Epistatic interaction between TLR4 and NOD2 in patients with Crohn’s Disease: relation with risk and phenotype in a Spanish cohort

Martínez-Chamorro, Alba; Moreno, Antonia Ruíz; Gómez‐García, María; Cabello, María José; Martı́n, Javier; Nevot, López

doi:10.1016/j.imbio.2016.05.015

Cited by 10 publications

(7 citation statements)

References 53 publications

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“…To date, the highest recorded incidence of IBD has been reported in non-Hispanic whites (inhabiting Central and Western Europe and North America)-three times higher than in other ethnic groups [33]. In this population, a strong association between mutant NOD2 and CD risk was reported for R702W, G908R, and 1007insC when they were considered separately (p-values: < 0.001, 0.002, and < 0.001, respectively) [34]. G908R and L1007fs were associated with Crohn's disease susceptibility in the Dutch population, and carrying of at least one of these mutations was associated with more severe and penetrating disease [35].…”

Section: Discussionmentioning

confidence: 79%

Crohn’s Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes

Kaczmarek-Ryś

Hryhorowicz

Lis

et al. 2021

JCM

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The genetic background and the determinants influencing the disease form, course, and onset of inflammatory bowel disease (IBD) remain unresolved. We aimed to determine the NOD2 gene haplotypes and their relationship with IBD occurrence, clinical presentation, and onset, analyzing a cohort of 578 patients with IBD, including children, and 888 controls. Imaging or endoscopy with a histopathological confirmation was used to diagnose IBD. Genotyping was performed to assess the differences in genotypic and allelic frequencies. Linkage disequilibrium was analyzed, and associations between haplotypes and clinical data were evaluated. We emphasized the prevalence of risk alleles in all analyzed loci in patients with Crohn disease (CD). Interestingly, c.2722G>C and c.3019_3020insC alleles were also overrepresented in ulcerative colitis (UC). T-C-G-C-insC, T-C-G-T-insC, and T-T-G-T-wt haplotypes were correlated with the late-onset form of CD (OR = 23.01, 5.09, and 17.71, respectively), while T-T-G-T-wt and C-C-G-T-wt were prevalent only in CD children (OR = 29.36, and 12.93, respectively; p-value = 0.001). In conclusion, the presence of c.3019_3020insC along with c.802C>T occurred as the most fundamental contributing diplotype in late-onset CD form, while in CD children, the mutual allele in all predisposing haplotypes was the c.2798 + 158T. Identifying the unique, high-impact haplotypes supports further studies of the NOD2 gene, including haplotypic backgrounds.

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Section: Discussionmentioning

confidence: 79%

Crohn’s Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes

Kaczmarek-Ryś

Hryhorowicz

Lis

et al. 2021

JCM

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“…Even though the exact roles of NOD2 during campylobacteriosis remain unknown, several reports have emphasized the complex modulatory crosstalk between NOD2 and TLR-4 signaling especially in pro-inflammatory cytokine regulation [150][151][152][153][154], given that NOD2 is able to regulate the IL-12 production depending on TLR-4 intensity [155]. Furthermore, a clinical study revealed that a distinct NOD2 gene mutation (homozygous for the 3020insC mutation) observed in Crohn's disease patients leads to massive TNF-α release by TLR-4 activation via LOS or LPS [156], indicating that a mutation in the NOD2 gene is associated with increased LOS susceptibility.…”

Section: The Use Of Novel Murine Models Of C Jejuni Infection In Actmentioning

confidence: 99%

Novel Clinical Campylobacter jejuni Infection Models Based on Sensitization of Mice to Lipooligosaccharide, a Major Bacterial Factor Triggering Innate Immune Responses in Human Campylobacteriosis

2020

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: Human Campylobacter jejuni infections inducing campylobacteriosis including post-infectious sequelae such as Guillain-Barré syndrome and reactive arthritis are rising worldwide and progress into a global burden of high socioeconomic impact. Intestinal immunopathology underlying campylobacteriosis is a classical response of the innate immune system characterized by the accumulation of neutrophils and macrophages which cause tissue destruction, barrier defects and malabsorption leading to bloody diarrhea. Clinical studies revealed that enteritis and post-infectious morbidities of human C. jejuni infections are strongly dependent on the structure of pathogenic lipooligosaccharides (LOS) triggering the innate immune system via Toll-like-receptor (TLR)-4 signaling. Compared to humans, mice display an approximately 10,000 times weaker TLR-4 response and a pronounced colonization resistance (CR) against C. jejuni maintained by the murine gut microbiota. In consequence, investigations of campylobacteriosis have been hampered by the lack of experimental animal models. We here summarize recent progress made in the development of murine C. jejuni infection models that are based on the abolishment of CR by modulating the murine gut microbiota and by sensitization of mice to LOS. These advances support the major role of LOS driven innate immunity in pathogenesis of campylobacteriosis including post-infectious autoimmune diseases and promote the preclinical evaluation of novel pharmaceutical strategies for prophylaxis and treatment.

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“…Although the etiology of Inflammatory Bowel Disease (IBD) is not completely understood, previous studies have underlined the contribution of an important genetic susceptibility. Recently, Martinez-Chamorro et al [32] detected an epistatic interaction between the genes NOD2 and TLR4. We applied our ap- ized on a list of 22 genes that contain SNPs that are suspected to be associated with IBD from an univariate analysis.…”

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

Eigen-Epistasis for detecting gene-gene interactions

2017

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BackgroundA large amount of research has been devoted to the detection and investigation of epistatic interactions in genome-wide association studies (GWASs). Most of the literature focuses on low-order interactions between single-nucleotide polymorphisms (SNPs) with significant main effects.ResultsIn this paper we propose an original approach for detecting epistasis at the gene level, without systematically filtering on significant genes. We first compute interaction variables for each gene pair by finding its Eigen-Epistasis component, defined as the linear combination of Gene SNPs having the highest correlation with the phenotype. The selection of significant effects is done using a penalized regression method based on Group Lasso controlling the False Discovery Rate.ConclusionThe method is tested against two recent alternative proposals from the literature using synthetic data, and shows good performances in different settings. We demonstrate the power of our approach by detecting new gene-gene interactions on three genome-wide association studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1488-0) contains supplementary material, which is available to authorized users.

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Epistatic interaction between TLR4 and NOD2 in patients with Crohn’s Disease: relation with risk and phenotype in a Spanish cohort

Cited by 10 publications

References 53 publications

Crohn’s Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes

Crohn’s Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes

Novel Clinical Campylobacter jejuni Infection Models Based on Sensitization of Mice to Lipooligosaccharide, a Major Bacterial Factor Triggering Innate Immune Responses in Human Campylobacteriosis

Eigen-Epistasis for detecting gene-gene interactions

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