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

María Chaparro1, Adrià Aterido2, Iván Guerra3

  • 1Gastroenterology Unit. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 62. 28006 Madrid, Spain.

Therapeutic Advances in Gastroenterology
|October 11, 2019
PubMed
Abstract

Insights

Rare genetic variations influence anti-tumor necrosis factor (TNF) therapy response in Crohn's disease (CD). Functional rare variants in genes like HLA-B and HLA-DRB1 impact treatment outcomes, with gut mucosa and T cells playing key roles.

Area of Science:

  • Genetics
  • Gastroenterology
  • Immunology

Background:

  • The impact of low-frequency genetic variations on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) is not well understood.
  • Investigating these variations could reveal new therapeutic targets and biomarkers for CD treatment.

Purpose of the Study:

  • To explore the association between functional rare variants and clinical response to anti-TNF therapy in CD patients.
  • To identify specific genes and pathways involved in anti-TNF treatment outcomes.

Main Methods:

  • Whole genome sequencing of 41 anti-TNF naïve CD patients.
  • Annotation and classification of low-frequency variants, including loss-of-function (LoF) mutations.
  • Analysis of TNF signaling pathway variants and cell-type specific epigenetic enrichment.

Main Results:

  • Identified 3250 functional rare variants, including 568 LoF variants.
  • Found homozygous LoF mutations in HLA-B and HLA-DRB1 associated with non-response and remission, respectively.
  • Enrichment of LoF variants in gastrointestinal tissues and damaging variants in TNF pathway genes within CD8+ and CD4+ T cells.

Conclusions:

  • Functional rare variants significantly influence anti-TNF therapy response in CD.
  • Gut mucosa and CD8+ T cells are implicated as key mediators of this response, suggesting potential therapeutic avenues.
Keywords:
Crohn’s diseaseadalimumabgenesinfliximabtumor necrosis factor alphawhole-genome analysis

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