Crohn's Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes.
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SUBMITTER: Kaczmarek-Rys M
PROVIDER: S-EPMC8432186 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimTo assess whether the polymorphisms of NOD2/CARD15, autophagy-related 16-like 1 (ATG16L1), and interleukin-23 receptor (IL23R) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn's disease (CD).MethodsPolymorphisms R702W, G908R, and 3020insC of NOD2/CARD15; rs2241880 A/G of ATG16L1, and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymorphism analysis. The polymorphisms rs2241880 A/G of the ATG16L1, and rs11209026 (R381Q) of the IL23R gene in the children's cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K).ResultsThe 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without colonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to controls (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype.ConclusionPolymorphism 3020insC in NOD2/CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not early-onset disease.
| S-EPMC2852824 | biostudies-literature
Project description:BackgroundInfluence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD).Methods85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD).ResultsChronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213).ConclusionsThese data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.
| S-EPMC3659055 | biostudies-literature
Project description:The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease.
| S-EPMC5554695 | biostudies-other
Project description:BACKGROUND: The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p?=?3.01×10(-5), OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p?=?4.01×10(-6); OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values <10(-10). The SNPs rs2066843 and rs2076756 were in linkage disequilibrium with each other and with the three main CD-associated NOD2 mutations (D'>0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p?=?0.015) and fistulas (rs2076756: p?=?0.015) and significant associations with CD-related surgery (rs2076756: p?=?0.003; rs2066843: p?=?0.015). However, in multivariate analysis only disease localization (p<2×10(-16)) and behaviour (p?=?0.02) were significantly associated with the need for surgery. CONCLUSION/SIGNIFICANCE: The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants.
| S-EPMC3012690 | biostudies-literature
Project description:To investigate the association of three polymorphisms in the receptor for advanced glycation end product (RAGE) gene with Crohn's disease (CD) risk in a Chinese population.A hospital-based case-control association study involving 312 CD patients and 479 healthy controls was conducted. Peripheral blood samples were collected from 791 study subjects, and genomic DNA was extracted. Genotyping was performed using polymerase chain reaction-ligase detection reaction method. The association between polymorphic genotype and CD predisposition was determined using odds ratio and 95% confidence interval (CI). Data were analyzed using Haplo.stats program.Significant differences were observed between patients and controls in allele/genotype distributions of rs1800624 (P(allele)=0.012; P(genotype)=0.005) and in allele distributions of rs2070600 (P=0.02). The risk for CD associated with the rs1800624-A mutant allele decreased by 36% (95%CI: 0.47-0.88, P = 0.005) under the additive model and by 35% (95%CI: 0.46-0.91, P=0.013) under the dominant model. Carriers of rs2070600-A mutant allele showed a 37% (95%CI: 1.02-1.83, P=0.036) increased risk of developing CD relative to the GG genotype carriers. In haplotype analysis, haplotype T-A-G (in the order rs1800625, rs1800624, and rs2070600) decreased the odds of CD by 33% (95%CI: 0.49-0.94, P=0.018).CD is an immune-related disease with genetic predisposition. Genetic defects in the RAGE gene are strongly associated with CD in Chinese population.
| S-EPMC3942844 | biostudies-literature
Project description:Studies of Crohn's disease have consistently implicated NOD2 as the most important gene in disease pathogenesis since first being identified in 2001. Thereafter, genome-wide association, next-generation sequencing and functional analyses have all confirmed a key role for NOD2, but despite this, NOD2 also has significant unresolved complexity. More recent studies have reinvigorated an early hypothesis that NOD2 may be a single-gene cause of disease, and the distinct ileal stricturing phenotype seen with NOD2-related disease presents an opportunity for personalized diagnosis, disease prediction and targeted therapy. The genomics of NOD2 has much that remains unknown, including the role of rare variation, phasing of variants across the haplotype block and the role of variation in the NOD2-regulatory regions. Here, we discuss the evidence and the unmet needs of NOD2 research, based on recently published evidence, and suggest methods that may meet these requirements.
| S-EPMC10069614 | biostudies-literature
Project description:BACKGROUND: Osteopontin represents a multifunctional molecule playing a pivotal role in chronic inflammatory and autoimmune diseases. Its expression is increased in inflammatory bowel disease (IBD). The aim of our study was to analyze the association of osteopontin (OPN/SPP1) gene variants in a large cohort of IBD patients. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2819 Caucasian individuals (n?=?841 patients with Crohn's disease (CD), n?=?473 patients with ulcerative colitis (UC), and n?=?1505 healthy unrelated controls) was analyzed for nine OPN SNPs (rs2728127, rs2853744, rs11730582, rs11739060, rs28357094, rs4754?=?p.Asp80Asp, rs1126616?=?p.Ala236Ala, rs1126772 and rs9138). Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22. For four OPN SNPs (rs4754, rs1126616, rs1126772 and rs9138), we observed significantly different distributions between male and female CD patients. rs4754 was protective in male CD patients (p?=?0.0004, OR?=?0.69). None of the other investigated OPN SNPs was associated with CD or UC susceptibility. However, several OPN haplotypes showed significant associations with CD susceptibility. The strongest association was found for a haplotype consisting of the 8 OPN SNPs rs2728127-rs2853744-rs11730582-rs11439060-rs28357094-rs112661-rs1126772-rs9138 (omnibus p-value?=?2.07×10??). Overall, the mean IL-22 secretion in the combined group of OPN minor allele carriers with CD was significantly lower than that of CD patients with OPN wildtype alleles (p?=?3.66×10??). There was evidence for weak epistasis between the OPN SNP rs28357094 with the IL23R SNP rs10489629 (p?=?4.18×10?²) and between OPN SNP rs1126616 and IL23R SNP rs2201841 (p?=?4.18×10?²) but none of these associations remained significant after Bonferroni correction. CONCLUSIONS/SIGNIFICANCE: Our study identified OPN haplotypes as modifiers of CD susceptibility, while the combined effects of certain OPN variants may modulate IL-22 secretion.
| S-EPMC3248444 | biostudies-literature
Project description:DNA samples from 339 Crohn's disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two in IL-12B (rs1363670 and rs6887695). While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17-40?y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild-type (d/d) genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population.
| S-EPMC3021847 | biostudies-literature
Project description: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.
| S-EPMC7946957 | biostudies-literature
Project description:BackgroundGenetic variation in NOD2 and cigarette smoking are well-established risk factors for the development of Crohn's disease (CD). However, little is known about a potential interaction between these risk factors. We investigated gene-environment interactions between CD-associated NOD2 alleles and cigarette smoking in a large sample of patients with CD.MethodsThree previously reported CD-associated variants in NOD2 (R702W, G908R, 1007fs) were genotyped in 1636 patients with CD continuously recruited between 1995 and 2010 based on physician referral. Data on history of smoking behaviour was obtained for all participants through a written questionnaire. Using a case-only design, we performed logistic regression analyses to investigate statistical interactions between NOD2 risk alleles and smoking status.ResultsWe detected a significant negative interaction between carriership of at least one of the NOD2 risk alleles and history of ever having smoked (OR = 0.71; p = 0.005) as well as smoking at the time of CD diagnosis (OR = 0.68; p = 0.005). Subsequent separate analyses of the three variants revealed a significant negative interaction between the 1007fs variant and history of ever having smoked (OR = 0.64; p = 9 × 10-4) and smoking at the time of CD diagnosis (OR = 0.53; p = 7 × 10-5).ConclusionsThe observed significant negative gene-environment interaction suggests that the risk increase for CD conferred simultaneously by cigarette smoking and the 1007fs NOD2 polymorphism is smaller than expected and may point to a biological interaction. Our findings warrant further investigation in epidemiological and functional studies to elucidate pathophysiology as well as to aid in the development of recommendations for disease prevention.
| S-EPMC3314543 | biostudies-literature