Crohn's disease and ulcerative colitis are inflammatory disorders of the gastrointestinal tract with a substantial heritable component. The IBD5 region on chromosome 5q31 is one of only two loci widely confirmed t...Crohn's disease and ulcerative colitis are inflammatory disorders of the gastrointestinal tract with a substantial heritable component. The IBD5 region on chromosome 5q31 is one of only two loci widely confirmed to be associated with Crohn's disease in multiple independent cohorts. Although many populations have demonstrated association with IBD5, there remains uncertainty as to the causal variant within the region. A recent report identified polymorphisms in SLC22A4 (OCTN1) and SLC22A5 (OCTN2) as being responsible for the IBD5 association, however, these findings have not been replicated. This review discusses the data evaluating the IBD5 locus and the OCTN genes and their relationship to inflammatory bowel disease. Several other genes, including IRF1 and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.展开更多
AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 lo...AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 locus in Crohn's disease(CD) patients. METHODS:A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped.Interactions and specific genotype combinations of a total of eight variants were tested.The variants of IBD5locus(IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868),CARD15(R702W rs2066845 and L1007fs rs2066847),ATG16L1(rs2241880)and IL23R (rs1004819,rs2201841)genes were genotyped by PCR-RFLP,the G908R(rs2066844)in CARD15 was determined by direct sequencing. RESULTS:The association of ATG16L1 T300A with CD was confirmed[P=0.004,odds ratio(OR)=1.69, 95%CI:1.19-2.41],and both IL23R variants were found to represent significant risk for the disease(P= 0.008,OR=2.05,95%CI:1.20-3.50 for rs1004819 AA;P<0.001,OR=2.97,95%CI:1.65-5.33 for rs2201841 CC).Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD)loci indicated that IL23R,ATG16L1,CARD15 and IBD5(IGR2198a_1)contribute independently to disease risk.We also analysed the specific combina- tions by pair of individual ATG16L1,IL23R rs1004819, rs2201841,IGR2198a_1,IGR2096a_1 and CARD15 genotypes for disease risk influence.In almost all cases,the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism.The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status(P<0.001,OR=9.15,95% CI:2.05-40.74). CONCLUSION:The present study suggests a cumulative effect of individual IBD susceptibility loci.展开更多
Background and aims:The OCTN1(SLC22A4 1672C→ T) and OCTN2(SLC22A5-207G→ C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn’s disease(CD) ,but their contribution in child...Background and aims:The OCTN1(SLC22A4 1672C→ T) and OCTN2(SLC22A5-207G→ C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn’s disease(CD) ,but their contribution in children has not been examined.Methods:These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms(SNPs) (IGR2096a-1,IGR2198a-1,and IGR2230a-1) were examined in 299 Scottish children(200 with CD,74 with ulcerative colitis(UC) ,and 25 with indeterminate colitis(IC) ) ,together with 502 parents(for transmission disequilibrium testing) and 250 controls.Results:All SNPs were in strong linkage disequilibrium(D’ >0.94) .TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease(IBD) (p = 0.01) and CD(p = 0.04) .Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases(p < 0.04) .The homozygous mutant OCTN1/2 haplotype was increased in IBD(24.3% v 16.1%,p = 0.02) and UC(28.2% v 16.1%,p = 0.02) compared with controls.The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility.Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight,height,and BMI centile(< 9th centile) at diagnosis(weight:87.9% v 67.3%(p = 0.002) ,odds ratio(OR) = 3.52(95% confidence interval,1.51 to 8.22) ;height:84.1% v 68.4%(p< 0.05) ,OR = 2.44(1.00 to 5.99) ;BMI:79.6% v 61.1%(p = 0.02) ,OR = 2.49(1.14 to 5.44) ) ,and lower weight centile at follow up(87.5% v 64.6%(p = 0.03) ,OR = 3.83(1.03 to 14.24) ) .Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis(p = 0.02,OR = 3.41(1.20 to 9.66) ) .Conclusions:These data implicate variants within the IBD5 haplotype,as determinants of disease susceptibility and growth indices in early onset IBD.The OCTN1/2 variants remain potential positional candidate genes,but require further analysis.展开更多
文摘Crohn's disease and ulcerative colitis are inflammatory disorders of the gastrointestinal tract with a substantial heritable component. The IBD5 region on chromosome 5q31 is one of only two loci widely confirmed to be associated with Crohn's disease in multiple independent cohorts. Although many populations have demonstrated association with IBD5, there remains uncertainty as to the causal variant within the region. A recent report identified polymorphisms in SLC22A4 (OCTN1) and SLC22A5 (OCTN2) as being responsible for the IBD5 association, however, these findings have not been replicated. This review discusses the data evaluating the IBD5 locus and the OCTN genes and their relationship to inflammatory bowel disease. Several other genes, including IRF1 and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.
基金Supported by Grant of Hungarian Scientific Research Foundation,No.OTKA T 73430
文摘AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 locus in Crohn's disease(CD) patients. METHODS:A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped.Interactions and specific genotype combinations of a total of eight variants were tested.The variants of IBD5locus(IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868),CARD15(R702W rs2066845 and L1007fs rs2066847),ATG16L1(rs2241880)and IL23R (rs1004819,rs2201841)genes were genotyped by PCR-RFLP,the G908R(rs2066844)in CARD15 was determined by direct sequencing. RESULTS:The association of ATG16L1 T300A with CD was confirmed[P=0.004,odds ratio(OR)=1.69, 95%CI:1.19-2.41],and both IL23R variants were found to represent significant risk for the disease(P= 0.008,OR=2.05,95%CI:1.20-3.50 for rs1004819 AA;P<0.001,OR=2.97,95%CI:1.65-5.33 for rs2201841 CC).Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD)loci indicated that IL23R,ATG16L1,CARD15 and IBD5(IGR2198a_1)contribute independently to disease risk.We also analysed the specific combina- tions by pair of individual ATG16L1,IL23R rs1004819, rs2201841,IGR2198a_1,IGR2096a_1 and CARD15 genotypes for disease risk influence.In almost all cases,the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism.The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status(P<0.001,OR=9.15,95% CI:2.05-40.74). CONCLUSION:The present study suggests a cumulative effect of individual IBD susceptibility loci.
文摘Background and aims:The OCTN1(SLC22A4 1672C→ T) and OCTN2(SLC22A5-207G→ C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn’s disease(CD) ,but their contribution in children has not been examined.Methods:These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms(SNPs) (IGR2096a-1,IGR2198a-1,and IGR2230a-1) were examined in 299 Scottish children(200 with CD,74 with ulcerative colitis(UC) ,and 25 with indeterminate colitis(IC) ) ,together with 502 parents(for transmission disequilibrium testing) and 250 controls.Results:All SNPs were in strong linkage disequilibrium(D’ >0.94) .TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease(IBD) (p = 0.01) and CD(p = 0.04) .Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases(p < 0.04) .The homozygous mutant OCTN1/2 haplotype was increased in IBD(24.3% v 16.1%,p = 0.02) and UC(28.2% v 16.1%,p = 0.02) compared with controls.The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility.Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight,height,and BMI centile(< 9th centile) at diagnosis(weight:87.9% v 67.3%(p = 0.002) ,odds ratio(OR) = 3.52(95% confidence interval,1.51 to 8.22) ;height:84.1% v 68.4%(p< 0.05) ,OR = 2.44(1.00 to 5.99) ;BMI:79.6% v 61.1%(p = 0.02) ,OR = 2.49(1.14 to 5.44) ) ,and lower weight centile at follow up(87.5% v 64.6%(p = 0.03) ,OR = 3.83(1.03 to 14.24) ) .Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis(p = 0.02,OR = 3.41(1.20 to 9.66) ) .Conclusions:These data implicate variants within the IBD5 haplotype,as determinants of disease susceptibility and growth indices in early onset IBD.The OCTN1/2 variants remain potential positional candidate genes,but require further analysis.
