NOD2/CARD15 gene mutations in North Algerian patients with inflammatory bowel disease

AIM: To analyse allelic frequency of NOD2 gene variantsand to assess their correlation with inflammatory bowel disease(IBD) in Algeria.METHODS: 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 CDassociated NOD2 variants(p.Arg702 Trp, p.Gly908 Arg and p.Leu1007 fsins C mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher's exact test where appropriate. Odds ratios(OR) and 95% confidence intervals(95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.RESULTS: The p.Arg702 Trp mutation showed the highest frequency in CD patients(8%) compared to UC patients(2%)(P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls(5%)(P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 3% vs 2%(P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1%(P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908 Arg and p.Leu1007 fsins C variants compared to HC were 1% vs 2%(P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1%(P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD(13%), than in HC(8%) and UC(5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.     

Smoking and inflammatory bowel disease: trends in familial and sporadic cohorts

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) result from genetic and environmental factors. Never smoking and formerly smoking increase the risk of UC, whereas smoking exacerbates the course of CD. We sought to define the age-dependent effects of smoking on the development of UC and CD in familial and sporadic cohorts. METHODS: University of Chicago patients diagnosed with UC or CD between 1990 and 2002 were surveyed about their tobacco use relative to their diagnosis. Smoking trends were used to estimate age-dependent odds ratios and the attributable risks of smoking in the IBD cohort compared to in the general population. RESULTS: One thousands and thirteen patients were included in the study: 245 with sporadic UC; 216 with sporadic CD; 249 with familial UC; and 303 with familial CD. Being an ex-smoker conferred an increased risk for UC in the 25-44 age group in both the sporadic and familial cohorts, but not in the 45-64 age group in the familial UC cohort. Furthermore, there was no difference in tobacco use between patients with sporadic CD and the general population, although there was a significant increase in smoking in younger patients with familial CD. CONCLUSIONS: Ex-smokers make up an increasing percentage of older patients diagnosed with UC, accounting for more than 35% of the attributable risk of late onset (>45 years) UC and a large component of the second peak in diagnosis. Current smokers account for a large percentage of patients diagnosed at a younger age with familial CD but not with sporadic CD. Families with IBD should be counseled that early tobacco use significantly increases the risk of developing CD or, if an ex-smoker, UC at a young age.     

Similar clinical characteristics of familial and sporadic inflammatory bowel disease in South Korea

AIM:To investigate differences of clinical characteristics and disease courses between familial and sporadic inflammatory bowel disease(IBD)patients.METHODS:We obtained clinical data on Crohn’s disease(CD)(n=691)and ulcerative colitis(n=1113)from a tertiary referral medical center between 2005and 2012.Seventeen patients(2.5%)with CD and27 patients(2.4%)with ulcerative colitis(UC)were identified as having a familial history of IBD,including the first and second degree relatives.For each control case,three times the number of age-,sex-,and diagnosis year-matched CD and UC patients,without a family history of IBD,were randomly selected in this case control study.RESULTS:There were no significant differences in age or main symptom at diagnosis,extraintestinal manifestation,location/extent,behavior of disease activity,number of hospitalizations,number of operations,operation type,number of relapses,or oral medical treatment between familial and sporadic CD and UC patients.Median(min-max)follow-up periods after diagnosis of familial CD and sporadic CD patients were 84(24-312)and 36(8-240)mo,respectively(P=0.008).Familial CD patients more frequently used anti-tumor necrosis factor(TNF)antibodies compared to sporadic CD patients(17.6%vs 0%,P=0.014).CONCLUSION:In conclusion,a family history of IBD does not seem to be an important predictive factor affecting clinical characteristics or disease course even if there is a more frequent use of anti-TNF antibodies in familial CD patients compared to sporadic CD patients.     

OCTN and CARD15 gene polymorphism in Chinese patients with inflammatory bowel disease

AIM： To investigate the single nucleotide polymorphism （SNPs） distribution of NOD2/CARD15 （R702W, G908R）, OCTN1 1672CFT and OCTN2-207G/C in Chinese patients with inflammatory bowel disease （IBD）. METHODS： A total of 61 patients with Crohn＇s disease （CD）, 151 patients with ulcerative colitis （UC）, and 200 unrelated healthy controls were genotyped. Genotyping was performed by sequence specific primer polymerase chain reaction （PCR-SSP） or by restriction fragment length polymorphism （PCR-RFLP） analysis. RESULTS： Among the subjects in our study groups, including patients with CD, UC and healthy controls, none had OCTN and CARD15 variants and very rare IBD family history was found in our patients with the percentage of 0 （0/61 with CD） and 1.3% （2/151 with UC）. CONCLUSION： Our results indicate that although OCTN or CARD15 variation is associated with susceptibility to IBD in Western populations, these might be rare and may not be associated with susceptibility to IBD in Chinese patients.     

CARD15 in inflammatory bowel disease and Crohn''s disease phenotypes: An association study and pooled analysis

BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies. METHODS: We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included. RESULTS: Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease (p<0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease. CONCLUSION: Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.     

CARD15 mutations and colorectal cancer in a South European country

Purpose  

CARD15 mutations are associated with higher susceptibility to Crohn's disease (CD) and longstanding colonic CD increases the risk of developing colorectal cancer (CRC). The relation between these mutations and sporadic CRC remains controversial. The aim of this study was to assess whether germline and/or somatic CARD15 mutations are risk factors for sporadic CRC in Portugal and whether there are genotype–phenotype correlations in these patients.     

OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease

PurposeA two-allele haplotype of TC (OCTN1 rs1050152 and OCTN2 -207G→C) is associated with Crohn's disease (CD). The association has been replicated in different populations, but also failed in some studies. The present study is to replicate the association of OCTN1 rs1050152 and examine another variant rs272879 with familial and sporadic inflammatory bowel disease (IBD) in a cohort from central Pennsylvania, USA.MethodsThe study samples (n = 465) included 212 inflammatory bowel disease patients (CD = 115, UC = 97), including 103 familial (CD = 55, UC = 46) and 111 sporadic (CD = 60, UC = 51) IBD, 139 non-IBD family members from a familial IBD registry, and 114 unrelated healthy controls. A total of 12 OCTN1 variants within exonic sequences were examined. Two nonsynonymous SNPs, rs1050152 (L503F) and rs272879 (L395V) were genotyped by a PCR-based RFLP/cRFLP method and statistically analyzed. These samples with an additional 141 unrelated healthy samples were also genotyped for rs1050152 using the SNPlex? Genotyping System.ResultsThe OCTN1 rs1050152 is associated with CD (OR = 1.745, 95% CI = 1.019–2.990, χ² = 4.129, p = 0.042) and with IBD (OR = 1.68, 95% CI = 1.052–2.676, χ² = 4.732, p = 0.030); while the variant rs272879 is not associated with IBD, CD or ulcerative colitis (UC). The distribution of the rs1050152 variant showed a high level of the T allele in male UC (OR = 2.585, 95% CI = 1.139–5.869, p = 0.023) and IBD (OR = 2.039, 95% CI = 1.024–4.059, p = 0.042) patients, and in female CD patients (OR = 2.329, 95% CI = 1.038–5.226, ρ value = 0.039).ConclusionThe present results replicated the association of the OCTN1 rs1050152 (L503F) variant with CD and IBD overall. A weak gender-specific effect of rs1050152 (L503F) on male UC and female CD was observed.     

Variation at NOD2/CARD15 in familial and sporadic cases of Crohn's disease in the Ashkenazi Jewish population

OBJECTIVE: Recent reports indicate that allelic variants in NOD2/CARD15 are associated with Crohn's disease (CD) susceptibility, and that homozygosity or compound heterozygosity at this locus for any of three recently defined sequence variants confers a greatly increased risk of CD. These sequence changes include two missense mutations, R702W and G908R, and a frameshift insertion, 1007insC. The aim of this study was to determine the frequency of these NOD2/CARD15 variants in familial and sporadic CD patients in the Ashkenazi population and to determine their effects on disease susceptibility and age of disease onset (AOO). METHODS: Allele and genotype frequencies of these three variants were determined in 481 CD patients of Jewish descent and 110 Jewish controls; 169 patients had a family history of CD, and 312 were "sporadic" cases. Variants were detected by polymerase chain reaction using allele-specific primers labeled with fluorescent dye. RESULTS: Familial cases had a significantly higher frequency of the G908R variant than sporadic cases (0.127 vs 0.059, p = 0.0003) and correspondingly, a significantly higher proportion of homozygotes and compound heterozygotes (11.8% vs 4.5%, p = 0.0027). Homozygotes and compound heterozygotes had an OR for CD of 14.6 for familial cases and 5.1 for sporadic cases. There was no increased risk of CD for simple heterozygotes. The AOO was significantly lower for CD patients who were homozygotes and compound heterozygotes for NOD2/CARD15 (17.5 vs 22.4 yr, p = 0.04), but only for familial cases. CONCLUSIONS: NOD2/CARD15 contributes more to CD susceptibility in familial cases than in sporadic cases, and to an earlier AOO. There is no increased risk of CD for individuals carrying only a single copy of these NOD2/ CARD15 variants, whereas individuals carrying two copies have a 5-15-fold increased risk. The penetrance of the NOD2/CARD15 mutations was estimated at less than 1%.     

Autoimmune disorders and extraintestinal manifestations in first-degree familial and sporadic inflammatory bowel disease: a case-control study

BACKGROUND: Genetic factors may play a role in determining the development of extraintestinal manifestations (EIMs) and autoimmune diseases (AD) in patients with inflammatory bowel disease (IBD). We sought to determine the association between EIMs and AD in patients with first-degree familial IBD and sporadic IBD. METHODS: All patients evaluated in the IBD Clinic at the Mayo Clinic between January and September 1999 were offered enrollment. One clinic patient who was matched on age, gender, and geographic area of residence to each case served as controls. Information regarding EIMs and AD was obtained from a questionnaire completed by all IBD patients and controls. The adjusted odds ratios (95% CIs) for EIM as a function of first-degree familial IBD compared with sporadic IBD and AD as a function of first-degree familial IBD compared with sporadic IBD were estimated with a matched one-to-one conditional logistic regression model. RESULTS: Two hundred forty-three patients with IBD (47 first-degree familial IBD, 196 sporadic IBD) were enrolled. Forty percent of IBD patients had one or more EIMs compared with 14% matched controls [p < 0.001; OR = 3.1 (95% CI: 1.8 to 5.2)]. A total of 259 of the 1122 IBD patients and their first-degree family members indicated one or more EIM diagnoses (23%). The association between "familial versus sporadic" status and any EIM diagnosis was not significant [p = 0.59, the odds for an individual from a familial IBD family relative to an individual from a sporadic IBD family was 1.2 (95% CI: 0.8 to 1.7)]. Ten percent of IBD patients had one or more AD diagnoses compared with 19% matched controls [p = 0.04; OR = 0.4 (95% CI: 0.1 to 0.96)]. A total of 153 of the 1122 IBD patients and their first-degree family members indicated one or more AD diagnoses (14%). The association between disease status ("familial or sporadic") versus any AD diagnosis was not significant [p = 0.68, the odds for any AD in an individual from a familial IBD family relative to an individual from a sporadic IBD family was 1.4 (95% CI: 0.9 to 2.3)]. CONCLUSIONS: There was a positive association between IBD status (patient vs control) versus EIM, but not AD. A significant positive association between disease type (familial or sporadic) versus either EIM or AD was not detected.     

TUCAN (CARD8) genetic variants and inflammatory bowel disease

BACKGROUND & AIMS: The identification of the association between Crohn's disease (CD) and NOD2 (CARD15) confirmed both the heritability of CD and highlighted the role of the nuclear factor kappaB (NFkappaB) pathway in disease pathogenesis. Other susceptibility loci exist. TUCAN (CARD8) is located beneath a CD peak of linkage on chromosome 19q. TUCAN is expressed in the gut and is a negative regulator of NFkappaB, making it an excellent candidate gene for gastrointestinal inflammation. METHODS: Ten single nucleotide polymorphisms (SNP) across TUCAN were genotyped in 365 controls, 372 patients with CD, and 373 patients with ulcerative colitis. A diagnostic panel for CD was constructed using smoking status and TUCAN, NOD2, IBD5, NOD1, and TNFSF15 data. RESULTS: We demonstrate significant association between a TUCAN SNP and CD (OR 1.35, P = .0083). The association was more pronounced with disease affecting sites other than the colon (odds ratio, 1.52) and NOD2-negative CD (odds ratio, 1.50). Combination of these data with smoking and NOD2, IBD5, NOD1, and TNFSF15 status demonstrated very strong associations with CD and high sensitivities (96.3%), specificities (99.4%), and likelihood ratios (12.8) for CD, although further work will be needed before this model can be translated into direct clinical utility. CONCLUSIONS: We have shown an association between a likely functional polymorphism in TUCAN and CD. The combination of these data in a genetic panel suggests that clinicians may soon be able to translate genetic advances into direct benefits for patients.     

Clinical patterns of familial inflammatory bowel disease.

BACKGROUND--Although many recent studies have shown the increased risk of inflammatory bowel disease in relatives of patients with Crohn's disease and ulcerative colitis, clinical patterns of disease within families remain relatively poorly documented. AIMS--In this study, clinical characteristics (disease type, extent, age on onset, need for surgery, and presence of extraintestinal manifestations) have been compared in affected subjects in multiply-affected families, with inflammatory bowel disease. METHODS--54 families in whom one parent and at least one child were affected (a total of 77 parent-child pairs) and 155 families in whom at least two siblings were affected (a total of 190 affected sibling pairs) were involved. RESULTS--In affected parent-child pairs, parent and child were concordant for disease type in 58 of 77 pairs (75.3%), for extent in 63.6%, extraintestinal manifestations in 70.1%, and smoking history in 85%. The median age of onset in parents was significantly higher than offspring (p < 0.0001). In 40 pairs, 60.6%, the parent was at least 10 years older than child. Siblings were concordant for disease type in 81.6% of the affected sibling pairs, extent in 76.0%, extraintestinal manifestations in 83.8%, and smoking history in 81.3%. In contrast with the parent-child pairs, 68.1% (111 sibling pairs) siblings were diagnosed within 10 years of each other. The median age of onset was 24.0 years. CONCLUSIONS--This study has shown consistent clinical patterns in many families with inflammatory bowel disease. The differences in age of onset between parents and children are not readily explained by a simple cohort effect or ascertainment bias, and may reflect effects of genetic factors, producing anticipation between generations.     

Transmission of CARD15 (NOD2) variants within families of patients with inflammatory bowel disease

OBJECTIVES: Three single nucleotide polymorphisms (SNPs) in CARD15 have been independently associated with Crohn's disease (CD). Since nothing is known about the transmission of these variants within families, this was the subject of our study in Flemish patients with inflammatory bowel disease (IBD) and their healthy relatives. METHODS: A cohort of 1,670 individuals (570 CD, 173 UC, 165 healthy controls, 762 first-degree unaffected relatives of CD patients) was genotyped for Arg702Trp, Gly908Arg, and Leu1007fsinsC. Mutant allele and carrier frequencies were compared between groups. Segregation patterns were compared using a bivariate Dale model. RESULTS: The carrier prevalence of CARD15 variants for CD patients was 46.3%, compared to 20.6% for healthy controls and 22.0% for ulcerative colitis (UC) patients (both p < 0.0001). An increased carriage rate of CARD15 variants was observed in unaffected relatives of CD patients (37.3%; p < 0.0001 vs controls), although this was significantly lower than in the CD patients (p = 0.001). Paternal transmission gave a 5.17-fold higher chance for the child to develop the disease compared to maternal transmission (95% CI [1.59, 16.78]; p = 0.0063). UC patients belonging to mixed IBD families carried significantly more mutations (42.3%) compared to other UC patients (18.4%) (p < 0.01). CONCLUSIONS: Maternal transmission of the CARD15 variant allele is associated with a lower proportion of affected individuals compared to paternal transmission. Therefore, maternal transmission does not carry an increased risk of transmission as does paternal transmission. The increased mutation carriage in unaffected siblings of CD patients and in UC patients belonging to mixed families suggests that other factors than CARD15 contribute to the eventual disease expression.     

NOD2/CARD15基因多态性与炎症性肠病遗传易感性关系分析

目的 研究NOD2/CARD15基因与我国汉族人群炎症性肠病遗传易感性的关系.方法 应用聚合酶链反应-序列特异性引物方法对45例克罗恩病NOD2/CARD15基因野生型和C2104T(4外显子处)、G2722C(8外显子处)和3020insC(11外显子处)三个主要碱基突变进行基因分型并测序.另对60例溃疡性结肠炎患者、50名健康献血者、2例克罗恩病患者的21名家系成员、3例溃疡性结肠炎患者的31名家系成员也进行了NOD2/CARD15基因多态性分析.结果 全部被调查人群中均未发现有NOD2/CARD15基因突变者,均携带野生型NOD2/CARD15基因.结论 在西方国家中与克罗恩病显著相关的NOD2/CARD15基因突变与我国汉族炎症性肠病人群无明显相关性,该基因可能不是我国汉族炎症性肠病人群的致病基因.     

Allele-sharing of cytokine genes in familial inflammatory bowel disease

BACKGROUND/AIMS: The pathogenesis of inflammatory bowel disease is complex, multifactorial, and involves genetic predisposition. This predisposition is likely to include various chromosomal loci, but simple Mendelian inheritance cannot be excluded in a subset of families with inflammatory bowel disease. METHODOLOGY: We evaluated allele-sharing in 17 sib-pairs with inflammatory bowel disease as an approach to select candidate genes for further studies in individual families. It was determined whether each sib-pair had inherited the same alleles for interleukin-2, interleukin-2 receptor beta, interleukin-4, interleukin-4 receptor, interleukin-10, interleukin-10 receptor, tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 and 2. RESULTS: The results were very different per individual family. The estimated probability of sharing both alleles identical-by-descent at interleukin-4 receptor, interleukin-10, interleukin-10 receptor, and tumor necrosis factor alpha were 50%, 39%, 40%, and 33% respectively. The LOD score was significant for interleukin-4 receptor (p = 0.04). CONCLUSIONS: In this small group of sib-pairs with inflammatory bowel disease a modestly increased allele-sharing was found for some inflammatory related genes. Different results per family may suggest genetic heterogeneity. This method can be useful as a first step to further evaluation of specific candidate genes which may play a pathogenetic role in individual families.     

Nutritional management of inflammatory bowel disease; an overview of the evidences

Background and aimsInflammatory bowel disease (IBD) is a chronic relapsing–remitting systemic disease and one of the most common gastrointestinal diseases that affect many people. This review designed to report the latest findings on the association between some nutrients and IBD.MethodsA review was performed to summarize the effect of various aspects of nutrition and diet on clinical course, the severity of disease, intestinal epithelial inflammation, inflammatory and oxidative stress markers. Literature searches were conducted in PubMed and Google Scholar up to June 27, 2021.ResultsVarious studies have shown that an unhealthy diet and deficiency of some nutrients are involved in the etiology of IBD. It has also been shown that intestinal dysbiosis can increase the risk of developing IBD. The results of some studies have shown that supplementation with some nutrients such as omega-3 polyunsaturated fatty acids and vitamin D and probiotics may have beneficial results in patients with IBD. Adherence to some restrictive diets has also been helpful in some studies.ConclusionsFollowing proper nutritional approaches can play an essential role in managing IBD symptoms. Further studies are needed to substantiate some of these findings.     

NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene polymorphisms in Turkish patients with inflammatory bowel disease

Purpose The genetic susceptibility of people with certain NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene variants to inflammatory bowel disease is still under investigation. The aim of this study was to investigate polymorphisms in the NOD2/CARD15 (R702W, G908R, and 3020insC), NOD1/CARD4 (E266K, D372N), and ICAM-1 (G241R, K469E) genes, which are known to be associated with inflammation, in Turkish patients with inflammatory bowel disease and healthy control groups. Methods The genotypes of 70 patients with endoscopically and histopathologically diagnosed Crohn's disease (38 men, 32 women; mean age, 38.8 ± 1.3), 120 patients with ulcerative colitis (67 men, 53 women; mean age, 41.7 ± 1.3) and 106 healthy control subjects (37 men, 69 women; mean age, 35.7 ± 1.4), who stated that they had never had any prior bowel disease history, were compared. A polymerase chain reaction-restriction fragment length polymorphism analysis was performed for two variants of the ICAM-1 gene, the three main variants of the NOD2/CARD15 gene, and the E266K variant of the NOD1/CARD4 gene, and DNA sequencing was used for the D372N polymorphism of the NOD1/CARD4 gene. Results In this study, the three previously described Crohn's disease-predisposing variants of the NOD2/CARD15 gene and the polymorphisms examined in the NOD1/CARD4 and ICAM-1 genes were not found to be associated with ulcerative colitis or Crohn's disease. Conclusions These findings suggest that the polymorphisms observed in the NOD2/CARD15, NOD1/CARD4, and ICAM-1 genes are not genetic susceptibility factors for Crohn's disease or ulcerative colitis in Turkey.