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease.

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