Association of NOD2/CARD15 mutations on Crohn's disease phenotype in an Italian population

AIMS: To confirm the prevalence of NOD2/CARD15 mutations in Italian inflammatory bowel disease patients and to define the role of the different mutations on Crohn's disease phenotype. PATIENTS AND METHODS: A total of 177 patients with Crohn's disease and 92 patients with ulcerative colitis and 164 control participants were investigated for the presence of Arg702Trp, Gly908Arg and Leu1007fsinsC NOD2/CARD15 mutations. Allele frequencies in Crohn's disease and ulcerative colitis patients were compared with those observed in the control population. Genotype-phenotype correlations with the major clinical features were also established and estimated risks (odds ratio with 95% confidence interval) for the mutations were calculated by logistic regression and multiple correspondent analysis. RESULTS: Gly908Arg and Leu1007fsinsC mutations were significantly more frequent in Crohn's disease patients compared with healthy controls (P<0.01 and <0.003 respectively). Indeed, using a logistic regression model adding terms for age (differently distributed between cases and controls) and sex, a significantly increased risk of having Crohn's disease compared with healthy controls was found for all NOD2 mutations: Leu1007fsinsC (odds ratio=7.35; 95% confidence interval: 1.73-31.3), Gly908Arg (odds ratio=5.70; 95% confidence interval: 1.37-23.7) and Arg702Trp (odds ratio=2.45; 95% confidence interval: 1.10-5.47). As far as the genotype-phenotype correlations are concerned, by multivariate conditional logistic regression methods, we found a significant association between Gly908Arg mutations and familial history of inflammatory bowel disease, between Leu1007fsinsC mutations and appendectomy and between Arg702Trp mutations and fibrostenotic phenotype of Crohn's disease. A nonsignificant association between Arg702Trp variants and ileal disease was also found (odds ratio=8, 95% confidence interval: 0.99-64.9). CONCLUSIONS: The results of the study confirm a significant association of CARD15 gene mutations in our Italian Crohn's disease population and the impact of different NOD2/CARD15 mutations on specific disease phenotypes.     

CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies

OBJECTIVES: The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohn's disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. METHODS: Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohn's disease, 34 probands with ulcerative colitis and 71 inflammatory bowel disease-affected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohn's disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. RESULTS: In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohn's disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohn's disease (P=0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohn's disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P>or=0.38). Inflammatory bowel disease-affected family members of Crohn's disease probands carrying L1007fs, however, were carriers significantly more often than expected (P<0.001). In Crohn's disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P=0.006 and 0.017, respectively). CONCLUSION: In the Dutch population, CARD15 G908R and L1007fs are associated with Crohn's disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohn's disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.     

Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan

BACKGROUND & AIMS: The NOD2 variants R702W, G908R, and L1007fsinsC are strongly associated with Crohn's disease (CD) in both European and American populations, but whether this susceptibility extends to all ethnic groups remains unknown. Except for the L1007fsinsC mutation, which produces a truncated NOD2 protein, the functional activity of the major CD-associated variants G908R and R702W is unknown. METHODS: Individuals were genotyped for R702W, G908R, and L1007fsinsC. The ability of G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S to confer responsiveness to lipopolysaccharide (LPS) and peptidoglycan (PGN) was determined in HEK293T kidney cells. RESULTS: G908R and L1007fsinsC, but not R702W, were associated with disease susceptibility in Ashkenazi Jews. Ashkenazi Jews with CD had significantly higher allele frequency carriage of G908R and lower carriage of R702W compared with non-Jewish whites with CD. Functional studies revealed that the G908R, R702W, and L1007fsinsC variants in the presence and absence of P268S are defective in their ability to respond to bacterial LPS and PGN, whereas P268S alone exhibited wild-type activity. CONCLUSIONS: R702W is not associated with susceptibility to CD in Ashkenazi Jews. The G908R, R702W, and L1007fsinsC variants share a common signaling defect in response to bacterial components, providing evidence for a unifying molecular mechanism whereby NOD2 mutations contribute to disease susceptibility.     

Frequency of three common mutations of CARD15/NOD2 gene in Iranian IBD patients.

BACKGROUND: The CARD15/NOD2 gene, located on the pericentromeric region of chromosome 16 (IBD1) has been reported to have an association with IBD, especially Crohn's disease. Three common mutations of CARD15 are variably associated with Crohn's disease in different ethnic groups. We evaluated the frequency of these mutations (R702W, G908R and 1007fsinsC) in Iranian IBD patients and compared it with the healthy control population. METHODS: One hundred patients with ulcerative colitis, 40 patients with Crohn's disease, and 100 sex- and age-matched controls were enrolled from a tertiary center during a one-year period (2005-2006). The three mutations were assessed in DNA of leukocytes by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequency of R702W mutation was significantly higher in Iranian patients with Crohn's disease (p< 0.001; OR 19.21; 95% CI 4.23-87.32) compared to healthy controls. No association was observed between the other mutations and Crohn's disease and none of these mutations was associated with ulcerative colitis. CONCLUSION: The R702W mutation of CARD15 gene was associated with Crohn's disease in the Iranian population.     

NOD2/CARD15 genotype and phenotype differences between Ashkenazi and Sephardic Jews with Crohn's disease

OBJECTIVE: NOD2/CARD15 has been identified as a major susceptibility gene for Crohn's disease (CD). Three mutations, Arg702Trp, Gly908Arg, and Leu1007fsinsC, are associated with CD. The incidence and prevalence rate of inflammatory bowel diseases is two- to four-fold higher in Ashkenazi Jews as compared to non-Jewish Caucasians. The aim of this study was to determine the significance of the NOD2/CARD15 mutations in Jewish CD patients in Israel, and more specifically, to compare the significance of the mutations to the expression of CD in the Ashkenazi and Sephardic Jewish populations. METHODS: Allele frequencies of the mutations were determined in 180 Jewish CD patients, 73 ulcerative colitis patients, and 159 ethnically matched controls. Variants were detected using allele-specific PCR and restriction enzyme digestion assay. Demographic and phenotypic characterizations of the CD patients were determined. RESULTS: The carrier rate of the three mutations in the entire Jewish Israeli CD cohort is 41.1% versus 10.7% in controls (p < 0.0001). The Ashkenazi Jewish CD patients have an increased carrier rate compared to Sephardic Jews (47.4%vs 27.45%, p= 0.034). Association analyses in Ashkenazi Jews reveal odds ratios of 10.5, 9, and 4.8 for carriage of Gly908Arg, Arg702Trp, and Leu1007fsinsC mutations, respectively. Significantly higher rates of smoking, family history of inflammatory bowel diseases, and extraintestinal manifestations were found among the Sephardic CD patients. CONCLUSIONS: NOD2/CARD15 CD-associated mutations confer increased risk mainly to the Ashkenazi Jewish CD patients in Israel. This suggests that NOD2/CARD15 mutations could contribute to the higher incidence and prevalence rates of CD among Ashkenazi Jews.     

NOD2,IL23R and ATG16L1 polymorphisms in Lithuanian patients with inflammatory bowel disease

AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Crohn‘s disease (CD) and 123 ulcerative colitis (UC)] and 186 healthy controls were genotyped for the following known genetic susceptibility variants:NOD2-Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847), as well as IL23R-Arg381Gln (rs11209026) and ATG16L1-Thr300Ala (rs2241...     

NOD2/CARD15基因R702W、G908R及L1007fs多态性与广西壮族人群炎症性肠病的相关性

目的:探讨我国广西壮族人群NOD2/CARD15基因R702W、G908R及L1007fs的遗传多态性与炎症性肠病的相关性.方法:分别收集2007-02/2010-10在广西地区无亲缘关系的壮族(n=70)和汉族(n=76)IBD患者及壮族(n=80)和汉族(n=84)正常对照者的肠黏膜组织.采用酚氯仿法提取各组织样本DNA,采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)方法对NOD2/CARD15基因R702W、G908R及L1007fs进行检测,统计基因型及等位基因频率,分析上述3个多态性位点与广西壮族人群炎症性肠病的相关性.结果:广西壮族和汉族IBD患者与正常对照者均未发现NOD2/CARD15基因R702W、G908R及L1007fs突变型基因型,所有多态性位点上的基因型全部为野生型纯合子,其基因型频率和等位基因频率分布在IBD患者和正常对照者中差异无统计学意义(P>0.05).结论:NOD2/CARD15基因R702W、G908R及L1007fs多态性与广西壮族人群炎症性肠病无明显相关性.     

CARD15 mutation analysis in an Italian population: Leu1007fsinsC but neither Arg702Trp nor Gly908Arg mutations are associated with Crohn's disease

BACKGROUND: CARD15 gene mutations have been demonstrated to confer a high risk of Crohn's disease (CD). Despite this, recent studies reported variable associations between CD and CARD15 mutations in distinct ethnic groups, thus raising the hypothesis that genetic and/or allelic heterogeneity may influence the relationship between CARD15 and CD. The purpose of this study was to evaluate the frequency of the main mutations of the CARD15 gene (Leu 1007fsinsC, Arg702Trp, and Gly908Arg) in Italian CD patients and to establish possible genotype-phenotype correlations. METHODS: One hundred sixty-five CD patients and 125 healthy subjects were consecutively enrolled from January to November 2001. The Leu1007fsinsC mutation was assessed by denaturing high-performance liquid chromatography and Arg702Trp and Gly908Arg mutations by Pyrosequencing technology. RESULTS: Among the CARD15 gene mutations tested, only the Leu1007fsinsC was associated with CD (30/165 CD patients, 18%, versus 3/125 healthy subjects, 2.4%; p < 0.001). In particular, 23 CD patients were heterozygotes and 7 were homozygotes. No healthy subject exhibited the mutant homozygous genotype. Odds ratios for CD were 6.9 for heterozygotes and 41.0 for homozygotes. The genotype-phenotype analysis revealed that a fibrostenosing CD of the distal ileum was more frequent in patients carrying the Leu1007fsinsC mutation. CONCLUSIONS: This study confirms the association between CARD15 gene mutations and CD and shows that only the Leu1007fsinsC mutation is a risk factor of CD in an Italian population.     

The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease

BACKGROUND & AIMS: Mutations in the NOD2 gene are strongly associated with susceptibility to Crohn's disease (CD). We analyzed a large cohort of European patients with inflammatory bowel disease to determine which mutations confer susceptibility, the degree of risk conferred, their prevalence in familial and sporadic forms of the disease, and whether they are associated with site of disease. METHODS: Individuals were genotyped for 4 NOD2 mutations: P268S, R702W, G908R, and 3020insC. Allelic transmission distortion to 531 CD- and 337 ulcerative colitis-affected offspring was assessed by the transmission disequilibrium test. Association was also tested in an independent cohort of 995 patients with inflammatory bowel disease and 290 controls. Cases were stratified by disease site and compared across NOD2 genotypes. RESULTS: R702W, G908R, and 3020insC were strongly associated with CD but not with ulcerative colitis. Linkage disequilibrium was observed between P268S and the other mutations, forming 3 independent disease haplotypes. Genotype relative risks were 3.0 for mutation heterozygotes and 23.4 for homozygotes or compound heterozygotes. The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004). CONCLUSIONS: The R702W, G908R, and 3020insC mutations are strong independent risk factors for CD and are associated particularly with ileal disease.     

Clinical significance of NOD2/CARD15 and Toll-like receptor 4 gene single nucleotide polymorphisms in inflammatory bowel disease

AIM： To evaluate the role of genetic factors in the pathogenesis of Crohn＇s disease （CD） and ulcerative colitis （UC）, we investigated the single nucleotide polymorphisms （SNPs） of NOD2/CARD15 （R702W, Gg08R and L1007finsC）, and Toll-like receptor 4 （TLR4） genes （D299G and T399I） in a selected inflammatory bowel disease （IBD） population coming from Southern Italy. METHODS： Allele and genotype frequencies of NOD2/ CARD15 （R702W, Gg08R and L1007finsC） and TLR4 （D299G and T399I） SNPs were examined in 133 CD patients, in 45 UC patients, and in 103 healthy controls. A genotype-phenotype correlation was performed. RESULTS： NOD2/CARD15 R702W mutation was significantly more frequent in CD （9.8%） than in controls （2.4%, P = 0.001） and in UC （2.3%, P = 0.03）. No significant 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）. CONCLUSION： These findings confirm that, in our IBD patients selected from Southern Italy, the NOD2/ CARD15, but not TLR4 SNPs, are associated with increased risk of CD.     

Contribution of CARD15 variants in determining susceptibility to Crohn's disease in Sweden

OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. Mutations in the CARD15 gene have been associated with CD. No previous case-control CARD15 study has been performed in the Swedish population. MATERIAL AND METHODS: The study comprised of 321 individuals: 178 with CD and 143 healthy controls (HCs), all from Stockholm County. All were genotyped for the three main CD-associated CARD15 variants (R702W, G908R and 1007fs) and phenotypic associations were investigated. RESULTS: The allele frequencies of the R702W variant (4.5% CD versus 0.7% HC, p=0.008, OR = 6.8) and the G908R variant (2.0% CD versus 0% HC, p=0.045) were more common in CD patients than in controls. No significant difference in1007fs variant allele frequency was found between CD patients and controls (2.0% CD versus 1.7% HC, p = 0.8, OR = 1.1). Carriage of CARD15 variants was more common in the CD patients than in controls (15.2% CD versus 4.2% HC, p = 0.001, OR = 4.1, population attributable risk (PAR) = 11.4%). Genotype-phenotype analysis demonstrated that CARD15 variants were associated with ileal disease (p=0.0006, OR = 9.3, CI = 2.2-34) and protective for colonic CD (p = 0.01, OR = 0.18). An association between CARD15 variants and ileal CD (p=0.004, OR = 6.6) was confirmed by multivariate analyses. CONCLUSIONS: The CARD15 variants R702W and G908R, but not 1007fs, are associated with susceptibility to CD in Stockholm County. Genotype-phenotype analysis shows an association with ileal CD. The contribution of these CARD15 mutations in Swedish CD patients overall is low in relation to studies elsewhere in Central Europe and North America, but is consistent with emerging data from elsewhere in Scandinavia and in Northern Europe.     

CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn's disease

BACKGROUND: Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn's disease (CD). Aim: Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD. PATIENTS AND METHODS: We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs. RESULTS: In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery. CONCLUSIONS: The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.     

Association of NOD2/CARD15 variants with Crohn's disease in a Greek population

OBJECTIVE: Single nucleotide polymorphisms in the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease (CD), but whether this susceptibility extends to all ethnic groups and geographic areas remains unknown. The aim of the present study was to evaluate the NOD2/CARD15 mutations in Greek patients with CD. METHODS: Individuals were genotyped for three NOD2/CARD15 mutations: R702W, G908R and L1007fsinsC. Blood samples were obtained from 120 patients with CD, 85 patients with ulcerative colitis, and 100 unrelated healthy controls. RESULTS: Mutations in NOD2/CARD15 were observed with significantly greater frequency in CD patients (98/120, 81.7%) than in ulcerative colitis patients (40/85, 47%) (P < 0.0001) or in healthy individuals (21/100, 21%) (P < 0.0001). For CD patients, compared with controls, the odds were increased for carriage of the R702W (odds ratio, 12.25) and less for the G908R (odds ratio, 5.2) and L1007fsinsC (odds ratio, 3.9) mutations. The age of onset of CD was lower in Greek mutation carriers as compared with non-carriers of Greek origin (28.2 +/- 14.6 years versus 34 +/- 12.3 years, respectively; P = 0.036). Additionally, the frequency of NOD2/CARD15 mutations was increased in ileitis or ileocolitis compared with non-ileal disease. CONCLUSIONS: The NOD2/CARD15 mutations are risk factors for CD in Greece, they appear to predict an earlier age of onset and are associated particularly with ileitis or ileocolitis.     

1007fs, G908R, R702W Mutations and P268S, IVS8+158 Polymorphisms of the CARD15 Gene in Turkish Inflammatory Bowel Disease Patients and Their Relationship with Disease-Related Surgery

Introduction CARD15 gene mutations may present different frequencies in populations and sometimes surgical interventions may become a necessary therapy for inflammatory bowel disease patients. Mutations of 1007fs, G908R, R702W and polymorphisms of P268S, IVS8⁺¹⁵⁸ of the CARD15 gene and their relation with disease-related surgery were investigated in Turkish inflammatory bowel disease patients in this study. Material and Method 1007fs, G908R, R702W mutations and P268S, IVS8⁺¹⁵⁸ polymorphisms of CARD15 gene were analyzed in 130 inflammatory bowel disease patients (67 Crohn’s disease, 63 ulcerative colitis) and 87 healthy controls. After obtaining DNA samples, genotyping was performed by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) analysis. Results were evaluated by statistical analysis and accepted as significant if P < 0.05. Results R702W gene mutation was significantly lower in the inflammatory bowel disease group (1.5%) than the controls (4.8%) (P < 0.05). The overall allele frequency of mutations in the inflammatory bowel disease group (2.7%) was lower than in controls (6.6%) (P < 0.05). Disease-related surgery history was present in 20 Crohn’s and 25 ulcerative colitis patients; familial history was present in four Crohn’s and five ulcerative colitis patients. Statistically, no relationship was detected between disease-related surgeries and the investigated genetic tests. Conclusion In Turkish patients, no important relationship was detected between the investigated allele frequencies of the CARD15 gene and inflammatory bowel disease nor between disease-related surgeries and inflammatory bowel disease. Dedicated to the memory of the Turkish scientist Turgut Tukel MD. Thanks for his contributions and supports.     

NOD2/CARD15 genotype,cardiovascular disease and cancer in 43 600 individuals from the general population

Abstract. Yazdanyar S, Nordestgaard BG (Herlev Hospital, Copenhagen University Hospital, University of Copenhagen; and Bispebjerg Hospital, Copenhagen University Hospital, University of Copenhagen; Herlev, Denmark). NOD2/CARD15 genotype, cardiovascular disease and cancer in 43 600 individuals from the general population. J Intern Med 2010; 268 : 162–170. Objectives. The NOD2/CARD15 gene is involved in the innate immune response, and thus in inflammation. Three polymorphisms in this gene (Arg702Trp rs2066844, Gly908Arg rs2066845 and Leu1007fsinsC rs5743293) have been associated with increased risk of the inflammatory bowel disease, the Crohn’s disease. We tested whether these polymorphisms are also associated with increased risk of cardiovascular disease and cancer, in which the innate immune system and inflammation may influence pathogenesis. Design, setting and subjects. We genotyped 43 596 white individuals from two large Danish general population cohorts followed for 31 years: the Copenhagen City Heart Study (n = 10 597) and the Copenhagen General Population Study (n = 32 999). We examined the risk of cardiovascular disease (2743 and 3890, respectively, in the two studies) and cancer (2144 and 3241, respectively) by NOD2/CARD15 genotype using Cox and logistic regressions in both studies. To maximize statistical power, the three NOD2/CARD15 genetic variants were analysed together as follows: noncarriers for all three variants, heterozygotes for one of the three variants and homozygotes for one of the three variants pooled with compound heterozygotes for two variants. Results. Multifactorially adjusted hazard ratios for cardiovascular disease and cancer in NOD2/CARD15 heterozygotes or homozygotes/compound heterozygotes versus noncarries did not differ from 1.0 in the Copenhagen City Heart Study or in the Copenhagen General Population Study. The corresponding multifactorially adjusted odds ratios likewise did not differ from 1.0 in either study. Conclusions. The NOD2/CARD15 Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms were not associated with increased risk of cardiovascular disease or cancer in the Danish general population.     

Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis

OBJECTIVE: The identification of CARD15 as a susceptibility gene for Crohn's disease (CD) offers new possibilities for patient classification and risk assessment. The purpose of this study was to carry out a CARD15 sequence analysis in a large single-center IBD cohort and to investigate the impact of different genotypes on disease phenotypes. MATERIAL AND METHODS: A total of 445 unrelated patients with IBD (68.1% CD, 28.5% ulcerative colitis (UC), 3.4% indeterminate colitis (IC)) were included in the study. Clinical data were recorded by detailed questionnaire and analysis of the charts. CARD15 variants (R702W, G908R, 1007fs (frameshift)) were identified by DNA sequence analysis. RESULTS: CARD15 variants were found in 142 inflammatory bowel disease (IBD) patients (31.9%) including 120 CD patients (39.6%). In CD, the presence of two CARD15 variants was associated with ileal disease (p=0.008 versus wild-type (wt); OR 4.04; 95% CI 1.36-11.96) and a fibrostenotic phenotype (p=0.002 versus wt; OR 5.47; 95% CI 1.61-18.58). Subgroup analysis of 19 patients (4.3%) homozygous for the CARD15 variant 1007fs (3020ins C) revealed an association with onset of CD at an early age (p=0.014 versus wt), ileal involvement (p=0.001), and intestinal stenoses in all patients (p=0.001) frequently requiring surgery (73.7%; p=0.093). Of these patients 78.6% developed re-stenoses after surgical resection; 52.6% of the homozygotes were diagnosed as having entero-enteral fistulas. CONCLUSIONS: Patients homozygous for the 1007fs mutation had an early disease onset with long-segment ileal stenoses and entero-enteral fistulas. They frequently needed surgical intervention and had a high risk of re-stenosis. Genotyping therefore appears to be an important diagnostic tool in identifying severely affected patients requiring individualized treatment strategies at an early stage of the disease.     

CARD15 mutations in patients with Crohn's disease in a homogeneous Spanish population

OBJECTIVES: Three mutations in CARD15 have been repeatedly shown to be involved in Crohn's disease susceptibility, mainly in Caucasian individuals. However, those findings were not replicated in all populations studied so far. In this work, we studied the role of CARD15 mutations in a relatively homogeneous population from the Northwest of Spain, Galicia. METHODS: One hundred and sixty-five patients with Crohn's disease and a similar number of healthy controls were recruited from a single center in Galicia. All individuals were genotyped for the three main Crohn's disease associated CARD15 variants (R702W, G908R, and 1007fs). Association analyses were performed to study the influence of those mutations on Crohn's disease overall and on clinical subphenotypes. RESULTS: The allele frequencies of CARD15 variants were lower in this population than in most of the European populations studied so far. G908R and 1007fs were significantly associated with overall susceptibility to Crohn's disease. However, these associations were lost after stratification to clinical subgroups, probably due to the small number of cases in these subgroups. Significant associations were found between G908R and 1007fs and the behavior of Crohn's disease, but they were due to the influence of years of disease on the behavior of the disease rather than being the result of a direct effect of these mutations on disease behavior. CONCLUSIONS: The CARD15 variants G908R and 1007fs, but not R702W, are associated with susceptibility to Crohn's disease in Galicia. Interestingly, the frequency of these mutations appears to be lower than in other Caucasian populations studied so far.     

Significant role of genetics in IBD: the NOD2 gene

Inflammatory bowel disease (IBD) clusters within families, suggesting a genetic component to disease pathogenesis. Studies have identified a gene on chromosome 16cen that confers susceptibility to Crohn's disease. The affected gene codes for the NOD2/CARD15 protein, which is involved in the immune system's response to bacterial infection. Multiple mutations have been identified, three of which have been shown to be independently associated with Crohn's disease-arg702trp, gly908arg, and leu1007fsinsC. Taken together, these three variants confer a 15%-20% attributable population risk among cases of familial Crohn's disease, with decreased contribution among the more common sporadic cases of the disease. The presence of an NOD2 risk allele has been shown to be associated with ilial disease as well as an earlier age of disease onset. Further studies are needed to clarify the relationship between IBD genotype and disease behavior.     

Analysis of CARD15 polymorphisms in Korean patients with ankylosing spondylitis reveals absence of common variants seen in western populations

OBJECTIVE: Substantial epidemiological and genetic evidence suggests that ankylosing spondylitis (AS) is likely due to an interplay of genetic and environmental factors. Recently, CARD15, located in chromosome 16q12, has been established as a disease susceptibility gene for Crohn's disease, Blau syndrome, and possibly psoriatic arthritis. Association studies in admixed populations from Northern European ancestry noted no such association between CARD15 mutations and AS. However, a homogenous population has yet to be studied. We investigated the prevalence of the 3 common CARD15 variants in a homogenous Korean population with AS. METHODS: All subjects were native Koreans with AS satisfying the modified New York criteria. Korean controls were examined and confirmed to be unaffected by AS. Subjects with AS were genotyped for the R702W, G908R, and Leu1007fsinsC variants of CARD15 using mass array MALDI-TOF mass spectrometry. RESULTS: A total of 205 AS subjects and 200 controls were genotyped. No subject with AS had any variants at the 702 and 1007 sites of CARD15. Only one subject was heterozygous for the 908 variant. The overall genotype frequency in AS for any CARD15 variant was 0.5%. No control had any of the 3 CARD15 variants. CONCLUSION: Our findings indicate that the CARD15 gene is not a major contributor to AS susceptibility in the Korean population.     

NOD2／CARD15 gene polymorphism in patients with inflammatory bowel disease： Is Hungary different？

AIM: To analyse the impact of NOD2/CARD15 mutations on the clinical course of Crohn 's disease patients from an eastern European country (Hungary). METHODS: We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 1007finsC) in 148 patients with Crohn's disease, 128 patients with ulcerative colitis and 208 controls recruited from the University of Szeged, Hungary. In patients with Crohn 's disease, the prevalence of NOD2/CARD15 mutations was correlated to the demographical and clinical parameters. RESULTS: In total, 32.4% of Crohn's disease patients carried at least one mutant allele within NOD2/CARD15 compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P相似文献