Novel missense mutation in the NOD2 gene in a patient with early onset ulcerative colitis: causal or chance association? (original) (raw)
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Genetic profile of patients with early onset inflammatory bowel disease
Gene, 2018
Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).
Scientific Reports, 2021
Inflammatory bowel disease (IBD), clinically defined as Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn's Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7-10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn's Disease. Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal (GI) tract that arises as part of an inappropriate response to commensal or pathogenic microbiota in a genetically susceptible individual . IBD encompasses Crohn's Disease (CD); ulcerative colitis (UC); and IBD unclassified (IBDU). The etiology of IBD is complex and has been attributed to defects in a number of cellular pathways including pathogen sensing, autophagy, maintenance of immune homeostasis, and intestinal barrier function, among other processes . Great effort has been invested into defining the genetic factors that confer IBD susceptibility. To date, > 200 unique loci have been associated with IBD through genome-wide association studies (GWAS), primarily in adult populations . Nearly all the identified susceptibility loci exhibit low effect sizes (ORs ~ 1.0-1.5) individually 19 , and collectively account for less than 20% of the heritable risk for IBD . These observations support a complex disease model in which common variants of modest effect sizes interact with environmental factors including diet, smoking, and the intestinal microbiome to give rise to IBD susceptibility.
Specific association of a CLEC16A/KIAA0350 polymorphism with NOD2/CARD15− Crohn's disease patients
European Journal of Human Genetics, 2009
Independent genome-wide association studies highlighted the function of CLEC16A/KIAA0350 polymorphisms modifying the risk to either multiple sclerosis (rs6498169) or type 1 diabetes (rs2903692). This C-type lectin gene maps to a linkage disequilibrium block at 16p13 and a functional role of this gene could be envisaged for other immune-related conditions, such as inflammatory bowel disease (IBD). The present study, aimed at investigating the association of those two polymorphisms with IBD, included 720 IBD patients and 550 ethnically matched healthy controls. The effect of rs2903692 previously described in diabetes was observed specifically for Crohn's disease (CD) patients lacking the main susceptibility factor described to date, that is, three polymorphisms within another pattern recognition gene, NOD2/CARD15 (NOD2 À vs NOD2 þ CD patients, G vs A: P ¼ 0.008; OR (95% CI) ¼ 1.54 (1.10-2.15); NOD2 À CD patients vs controls: P ¼ 0.008; OR (95% CI) ¼ 1.37 (1.08-1.73)). Replication of these findings was performed in independent Spanish cohorts of 544 IBD patients and 340 controls and the combined data yielded significant differences (405 NOD2 À vs 204 NOD2 þ CD patients, G vs A: P ¼ 0.0012; OR M-H (95% CI) ¼ 1.49 (1.17-1.90); NOD2 À CD patients vs controls: P ¼ 0.0007; OR M-H (95% CI) ¼ 1.35 (1.13-1.60)). The pooled analysis of the ulcerative colitis patients vs controls also yielded a significant risk (P ¼ 0.0005; OR (95% CI) ¼ 1.52 (1.19-1.93)). These data would suggest that microbial recognition through different pathways seems to converge in the development of these polygenic bowel diseases.
World Journal of Gastroenterology, 2008
nificant difference was found between UC patients and control group (P > 0.05). In CD and UC patients, no significant association with G908R variant was found. L1007finsC SNP showed an association with CD (9.8%) compared with controls (2.9%, P = 0.002) and UC patients (2.3%, P = 0.01). Moreover, in CD patients, G908R and L1007finsC mutations were significantly associated with different phenotypes compared to CD wild-type patients. No association of IBD with the TLR4 SNPs was found in either cohort (allele frequencies: D299G-controls 3.9%, CD 3.7%, UC 3.4%, P > 0.05; T399I-controls 2.9%, CD 3.0%, UC 3.4%, P > 0.05).
Homology modeling and in silico prediction of Ulcerative colitis associated polymorphisms of NOD1
Molecular and Cellular Probes, 2017
Cytosolic pattern recognition receptors play key roles in innate immune response. Nucleotide binding and oligomerisation domain containing protein 1 (NOD1) belonging to the Nod-like receptor C (NLRC) sub-family of Nod-like receptors (NLRs) is important for detection and clearance of intra-cellular Gram negative bacteria. NOD1 is involved in activation of pro-inflammatory pathways. Limited structural data is available for NOD1. Using different templates for each domain of NOD1, we determined the full-length homology model of NOD1. ADP binding amino acids within the nucleotide binding domain (NBD) of NOD1 were also predicted. Key residues in inter-domain interaction were identified by sequence comparison with Oryctolagus cuniculus NOD2, a related protein. Interactions between NBD and winged helix domain (WHD) were found to be conserved in NOD1. Functional and structural effect of single nucleotide polymorphisms within the NOD1 NBD domain associated with susceptibility risk to Ulcerative colitis (UC), an inflammatory disorder of the colon was evaluated by in silico studies. Mutations W219R and L349P were predicted to be damaging and disease associated by prediction programs SIFT, PolyPhen2, PANTHER, SNP&GO, PhD SNP and SNAP2. We further validated the effect of W219R and L349P mutation on NOD1 function in vitro. Elevated mRNA expression of pro-inflammatory cytokines IL8 and IL-1β was seen as compared to the wild type NOD1 in intestinal epithelial cell line HT29 when stimulated with NOD1 ligand. Thus, these mutations may indeed have a bearing on pathogenesis of inflammation during UC.
NOD2/CARD15 gene mutations in North Algerian patients with inflammatory bowel disease
World journal of gastroenterology : WJG, 2015
To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammatory bowel disease (IBD) in Algeria. We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's disease (CD) and 46 with ulcerative colitis (UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CD-associated NOD2 variants (p.Arg(702)Trp, p.Gly908Arg and p.Leu(1007)fsinsC mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ...
Crohn’s Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes
Journal of Clinical Medicine
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), wh...
Review article: inflammatory bowel disease and genetics
Alimentary Pharmacology & Therapeutics, 2007
SummaryIntroduction Inflammatory bowel disease (IBD) comprising ulcerative colitis (UC) and Crohn's disease (CD) is multigenic disorder. Tremendous progress has been achieved in unravelling the genetic background of IBD. It has led to the discovery of mutations in NOD2 associated with ileal CD and numerous other genes have been found to be associated with IBD susceptibility.Methods A review of the literature on the genetic background of IBD was performed.Results It is only partially understood how mutations in NOD2 lead to CD. Mouse models, in vitro data and studies in humans offer conflicting data as regards whether there is a loss or gain of function of NOD2 in CD. Several additional genes have been identified of which only a few are currently being recognized as potential disease causing or disease modifying genes. Promising candidate genes include TLR4, MDR1, NOD1 (CARD4), DLG5 as well as the IBD5 locus including SLC22A4/5.Conclusions Although genetic research has not ye...
Proceedings of the National Academy of Sciences, 2002
Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic analysis. Linkage of IBD to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2, located on proximal 16q, was recently identified as an IBD gene. As the linkage regions on chromosome 16 are large, we have investigated the possibility that NOD2 is not the only IBD gene located on this chromosome. A high-density experiment using 39 microsatellite markers was performed to identify additional regions of association, and to indicate areas of interest for further investigation. A triple-peaked configuration of the linkage curve with peak logarithm of odds (lod) scores of 2.7, 3.2, and 3.1 was observed on proximal 16p, proximal 16q, and central 16q, respectively. The cohort was stratified by coding individuals carrying the NOD2 single nucleotide polymorphism (SNP)8 and SNP13 ''unknown.'' Significance at the central peak, corresponding to the genomic location of NOD2, then decreased from 3.2 to 1.2. The maximal lod scores on the proximal p-arm (lod ؍ 2.1) and central q-arm (lod ؍ 2.6) changed only moderately. An exploratory association analysis (TRANSMIT) yielded a strong lead at D16S3068 (P ؍ 0.00028). The region around this marker was further investigated by using anonymous SNPs. An associated haplotype containing three SNPs was identified (peak significance P ؍ 0.00027, IBD phenotype). On stratification based on NOD2 genotype, this significance increased to P ؍ 0.0001. These results confirm the importance of NOD2 and provide evidence for a second IBD gene located on chromosome 16p.