AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD.METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 heal...AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD.METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing highperformance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP.RESULTS: NOD2/CARD15 mutations were found in 185patients (35.1%) and in 33 controls (16.5%, P<0.0001).SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vscontrols: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet = 1.71,95%CI = 1.12-2.6, P= 0.0001, ORtwo-riskalleles = 25.2,95%CI = 4.37- , P<0.0001), early disease onset (carrier:26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08,P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55,P = 0.026) and increased need for resection (OR=1.71,95%CI: 1.13-2.62, P= 0.01), but not with duration, extraintestinal manifestations, familial disease or smoking. TLR4exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P= 0.06), in NOD2mut/wt: 26.7 years.CONCLUSION: These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease,stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4mutation carriers tended to present at earlier age.展开更多
AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). MET...AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn’s disease (CD), 186 ulcerative colitis (UC) patients, 434 par- ents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more com- mon in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an in- creased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was morefrequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric on- set of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.展开更多
AIM:To assess the relationship between the P268S,JW1 and N852S polymorphisms and Crohn’s disease(CD)susceptibility in Zhuang patients in Guangxi,China.METHODS:Intestinal tissues from 102 Zhuang[48CD and 54 ulcerative...AIM:To assess the relationship between the P268S,JW1 and N852S polymorphisms and Crohn’s disease(CD)susceptibility in Zhuang patients in Guangxi,China.METHODS:Intestinal tissues from 102 Zhuang[48CD and 54 ulcerative colitis(UC)]and 100 Han(50 CD and 50 UC)unrelated patients with inflammatory bowel disease and 72 Zhuang and 78 Han unrelated healthy individuals were collected in the Guangxi Zhuang Autonomous Region from January 2009 to March 2013.Genomic DNA was extracted using the phenol chloroform method.The P268S,JW1 and N852S polymorphisms were amplified using polymerase chain reaction(PCR),detected by restriction fragment length polymorphism(RFLP),and verified by gene sequencing.RESULTS:Heterozygous mutation of P268S in the NOD2/CARD15 gene was detected in 10 CD cases(six Zhuang and four Han),two Han UC cases,and one Zhuang healthy control,and P268S was strongly associated with the Chinese Zhuang and Han CD populations(P=0.016 and 0.022,respectively).No homozygous mutant P268S was detected in any of the groups.No significant difference was found in P268S genotype and allele frequencies between UC and control groups(P>0.05).Patients with CD who carried P268S were likely to be≤40 years of age(P=0.040),but were not significantly different with regard to race,lesion site,complications,and other clinical features(P>0.05).Neither JW1 nor N852S polymorphisms of the NOD2/CARD15gene were found in any of the subjects(P>0.05).CONCLUSION:P268S polymorphism may be associated with CD susceptibility in the Zhuang population in the Guangxi Zhuang Autonomous Region,China.In contrast,JW1 and N852S polymorphisms may not be related to CD susceptibility in these patients.展开更多
AIM: To 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 ...AIM: To 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). METHODS: Polymorphisms 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 polymor-phism 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). RESULTS: The 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 co- lonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to con- trols (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. CONCLUSION: Polymorphism 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 earlyonset disease.展开更多
AIM: Crohn's disease(CD)and ulcerative colitis(UC)are multifactorial diseases with a significant genetic background.Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune...AIM: Crohn's disease(CD)and ulcerative colitis(UC)are multifactorial diseases with a significant genetic background.Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune response such as CD14 or Toll-like receptor 4 (TLR4), are involved in their pathogenesis. In further exploring the genetic background of these diseases, we investigated the variations in the CARD15/NOD2 gene (Arg702Trp,Gly908Arg and Leu1007fsinsC), and polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) as well as in the promoter of the CD14 gene (T/C at position -159) in Greek patients with CD and UC.METHODS: DNA was obtained from 120 patients with CD,85 with UC and 100 healthy individuals. Genotyping was performed by allele specific PCR or by PCR-RFLP analysis.RESULTS: The 299Gly allele frequency of the TLR4 gene and the T allele and TT genotype frequendes of the CD14 promoter were significantly higher in CD patients only compared to healthy individuals (P = 0.026<0.05; P = 0.0048<0.01 and P= 0.047<0.05 respectively). Concerning the NOD2/CARD15mutations the overall presence in CD patients was significantly higher than that in UC patients or in controls.Additionally, 51.67% of the CD patients were carriers of a TLR4 and/or CD14 polymorphic allele and at least one variant of the NOD2/CARD15, compared to 27% of the UC patients. It should be pointed out that both frequencies significantly increased as compared with the 10% frequency of multiple carriers found in healthy controls. A possible interaction of the NOD2/CARD15 with TLR4 and especially CD14, increased the risk of developing inflammatory bowel disease (IBD).CONCLUSION: Our results indicate that co-existence of a mutation in either the TLR4 or CD14 gene, and in NOD2/CARD15is associated with an increased susceptibility to developing CD compared to UC, and to developing either CD or UC compared to healthy individuals.展开更多
AIM: To investigate the frequency of the common NOD2/CARD15 susceptibility variants and two functional polymorphisms of OCTN cation transporter genes in Hungarian pediatric patients with Crohn’s disease (CD). METHODS...AIM: To investigate the frequency of the common NOD2/CARD15 susceptibility variants and two functional polymorphisms of OCTN cation transporter genes in Hungarian pediatric patients with Crohn’s disease (CD). METHODS: A cohort of 19 unrelated pediatric and 55 unrelated adult patients with Crohn’s disease and 49 healthy controls were studied. Genotyping of the three common CD-associated CARD15 variants (Arg702Trp, Gly908Arg and 1007finsC changes) with the SLC22A4 1672C→T, and SLC22A5 -207G→C mutations was performed by direct sequencing of the specifi c regions of these genes.RESULTS: At least one CARD15 mutation was present in 52.6% of the children and in 34.5% of the adults compared to 14.3% in controls. Surprisingly, strongly different mutation profi le was detected in the pediatric versus adult patients. While the G908R and 1007finsC variants were 18.4% and 21.1% in the pediatric group, they were 1.82% and 11.8% in the adults, and were 1.02% and 3.06% in the controls, respectively. The R702W allele was increased approximately two-fold in the adult subjects, while in the pediatric group it was only approximately 64% of the controls (9.09% in the adults, 2.63% in pediatric patients, and 4.08% in the controls). No accumulation of the OCTN variants was observed in any patient group versus the controls.CONCLUSION: The frequency of the NOD2/CARD15 susceptibility variants in the Hungarian pediatric CD population is high and the profile differs from the adult CD patients, whereas the results for SLC22A4 and SLC22A5 mutation screening do not confirm the assumption that the carriage of these genotypes means an obligatory susceptibility to CD.展开更多
There have been multiple NOD2/CARD15 genotype- phenotype analyses undertaken in patients with Crohn’s disease since the gene’s discovery in 2001. This review focuses on the major published series based upon their si...There have been multiple NOD2/CARD15 genotype- phenotype analyses undertaken in patients with Crohn’s disease since the gene’s discovery in 2001. This review focuses on the major published series based upon their size and on the presence of specific clinical and genetic information provided in the published material from 2001 to 2005. Twelve studies provided raw data to carry out comparisons of disease location while ten studies included analysis of NOD2/CARD15 genotypes. NOD2/CARD15 variant frequency in ileal disease did not differ significantly among studies, whereas a comparison of disease location demonstrated highly significant differences among studies. Meta-analysis confirmed significant associations between NOD2/CARD15 variants and both ileal and ileocolonic disease locations, and with both stricturing and penetrating forms of disease behavior. This review underlines the significant phenotypic differences that exist among populations, including similar ethnic groups, and has demonstrated the need for further studies of patients with long-term “inflammatory” Crohn’s disease.展开更多
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/CA...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, 128patients 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/CARD15compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P<0.0001). In Crohn's disease patients, the allele frequencies for Arg702Trp,Gly908Arg and 1007finsC were 7.1%, 3.0% and 10.8%respectively. Interestingly, only the 1007finsC mutation was associated with a distinct clinical phenotype. The patients positive for the 1007finsC mutation suffered more frequently from stenotic disease behaviour (P = 0.008). Furthermore,51.9% of patients positive for the 1007finsC mutation underwent a surgical resection within the ileum compared to only 17.4% of patients without the 1007finsC mutation (P = 0.001). With respect to the other two mutations (Arg702Trp and Gly908Arg), no associations were found with all investigated clinical parameters.CONCLUSION: NOD2/CARD15 mutations are frequently found in Crohn's disease patients from Hungary. The 1007finsC mutation is associated with stenotic disease behaviour and frequent ileal resections.展开更多
The prevalence of Crohn’ s disease depends on geographic location and racial background. Arg702Trp, Gly908Arg, and Leu1007fsinsC mutations in the NOD2/CARD15 gene are associated with Crohn’ s disease in Caucasians. ...The prevalence of Crohn’ s disease depends on geographic location and racial background. Arg702Trp, Gly908Arg, and Leu1007fsinsC mutations in the NOD2/CARD15 gene are associated with Crohn’ s disease in Caucasians. The mutation rate among Israeli Jewish patients is 27% - 41% . The prevalence of Crohn’ s disease is much lower in the Israeli Arab compared to the Israeli Jewish population. We studied the NOD2/CARD15 mutation rate and disease phenotype (according to the Vienna classification) among the Israeli Arabs and compared them with those in an Israeli Jewish cohort. We recruited 66 Israeli Arab patients and 122 ethnically matched controls. Five patients (8.2% ) and three controls (2.3% ) carried one NOD2/CARD15 mutation. The phenotypic characteristics of the Arab and Jewish patients were very similar. We conclude that NOD2/CARD15 mutations do not contribute to Crohn’ s susceptibility in the Israeli Arab population and suggest that NOD2/CARD15 mutations have an important effect on Crohn’ s prevalence within a specific population but not on the phenotype.展开更多
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 b...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 phen-otypic 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 in 1007fs variant allele frequencywas 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-phen-otype 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.展开更多
Background: A North-South gradient in Crohn’s disease (CD) implying a higher incidence in northern Europe compared to southern Europe has been established. Aims: To investigate whether there is a difference between D...Background: A North-South gradient in Crohn’s disease (CD) implying a higher incidence in northern Europe compared to southern Europe has been established. Aims: To investigate whether there is a difference between Denmark and Portugal in the frequency of CARD15 mutations in CD patients compared to a healthy background population and to compare genotype-phenotype relations in the two countries. Methods: 58 Danish patients and 29 Portuguese patients with CD were matched for age, sex and disease behaviour at time of diagnosis and compared with 200 healthy Danish and Portuguese controls. Phenotypes were recorded at year of diagnosis, 3 years after diagnosis and at end of follow-up. Patients were genotyped for Arg702Trp, Gly908Arg and Leu1007InsC. Results: 22%of the Danish patients vs. 9%of Danish controls compared to 21%of the Portuguese patients vs. 16%had at least one mutation. Mutation rates in Danish patients were significantly different (p = 0.02) compared with Danish controls, no difference (p = 0.51) was found between Portuguese patients and controls. However, a possible relationship between CD and presence of genetic mutations was found when comparing the two countries (p = 0.03) using the Mantel-Haenszel test. No difference in evolution of phenotypes and the CARD15 status in CD was found during follow-up between the two matched populations. Ileal disease correlated to high occurrence of CARD15. Conclusion: No North-South gradient regarding occurrence of CARD15 was revealed. Although a trend towards more mutations in the Portuguese controls was seen, a relationship between CD and CARD15 mutations was observed in both countries.展开更多
文摘AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD.METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing highperformance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP.RESULTS: NOD2/CARD15 mutations were found in 185patients (35.1%) and in 33 controls (16.5%, P<0.0001).SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vscontrols: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet = 1.71,95%CI = 1.12-2.6, P= 0.0001, ORtwo-riskalleles = 25.2,95%CI = 4.37- , P<0.0001), early disease onset (carrier:26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08,P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55,P = 0.026) and increased need for resection (OR=1.71,95%CI: 1.13-2.62, P= 0.01), but not with duration, extraintestinal manifestations, familial disease or smoking. TLR4exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P= 0.06), in NOD2mut/wt: 26.7 years.CONCLUSION: These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease,stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4mutation carriers tended to present at earlier age.
文摘AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn’s disease (CD), 186 ulcerative colitis (UC) patients, 434 par- ents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more com- mon in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an in- creased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was morefrequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric on- set of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.
基金Supported by Guangxi Graduate Education Innovation Project Fund,No.YCSZ2012035the Natural Science Foundation of Guangxi Zhuang Autonomous Region,No.0832009,No.2012GXNSFAA053143Traditional Chinese Medicine Science Fund of Guangxi Zhuang Autonomous Region,China,No.GZPT1238
文摘AIM:To assess the relationship between the P268S,JW1 and N852S polymorphisms and Crohn’s disease(CD)susceptibility in Zhuang patients in Guangxi,China.METHODS:Intestinal tissues from 102 Zhuang[48CD and 54 ulcerative colitis(UC)]and 100 Han(50 CD and 50 UC)unrelated patients with inflammatory bowel disease and 72 Zhuang and 78 Han unrelated healthy individuals were collected in the Guangxi Zhuang Autonomous Region from January 2009 to March 2013.Genomic DNA was extracted using the phenol chloroform method.The P268S,JW1 and N852S polymorphisms were amplified using polymerase chain reaction(PCR),detected by restriction fragment length polymorphism(RFLP),and verified by gene sequencing.RESULTS:Heterozygous mutation of P268S in the NOD2/CARD15 gene was detected in 10 CD cases(six Zhuang and four Han),two Han UC cases,and one Zhuang healthy control,and P268S was strongly associated with the Chinese Zhuang and Han CD populations(P=0.016 and 0.022,respectively).No homozygous mutant P268S was detected in any of the groups.No significant difference was found in P268S genotype and allele frequencies between UC and control groups(P>0.05).Patients with CD who carried P268S were likely to be≤40 years of age(P=0.040),but were not significantly different with regard to race,lesion site,complications,and other clinical features(P>0.05).Neither JW1 nor N852S polymorphisms of the NOD2/CARD15gene were found in any of the subjects(P>0.05).CONCLUSION:P268S polymorphism may be associated with CD susceptibility in the Zhuang population in the Guangxi Zhuang Autonomous Region,China.In contrast,JW1 and N852S polymorphisms may not be related to CD susceptibility in these patients.
文摘AIM: To 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). METHODS: Polymorphisms 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 polymor-phism 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). RESULTS: The 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 co- lonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to con- trols (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. CONCLUSION: Polymorphism 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 earlyonset disease.
基金Supported by the EU Project "Sacrohn" N. QLK2-CT-2000-00928.
文摘AIM: Crohn's disease(CD)and ulcerative colitis(UC)are multifactorial diseases with a significant genetic background.Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune response such as CD14 or Toll-like receptor 4 (TLR4), are involved in their pathogenesis. In further exploring the genetic background of these diseases, we investigated the variations in the CARD15/NOD2 gene (Arg702Trp,Gly908Arg and Leu1007fsinsC), and polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) as well as in the promoter of the CD14 gene (T/C at position -159) in Greek patients with CD and UC.METHODS: DNA was obtained from 120 patients with CD,85 with UC and 100 healthy individuals. Genotyping was performed by allele specific PCR or by PCR-RFLP analysis.RESULTS: The 299Gly allele frequency of the TLR4 gene and the T allele and TT genotype frequendes of the CD14 promoter were significantly higher in CD patients only compared to healthy individuals (P = 0.026<0.05; P = 0.0048<0.01 and P= 0.047<0.05 respectively). Concerning the NOD2/CARD15mutations the overall presence in CD patients was significantly higher than that in UC patients or in controls.Additionally, 51.67% of the CD patients were carriers of a TLR4 and/or CD14 polymorphic allele and at least one variant of the NOD2/CARD15, compared to 27% of the UC patients. It should be pointed out that both frequencies significantly increased as compared with the 10% frequency of multiple carriers found in healthy controls. A possible interaction of the NOD2/CARD15 with TLR4 and especially CD14, increased the risk of developing inflammatory bowel disease (IBD).CONCLUSION: Our results indicate that co-existence of a mutation in either the TLR4 or CD14 gene, and in NOD2/CARD15is associated with an increased susceptibility to developing CD compared to UC, and to developing either CD or UC compared to healthy individuals.
基金Supported by the grant of Hungarian Science Foundation No. OTKA T 49589
文摘AIM: To investigate the frequency of the common NOD2/CARD15 susceptibility variants and two functional polymorphisms of OCTN cation transporter genes in Hungarian pediatric patients with Crohn’s disease (CD). METHODS: A cohort of 19 unrelated pediatric and 55 unrelated adult patients with Crohn’s disease and 49 healthy controls were studied. Genotyping of the three common CD-associated CARD15 variants (Arg702Trp, Gly908Arg and 1007finsC changes) with the SLC22A4 1672C→T, and SLC22A5 -207G→C mutations was performed by direct sequencing of the specifi c regions of these genes.RESULTS: At least one CARD15 mutation was present in 52.6% of the children and in 34.5% of the adults compared to 14.3% in controls. Surprisingly, strongly different mutation profi le was detected in the pediatric versus adult patients. While the G908R and 1007finsC variants were 18.4% and 21.1% in the pediatric group, they were 1.82% and 11.8% in the adults, and were 1.02% and 3.06% in the controls, respectively. The R702W allele was increased approximately two-fold in the adult subjects, while in the pediatric group it was only approximately 64% of the controls (9.09% in the adults, 2.63% in pediatric patients, and 4.08% in the controls). No accumulation of the OCTN variants was observed in any patient group versus the controls.CONCLUSION: The frequency of the NOD2/CARD15 susceptibility variants in the Hungarian pediatric CD population is high and the profile differs from the adult CD patients, whereas the results for SLC22A4 and SLC22A5 mutation screening do not confirm the assumption that the carriage of these genotypes means an obligatory susceptibility to CD.
文摘There have been multiple NOD2/CARD15 genotype- phenotype analyses undertaken in patients with Crohn’s disease since the gene’s discovery in 2001. This review focuses on the major published series based upon their size and on the presence of specific clinical and genetic information provided in the published material from 2001 to 2005. Twelve studies provided raw data to carry out comparisons of disease location while ten studies included analysis of NOD2/CARD15 genotypes. NOD2/CARD15 variant frequency in ileal disease did not differ significantly among studies, whereas a comparison of disease location demonstrated highly significant differences among studies. Meta-analysis confirmed significant associations between NOD2/CARD15 variants and both ileal and ileocolonic disease locations, and with both stricturing and penetrating forms of disease behavior. This review underlines the significant phenotypic differences that exist among populations, including similar ethnic groups, and has demonstrated the need for further studies of patients with long-term “inflammatory” Crohn’s disease.
文摘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, 128patients 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/CARD15compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P<0.0001). In Crohn's disease patients, the allele frequencies for Arg702Trp,Gly908Arg and 1007finsC were 7.1%, 3.0% and 10.8%respectively. Interestingly, only the 1007finsC mutation was associated with a distinct clinical phenotype. The patients positive for the 1007finsC mutation suffered more frequently from stenotic disease behaviour (P = 0.008). Furthermore,51.9% of patients positive for the 1007finsC mutation underwent a surgical resection within the ileum compared to only 17.4% of patients without the 1007finsC mutation (P = 0.001). With respect to the other two mutations (Arg702Trp and Gly908Arg), no associations were found with all investigated clinical parameters.CONCLUSION: NOD2/CARD15 mutations are frequently found in Crohn's disease patients from Hungary. The 1007finsC mutation is associated with stenotic disease behaviour and frequent ileal resections.
文摘The prevalence of Crohn’ s disease depends on geographic location and racial background. Arg702Trp, Gly908Arg, and Leu1007fsinsC mutations in the NOD2/CARD15 gene are associated with Crohn’ s disease in Caucasians. The mutation rate among Israeli Jewish patients is 27% - 41% . The prevalence of Crohn’ s disease is much lower in the Israeli Arab compared to the Israeli Jewish population. We studied the NOD2/CARD15 mutation rate and disease phenotype (according to the Vienna classification) among the Israeli Arabs and compared them with those in an Israeli Jewish cohort. We recruited 66 Israeli Arab patients and 122 ethnically matched controls. Five patients (8.2% ) and three controls (2.3% ) carried one NOD2/CARD15 mutation. The phenotypic characteristics of the Arab and Jewish patients were very similar. We conclude that NOD2/CARD15 mutations do not contribute to Crohn’ s susceptibility in the Israeli Arab population and suggest that NOD2/CARD15 mutations have an important effect on Crohn’ s prevalence within a specific population but not on the phenotype.
文摘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 phen-otypic 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 in 1007fs variant allele frequencywas 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-phen-otype 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.
文摘Background: A North-South gradient in Crohn’s disease (CD) implying a higher incidence in northern Europe compared to southern Europe has been established. Aims: To investigate whether there is a difference between Denmark and Portugal in the frequency of CARD15 mutations in CD patients compared to a healthy background population and to compare genotype-phenotype relations in the two countries. Methods: 58 Danish patients and 29 Portuguese patients with CD were matched for age, sex and disease behaviour at time of diagnosis and compared with 200 healthy Danish and Portuguese controls. Phenotypes were recorded at year of diagnosis, 3 years after diagnosis and at end of follow-up. Patients were genotyped for Arg702Trp, Gly908Arg and Leu1007InsC. Results: 22%of the Danish patients vs. 9%of Danish controls compared to 21%of the Portuguese patients vs. 16%had at least one mutation. Mutation rates in Danish patients were significantly different (p = 0.02) compared with Danish controls, no difference (p = 0.51) was found between Portuguese patients and controls. However, a possible relationship between CD and presence of genetic mutations was found when comparing the two countries (p = 0.03) using the Mantel-Haenszel test. No difference in evolution of phenotypes and the CARD15 status in CD was found during follow-up between the two matched populations. Ileal disease correlated to high occurrence of CARD15. Conclusion: No North-South gradient regarding occurrence of CARD15 was revealed. Although a trend towards more mutations in the Portuguese controls was seen, a relationship between CD and CARD15 mutations was observed in both countries.