Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn’s Disease

Objective. To clarify the incidence of monogenic IBD-like diseases and the features of clinical course and response to therapy of major types of inflammatory bowel diseases (IBD) among children under the age of 6 with manifestation of the disease. Patients and methods. The study included 135 children under the age of 6 with manifestation of IBD; in the comparison group, there were 128 children after the age of 6 with manifestation of IBD (97 children with ulcerative colitis (UC) and 31 children with Crohn’s disease (CD)) who were observed for at least 1 year. All children underwent a standard examination, including calprotectin and antineutrophil antibodies testing, determination of activity by the Pediatric Ulcerative Colitis Activity Index (PUCAI) or the Pediatric Crohn’s Disease Activity Index (PCDAI), depending on the nosology. Children with the onset of IBD under 6 years of age underwent a genetic testing using Primary Immunodeficiency Panel by next-generation sequencing. All children were analyzed for efficacy of therapy during catamnestic observation. Results. It was revealed that in the study group the incidence of monogenic IBD-like diseases was 6.7%, of UC – 71.1%, of CD – 22.2%. Major types of IBD with very early onset differed little in their clinical, endoscopic and laboratory features from the forms with manifestation at an older age. In most cases, both CD (57%) and UC (71%) were characterized by low activity. Very earlyonset CD was characterized by isolated localization of the colon (53%, p = 0.037) and a non-stenotic and non-penetrating behaviour of the disease (60% of cases). The leading clinical symptoms were diarrhea (67%) and blood in the stool (63%, p = 0.04). Very early-onset UC was characterized by total lesion of the colon (84%, p = 0.001) and the development of anemia (48%, p = 0.01). Among children with very early-onset UC, the percentage of glucocorticosteroid-dependence and glucocorticosteroid-resistance was high, but anti-TNFα therapy was prescribed late. Conclusion. It is advisable to observe children with very early-onset IBD in federal multidisciplinary clinics, where there is experience in managing patients with this pathology. Key words: inflammatory bowel disease, very early onset, Crohn’s disease, ulcerative colitis, primary immunodeficiency, treatment, children

Download Full-text

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

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819867848 ◽

2019 ◽

Vol 12 ◽

pp. 175628481986784

Author(s):

María Chaparro ◽

Adrià Aterido ◽

Iván Guerra ◽

Marisa Iborra ◽

Jose Luis Cabriada ◽

...

Keyword(s):

T Cells ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Response ◽

Signaling Pathway ◽

Rare Variants ◽

Low Frequency ◽

Whole Genome ◽

Cell Type ◽

Epigenetic Marks

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.

Download Full-text

Defensins couple dysbiosis to primary immunodeficiency in Crohn’s disease

World Journal of Gastroenterology ◽

10.3748/wjg.v17.i5.567 ◽

2011 ◽

Vol 17 (5) ◽

pp. 567 ◽

Cited By ~ 13

Author(s):

Mathias Chamaillard

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Primary Immunodeficiency

Download Full-text

Revisiting Crohn's disease as a primary immunodeficiency of macrophages

Journal of Experimental Medicine ◽

10.1084/jem.20091683 ◽

2009 ◽

Vol 206 (9) ◽

pp. 1839-1843 ◽

Cited By ~ 86

Author(s):

Jean-Laurent Casanova ◽

Laurent Abel

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Primary Immunodeficiency ◽

Human Genetics ◽

Genetic Dissection ◽

Inborn Errors ◽

Clinical Investigations ◽

Mendelian Genetic ◽

The Way

Despite two decades of mouse immunology and human genetics studies, the pathogenesis of Crohn's disease (CD) remains elusive. New clinical investigations suggest that CD may be caused by inborn errors of macrophages. These errors may result in impaired attraction of granulocytes to the gut wall, causing impaired clearance of intruding bacteria, thereby precipitating the formation of granulomas. This theory paves the way for a macrophage-based Mendelian genetic dissection of CD.

Download Full-text