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S1168a Faecal Calprotectin and Lactoferrin for the Prediction of Inflammatory Bowel Disease Relapse
S1169 S1168
KCNN4 Gene Variant Is Associated with Ileal Crohn's Disease Lisa A. Simms, James D. Doecke, Elizabeth V. Fowler, Zhen Zhen Zhao, Michael A. McGuckin, Ning Huang, Nicholas K. Hayward, Penelope M. Webb, David Whiteman, Juleen Cavanaugh, Ruth K. McCallum, Tony R. Merriman, Timothy H. Florin, Murray L. Barclay, Richard B. Gearry, Rebecca L. Roberts, Grant W. Montgomery, Graham L. Radford-Smith
Postcolectomy Burden in Ulcerative Colitis Patients Undergoing Colectomy Carlos Taxonera, Xavier Calvet, Javier P. Gisbert, Luis Rodrigo, Luis Bujanda, Fernando Muñoz, Marta Ponce, Federico Gómez-Camacho, Juan L. Mendoza, Itziar Oyagüez, Francisco Javier Sabater Aim: This study, part of the COSCOL study, aimed to establish the types of colectomies and the number of stages for ulcerative colitis (UC) performed in this population with a high previous use of immunomodulators. Design and Methods: A retrospective audit was undertaken at 35 Spanish centres which reviewed the medical records of UC patients who had undergone total colectomy between 2000 and 2005. Patients were followed up for a period of at least 24 months after the initial colectomy and data were recorded for all surgeries needed to complete the staged procedure. Results: 209 patients with total colectomy due to UC were included (44.5% women, mean age 41.6 ± 13.2 years at initial colectomy). Mean duration of the disease was 5.0 ± 6.3 years. UC was left-sided in 19.6% and extensive in 80.4%. Early surgery, defined as colectomy performed within the first two years of disease, was recorded in 77 patients (36.8%). 143 patients (68.4%) received immunomodulators (30.8% azathioprine and/or mercaptopurine and/or methotrexate only, 28% cyclosporine only, and 41,2% were receiving both). In 46.9% of patients the initial colectomy was performed as an emergency surgery. Table I shows the types of colectomy performed and the number of stages needed to complete the procedure. Conclusions: Although restorative proctocolectomy with IPAA has become the gold standard surgery for UC, it was only performed in 54% patients. Colectomy due to UC places a high burden on the patient: in 75% of patients at least two operations are required to complete it, and in 25% at least three. As many as 41% of patients carry a permanent ileostomy. Table I: Type of colectomy and number of stages performed
Background & Aims: Crohn's disease (CD[MIM# 266600]) and ulcerative colitis (UC[MIM# 191390]) are the two most common forms of inflammatory bowel disease (IBD), and represent a significant burden to healthcare in developed countries. Our aim was to establish whether a gene in the IBD-linkage region on chromosome 19q13, with a role in Paneth cell secretion and T cell activation, conferred genetic susceptibility to development of IBD. Methods: 1,222 cases and 1,244 controls of Australian origin (Caucasian) were genotyped for 7 single nucleotide polymorphisms (SNPs) in the gene encoding the intermediate conductance calcium-activated potassium channel protein (KCNN4) at 19q13.2. IBD cases were phenotyped using the Montreal classification. The replication dataset comprised 799 additional cases and 525 additional controls came from the Australian and New Zealand (ANZ) IBD Consortium, and 426 controls from Canberra, Australia. Analysis of the KCNN4 mRNA transcript was carried out using quantitative RT-PCR. Results: KCNN4 SNP rs2306801 was associated with a reduced risk of CD (primary MAF = 0.18, OR 95%CI: 0.77 (0.65 - 0.90), P = 0.001, replication MAF= 0.18, OR 95%CI: 0.77 (0.61 - 0.97), P = 0.01). Stratification by disease location identified association between SNP rs2306801 and ileal CD (P = 0.01). CD cases either carrying a rare NOD2 R702W variant genotype, or a common NOD2 G908R wildtype genotype were less likely to have the rs2306801 T allele (P = 0.001, and P = 0.006 respectively) as compared with controls. Uninvolved ileal mucosa from CD patients carrying the common disease-predisposing NOD2 variants (any variant; R702W, G908R, 1007fs), or NOD2 R702W only, had significantly reduced levels of KCNN4 mRNA expression (P = 0.001 and P = 0.01, respectively). Conclusion: Our data implicate KCNN4 in ileal CD. The dual roles of KCNN4 in Paneth cell secretion and T cell activation and its nature as a potassium channel make it an important and practical therapeutic target. S1170 Integration of Genomic and Gene Expression Data to Define Transcriptional Networks in Crohn's Disease Nancy M. McGreal, Andrew Skol, Kenan Onel Background: Genome-wide association studies have identified several genetic variants associated with Crohn's disease (CD); however, because these variants are common, their individual contribution to overall disease risk is modest. Recently, it has been shown that gene expression is a heritable trait, and that some CD-associated genetic variants are linked with altered gene expression. We hypothesized that genetic signals could be amplified by identifying target genes in disease associated transcriptional networks co-regulated by CD-associated genetic variants. To test this, we performed a novel bioinformatics analysis linking CDassociated variants with target genes they transcriptionally regulate. Methods: Using a database of gene expression in HapMap CEU lymphoblastoid cell lines, we identified genes transcriptionally regulated by CD-associated single nucleotide polymorphisms (SNPs) from the Wellcome Trust Case Control Consortium meeting a significance threshold of p < 0.0001. We further organized these genes into transcriptional pathways and networks by bioinformatics analysis based upon gene ontologies (GO) to identify biological functions and molecular processes enriched over chance in CD. Results: Of 110 CD-associated SNPs, 98 regulated 1 or more transcripts. We found 93 transcripts jointly regulated by 2 SNPs and 5 transcripts regulated by 3 SNPs. These 5 transcripts encoded 8 genes, including members of the major histocompatibility complex (HLA-DQA1, HLA-DQA2) and cytokines (IL20, IL24). GO analysis revealed significant enrichment for transcription factor/regulator activity and nucleic acid/DNA binding. Most SNPs (74/110) regulated 10 or fewer transcripts; however, 5 SNPs (rs375506, rs880324, rs2517646, rs2542151, rs17234657) regulated 35113 transcripts. These “master regulator” SNPs are of particular interest because they alone regulate 26.8% of transcripts identified, suggesting they may be central nodes in networks that contribute to CD susceptibility. GO analysis performed on the transcriptional network of these 5 SNPs indicates they are enriched for chromatin binding/modification, DNA packaging, nucleotide/ATP binding, and cofactor metabolic processes. Conclusions: Integration of genomic and gene expression data suggests that CD-associated variants regulate rich transcriptional networks. Convergent regulation of transcripts may amplify genetic signals associated with disease that can be translated clinically. This novel strategy may provide insight not only into disease mechanism, but may also be an early step towards the identification of prognostic biomarkers or rational targets for molecular therapeutics in CD.
S1168a Faecal Calprotectin and Lactoferrin for the Prediction of Inflammatory Bowel Disease Relapse Javier P. Gisbert AIM: To determine the role of faecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis (UC) and Crohn's disease (CD), in a large, long-term follow-up study. METHODS: Prospective multicenter study including CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow-up was 12 months in patients showing no relapse and until activity flare in relapsing patients. RESULTS: 163 patients (89 CD, 74 UC) were included. Twenty-six patients (16%) relapsed during follow-up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 ± 150 vs. 136 ± 158 μg/ g; p<0.001). Relapse risk was higher in patients having high (>150 μg/g) calprotectin (30% vs. 7.8%; p<0.001) or lactoferrin (25% vs. 10%; p<0.05) concentrations. Faecal calprotectin (>150 μg/g) sensitivity and specificity to predict relapse was 69% and 69%. Corresponding values for lactoferrin were 62% and 65%. The area under the ROC curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months
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AGA Abstracts
AGA Abstracts
were considered (100% sensitivity). High faecal calprotectin or lactoferrin levels were associated with clinical relapse in Kaplan-Meier survival analysis, and both faecal tests associated with relapse in the multivariate analysis. CONCLUSIONS: Faecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse −specially during the following 3 months− in both CD and UC patients.
KCNN4 Gene Variant Is Associated with Ileal Crohn's Disease Lisa A. Simms, James D. Doecke, Elizabeth V. Fowler, Zhen Zhen Zhao, Michael A. McGuckin, Ning Huang, Nicholas K. Hayward, Penelope M. Webb, David Whiteman, Juleen Cavanaugh, Ruth K. McCallum, Tony R. Merriman, Timothy H. Florin, Murray L. Barclay, Richard B. Gearry, Rebecca L. Roberts, Grant W. Montgomery, Graham L. Radford-Smith
Postcolectomy Burden in Ulcerative Colitis Patients Undergoing Colectomy Carlos Taxonera, Xavier Calvet, Javier P. Gisbert, Luis Rodrigo, Luis Bujanda, Fernando Muñoz, Marta Ponce, Federico Gómez-Camacho, Juan L. Mendoza, Itziar Oyagüez, Francisco Javier Sabater Aim: This study, part of the COSCOL study, aimed to establish the types of colectomies and the number of stages for ulcerative colitis (UC) performed in this population with a high previous use of immunomodulators. Design and Methods: A retrospective audit was undertaken at 35 Spanish centres which reviewed the medical records of UC patients who had undergone total colectomy between 2000 and 2005. Patients were followed up for a period of at least 24 months after the initial colectomy and data were recorded for all surgeries needed to complete the staged procedure. Results: 209 patients with total colectomy due to UC were included (44.5% women, mean age 41.6 ± 13.2 years at initial colectomy). Mean duration of the disease was 5.0 ± 6.3 years. UC was left-sided in 19.6% and extensive in 80.4%. Early surgery, defined as colectomy performed within the first two years of disease, was recorded in 77 patients (36.8%). 143 patients (68.4%) received immunomodulators (30.8% azathioprine and/or mercaptopurine and/or methotrexate only, 28% cyclosporine only, and 41,2% were receiving both). In 46.9% of patients the initial colectomy was performed as an emergency surgery. Table I shows the types of colectomy performed and the number of stages needed to complete the procedure. Conclusions: Although restorative proctocolectomy with IPAA has become the gold standard surgery for UC, it was only performed in 54% patients. Colectomy due to UC places a high burden on the patient: in 75% of patients at least two operations are required to complete it, and in 25% at least three. As many as 41% of patients carry a permanent ileostomy. Table I: Type of colectomy and number of stages performed
Background & Aims: Crohn's disease (CD[MIM# 266600]) and ulcerative colitis (UC[MIM# 191390]) are the two most common forms of inflammatory bowel disease (IBD), and represent a significant burden to healthcare in developed countries. Our aim was to establish whether a gene in the IBD-linkage region on chromosome 19q13, with a role in Paneth cell secretion and T cell activation, conferred genetic susceptibility to development of IBD. Methods: 1,222 cases and 1,244 controls of Australian origin (Caucasian) were genotyped for 7 single nucleotide polymorphisms (SNPs) in the gene encoding the intermediate conductance calcium-activated potassium channel protein (KCNN4) at 19q13.2. IBD cases were phenotyped using the Montreal classification. The replication dataset comprised 799 additional cases and 525 additional controls came from the Australian and New Zealand (ANZ) IBD Consortium, and 426 controls from Canberra, Australia. Analysis of the KCNN4 mRNA transcript was carried out using quantitative RT-PCR. Results: KCNN4 SNP rs2306801 was associated with a reduced risk of CD (primary MAF = 0.18, OR 95%CI: 0.77 (0.65 - 0.90), P = 0.001, replication MAF= 0.18, OR 95%CI: 0.77 (0.61 - 0.97), P = 0.01). Stratification by disease location identified association between SNP rs2306801 and ileal CD (P = 0.01). CD cases either carrying a rare NOD2 R702W variant genotype, or a common NOD2 G908R wildtype genotype were less likely to have the rs2306801 T allele (P = 0.001, and P = 0.006 respectively) as compared with controls. Uninvolved ileal mucosa from CD patients carrying the common disease-predisposing NOD2 variants (any variant; R702W, G908R, 1007fs), or NOD2 R702W only, had significantly reduced levels of KCNN4 mRNA expression (P = 0.001 and P = 0.01, respectively). Conclusion: Our data implicate KCNN4 in ileal CD. The dual roles of KCNN4 in Paneth cell secretion and T cell activation and its nature as a potassium channel make it an important and practical therapeutic target. S1170 Integration of Genomic and Gene Expression Data to Define Transcriptional Networks in Crohn's Disease Nancy M. McGreal, Andrew Skol, Kenan Onel Background: Genome-wide association studies have identified several genetic variants associated with Crohn's disease (CD); however, because these variants are common, their individual contribution to overall disease risk is modest. Recently, it has been shown that gene expression is a heritable trait, and that some CD-associated genetic variants are linked with altered gene expression. We hypothesized that genetic signals could be amplified by identifying target genes in disease associated transcriptional networks co-regulated by CD-associated genetic variants. To test this, we performed a novel bioinformatics analysis linking CDassociated variants with target genes they transcriptionally regulate. Methods: Using a database of gene expression in HapMap CEU lymphoblastoid cell lines, we identified genes transcriptionally regulated by CD-associated single nucleotide polymorphisms (SNPs) from the Wellcome Trust Case Control Consortium meeting a significance threshold of p < 0.0001. We further organized these genes into transcriptional pathways and networks by bioinformatics analysis based upon gene ontologies (GO) to identify biological functions and molecular processes enriched over chance in CD. Results: Of 110 CD-associated SNPs, 98 regulated 1 or more transcripts. We found 93 transcripts jointly regulated by 2 SNPs and 5 transcripts regulated by 3 SNPs. These 5 transcripts encoded 8 genes, including members of the major histocompatibility complex (HLA-DQA1, HLA-DQA2) and cytokines (IL20, IL24). GO analysis revealed significant enrichment for transcription factor/regulator activity and nucleic acid/DNA binding. Most SNPs (74/110) regulated 10 or fewer transcripts; however, 5 SNPs (rs375506, rs880324, rs2517646, rs2542151, rs17234657) regulated 35113 transcripts. These “master regulator” SNPs are of particular interest because they alone regulate 26.8% of transcripts identified, suggesting they may be central nodes in networks that contribute to CD susceptibility. GO analysis performed on the transcriptional network of these 5 SNPs indicates they are enriched for chromatin binding/modification, DNA packaging, nucleotide/ATP binding, and cofactor metabolic processes. Conclusions: Integration of genomic and gene expression data suggests that CD-associated variants regulate rich transcriptional networks. Convergent regulation of transcripts may amplify genetic signals associated with disease that can be translated clinically. This novel strategy may provide insight not only into disease mechanism, but may also be an early step towards the identification of prognostic biomarkers or rational targets for molecular therapeutics in CD.
S1168a Faecal Calprotectin and Lactoferrin for the Prediction of Inflammatory Bowel Disease Relapse Javier P. Gisbert AIM: To determine the role of faecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis (UC) and Crohn's disease (CD), in a large, long-term follow-up study. METHODS: Prospective multicenter study including CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow-up was 12 months in patients showing no relapse and until activity flare in relapsing patients. RESULTS: 163 patients (89 CD, 74 UC) were included. Twenty-six patients (16%) relapsed during follow-up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 ± 150 vs. 136 ± 158 μg/ g; p<0.001). Relapse risk was higher in patients having high (>150 μg/g) calprotectin (30% vs. 7.8%; p<0.001) or lactoferrin (25% vs. 10%; p<0.05) concentrations. Faecal calprotectin (>150 μg/g) sensitivity and specificity to predict relapse was 69% and 69%. Corresponding values for lactoferrin were 62% and 65%. The area under the ROC curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months
A-205
AGA Abstracts
AGA Abstracts
were considered (100% sensitivity). High faecal calprotectin or lactoferrin levels were associated with clinical relapse in Kaplan-Meier survival analysis, and both faecal tests associated with relapse in the multivariate analysis. CONCLUSIONS: Faecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse −specially during the following 3 months− in both CD and UC patients.