Ulcerative Colitis: Silverberg MS

Silverberg MS. · Mount Sinai Hospital IBD Centre, Department of Medicine, Toronto, Ontario, Canada. · World J Gastroenterol. · Pubmed #16773684 links to  free full text

Abstract: 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.

Seow CH, Stempak JM, Xu W, Lan H, Griffiths AM, Greenberg GR, Steinhart AH, Dotan N, Silverberg MS. · Division of Gastroenterology, Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Am J Gastroenterol. · Pubmed #19491856 No free full text.

Abstract: OBJECTIVES: We sought to evaluate whether two novel immunoglobulin A (IgA) cell wall polysaccharide antibodies, anti-laminarin (anti-L) and anti-chitin (anti-C), aid in the diagnosis and phenotype differentiation of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A cohort of 818 individuals with inflammatory bowel disease (IBD; 517 CD and 301 UC) from two IBD tertiary referral centers, with median ages of 33 and 39 years, respectively, and disease duration of 8.9 years, were phenotyped using the Montreal classification, and analyzed for seven anti-glycan antibodies (gASCA (anti-Saccharomyces cerevisiae) IgG, gASCA IgA, anti-chitobioside (GlcNAc(beta1,4)GlcNAc(beta)), anti-laminaribioside (Glc(beta1,3)Glb(beta)), anti-mannobioside (Man(alpha1,3)Man(alpha)), anti-L, and anti-C) and perinuclear atypical neutrophil cytoplasmic antibodies (pANCA). RESULTS: In the CD patient population, 73% were positive for >/=1 anti-glycan antibody. All glycan markers were specific for CD (85.4-97.7%) and more prevalent in CD vs. UC (P<0.0015). gASCA IgG and IgA best differentiated CD from UC followed by anti-L (area under the curve 0.818, 0.815, and 0.702, respectively). The addition of anti-L and anti-C to gASCA IgG and pANCA improved discrimination between CD and UC (P<0.001). Adding anti-L to gASCA and pANCA differentiated colonic CD and UC (P=0.02). An increasing number of positive antibodies was associated with early CD onset, penetrating phenotype, perianal disease, and the need for surgery (P<0.001). Anti-L was associated with ileocolonic CD (odds ratio (OR) 2.28, 95% confidence interval (CI) 1.40-3.69; P=0.001), and anti-C with penetrating (OR 2.75, 95% CI 1.50-5.04; P=0.001) and perianal disease (OR 1.95, 95% CI 1.06-3.59; P=0.03). CONCLUSIONS: Anti-L and anti-C improve differentiation between CD and UC. Anti-L may also differentiate between isolated colonic CD and UC. Both anti-L and anti-C are independently associated with a more aggressive CD phenotype.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · No affiliation provided · Nat Genet. · Pubmed #19471306 No free full text.

This publication has no abstract.

Festen EA, Goyette P, Scott R, Annese V, Zhernakova A, Lian J, Lefèbvre C, Brant SR, Cho JH, Silverberg MS, Taylor KD, de Jong DJ, Stokkers PC, Mcgovern D, Palmieri O, Achkar JP, Xavier RJ, Daly MJ, Duerr RH, Wijmenga C, Weersma RK, Rioux JD. · Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. · Gut. · Pubmed #19201773 No free full text.

Abstract: OBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs. METHODS: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed. RESULTS: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35 x 10(-10), rs13119723 p = 8.60 x 10(-8), rs6840978 p = 3.0 7x 10(-8), rs6822844 p = 2.77 x 10(-9)). A moderate association with CD was also found in the pooled analysis (p value range 0.0016-9.86 x 10(-5)). CONCLUSIONS: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, 600 University Avenue, Toronto, ON M5G1X5, Canada. · Nat Genet. · Pubmed #19122664 links to  free full text

Abstract: Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Goyette P, Lefebvre C, Ng A, Brant SR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Latiano A, Aumais G, Deslandres C, Jobin G, Annese V, Daly MJ, Xavier RJ, Rioux JD. · Department of Medicine, Université de Montréal and Montreal Heart Institute, Research Center, Montreal, Québec, Canada. · Mucosal Immunol. · Pubmed #19079170 No free full text.

Abstract: Association mapping and candidate gene studies within inflammatory bowel diseases (IBD) linkage regions, as well as genome-wide association studies in Crohn's disease (CD) have led to the discovery of multiple risk genes, but these explain only a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and ulcerative colitis (UC) using a gene-centric association mapping approach. We identified 12 functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/intestinal function. We then performed an association study composed of a screening phase, where tagging single nucleotide polymorphisms (SNPs) were evaluated in 1,020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association with IBD for four SNPs within a 1.2 Mb linkage disequilibrium region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage-stimulating 1 (MST1) gene (P-value 3.62 x 10(-6)) that accounts for the association signal, and shows association with both CD and UC. MST1 encodes macrophage-stimulating protein (MSP), a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.

Kotlowski R, Bernstein CN, Silverberg MS, Krause DO. · Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada. · Inflamm Bowel Dis. · Pubmed #18340647 links to  free full text

Abstract: BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the digestive tract. Genetic factors and an abnormal immune response to infections are suspected to be involved in inflammatory bowel diseases. METHODS: In the present study 300 blood samples from CD patients (n = 100), UC patients (n = 100), and healthy controls (n = 100) were taken from a population-based case-control study. PCR assays and capillary electrophoresis were used to detect alpha 1 antitrypsin M, S, and Z alleles and the C-to-T transition at the -237 nucleotide position of the SLC11A1 promoter. Additionally, length polymorphism of (gt)n alleles in the promoter region and TGTG and CAAA insertion/deletion in the untranslated region (3' UTR) of the SLC11A1 gene were evaluated. RESULTS: The Z allele only for AAT was associated (P < 0.05) with CD. No other significant results were detected for AAT alleles. For SLC11A1, alleles 1 and 2 were significant (P < 0.05) for UC, but only allele 3 was significant (P < 0.05) for CD. There was a significant (P < 0.05) association of a CAAA insertion with CD but not for deletion in the 3' UTR. No differences (P < 0.05) were detected for TAAA. CONCLUSIONS: Because AAT and SLC11A1 proteins directly or indirectly function as inhibitors of human leukocyte elastase, mutations in the AAT and SLC11A1 genes may change the balance between elastase produced by leukocytes during phagocytosis.

Shugart YY, Silverberg MS, Duerr RH, Taylor KD, Wang MH, Zarfas K, Schumm LP, Bromfield G, Steinhart AH, Griffiths AM, Kane SV, Barmada MM, Rotter JI, Mei L, Bernstein CN, Bayless TM, Langelier D, Cohen A, Bitton A, Rioux JD, Cho JH, Brant SR. · Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA. · Genes Immun. · Pubmed #18246054 No free full text.

Abstract: Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Maunder RG, Greenberg GR, Lancee WJ, Steinhart AH, Silverberg MS. · Mount Sinai Hospital and University of Toronto, Toronto, Canada. · Can J Gastroenterol. · Pubmed #18026574 links to  free full text

Abstract: GOALS: To determine whether the perceived impact of ulcerative colitis (UC) on activities of living (illness intrusiveness) is greater for people who are not living in a married or common-law relationship. BACKGROUND: In general, social and occupational achievement is not greatly impaired by UC, yet patients, especially young adults, often have interpersonal concerns. METHODS: One hundred fifty-five outpatients with UC were assessed for disease activity, and completed self-reports of marital status, income, social support and illness intrusiveness. RESULTS: Fifty-one patients (32.9%) were single, separated or divorced, and 104 patients (67.1%) were married or in common-law relationships. Compared with those who were married or in common-law relationships, single or separated patients were younger, had a lower household income, had lived with UC for fewer years and were less satisfied with social support. Among 135 patients in remission, marital status was significantly associated with illness intrusiveness, controlling for age, income and perceived social support (F=5.73; P=0.02). Low social support (F=4.94; P=0.03) and younger age (F=7.24; P=0.008) were independently associated with illness intrusiveness. Single patients in remission reported illness intrusiveness of similar severity to that reported by patients with active disease. CONCLUSIONS: The perceived impact of UC on the lives of patients is greater in those who are not married or living in common-law relationships. Youth, single status and lower social support commonly coexist, and exert additive effects on the functional impact of UC. Resources to improve social support should be directed toward this group of patients.

Muise AM, Walters T, Wine E, Griffiths AM, Turner D, Duerr RH, Regueiro MD, Ngan BY, Xu W, Sherman PM, Silverberg MS, Rotin D. · Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, 555 University Ave, Toronto, Ontario, Canada. · Curr Biol. · Pubmed #17614280 No free full text.

Abstract: Inflammatory bowel disease (IBD), a relatively common chronic debilitating intestinal illness, is composed of two broadly defined groups, Crohn's disease (CD) and ulcerative colitis (UC). Although several susceptibility genes for CD have been recently described, susceptibility genes exclusive for UC have not been forthcoming. Here, we show that receptor protein-tyrosine phosphatase sigma (PTPRS-encoding PTPsigma) knockout mice spontaneously develop mild colitis that becomes severe when challenged with two known inducers of colitis. We also demonstrate that E-cadherin and beta-catenin, two important adherens junction proteins involved in maintenance of barrier defense in the colon, act as colonic substrates for PTPsigma. Furthermore, we show that three SNPs (rs886936, rs17130, and rs8100586) that flank exon 8 in the human PTPRS gene are associated with UC. The presence of these SNPs is associated with novel splicing that removes the third immunoglobulin-like domain (exon 9) from the extracellular portion of PTPsigma, possibly altering dimerization or ligand recognition. We propose that polymorphisms in the human PTPRS gene lead to ulcerative colitis.

De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield GP, Dubois B, Cho JH, Brant SR, Duerr RH, Yang H, Rotter JI, Silverberg MS, Steinhart AH, Daly MJ, Podolsky DK, Louis E, Hafler DA, Rioux JD, Anonymous00242, Anonymous00243. · Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Genes Immun. · Pubmed #17538633 No free full text.

Abstract: The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.

Dassopoulos T, Nguyen GC, Bitton A, Bromfield GP, Schumm LP, Wu Y, Elkadri A, Regueiro M, Siemanowski B, Torres EA, Gregory FJ, Kane SV, Harrell LE, Franchimont D, Achkar JP, Griffiths A, Brant SR, Rioux JD, Taylor KD, Duerr RH, Silverberg MS, Cho JH, Steinhart AH. · Johns Hopkins University Meyerhoff Inflammatory Bowel Disease Center, Baltimore MD, USA. · Inflamm Bowel Dis. · Pubmed #17427244 links to  free full text

Abstract: BACKGROUND: The NIDDK IBD Genetics Consortium (IBDGC) collects DNA and phenotypic data from inflammatory bowel disease (IBD) subjects to provide a resource for genetic studies. No previous studies have been performed on the reliability and validity of phenotypic determinations in either Crohn's disease (CD) or ulcerative colitis (UC) using primary records. Our aim was to determine the reliability and validity of these phenotypic assessments. METHODS: The de-identified records of 30 IBD patients were reviewed by 2 phenotypers per center using a standard protocol for phenotypic assessment. Each phenotyper evaluated 10 charts on 2 occasions 5 months apart. Reliability was expressed as the kappa (kappa) statistic. Performance characteristics were determined by comparison to a consensus-derived "gold standard" and by generation of receiver operating characteristic (ROC) curves. RESULTS: Agreement for diagnosis was excellent (kappa = 0.82; 95% confidence interval [CI]: 0.71-0.92). Agreement for CD location was good for jejunal, ileal, colorectal, and perianal disease with kappa between 0.60 and 0.74 but was fair for esophagogastroduodenal (kappa = 0.36). Agreement for UC extent (kappa = 0.67; 95% CI: 0.48-0.85), and CD behavior (kappa = 0.67; 95% CI: 0.49-0.83) were very good. Area under the ROC curves was greater than 0.84 for diagnosis, CD behavior, UC extent, and ileal and colonic CD location. CONCLUSIONS: IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype-phenotype studies.

Lal S, Appelton J, Mascarenhas J, Stempak JM, Esplen MJ, Silverberg MS. · Inflammatory Bowel Disease Centre, Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada. · Eur J Gastroenterol Hepatol. · Pubmed #17353697 No free full text.

Abstract: OBJECTIVES: Significant progress has been observed in our understanding of the role of genetics in inflammatory bowel disease susceptibility and phenotype. The clinical role of genetic testing for inflammatory bowel disease is not well developed, but may become important as more susceptibility genes are found. The aim of this study was to evaluate the attitudes of patients with inflammatory bowel disease toward genetic testing. METHODS: Two hundred and fifty patients (108 ulcerative colitis, 142 Crohn's disease) attending the outpatient clinic completed a questionnaire regarding clinical and family history data, as well as their attitudes toward genetic testing for inflammatory bowel disease. RESULTS: Ninety percent (225/250) of all patients expressed an interest in undergoing genetic testing themselves, with 87.6% (219/250) also expressing a desire for their children to be tested. Although the proportion of ulcerative colitis and Crohn's disease patients interested in testing was similar, levels of interest decreased as the predictive value of a putative genetic test decreased. A comparable proportion of those with [80/86 (93.0%)] and those without [145/164 (88.4%)] a family history of inflammatory bowel disease expressed an interest in genetic testing. More patients who had received immunomodulating or biologic therapies [123/128 (96.1%)], however, wished to undergo testing than those who had not received these medications [78/93 (83.9%; P<0.01)]. CONCLUSION: Patients with inflammatory bowel disease have a high level of interest in genetic testing, both for themselves and for their children, and this will have an impact upon the provision of genetic services as progress is made toward defining a clinical role for inflammatory bowel disease susceptibility genes.

Silverberg MS, Duerr RH, Brant SR, Bromfield G, Datta LW, Jani N, Kane SV, Rotter JI, Philip Schumm L, Hillary Steinhart A, Taylor KD, Yang H, Cho JH, Rioux JD, Daly MJ, Anonymous00254. · Department of Medicine, Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada. · Eur J Hum Genet. · Pubmed #17213842 links to  free full text

Abstract: Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohn's disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, P<0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P=0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only, and establish that IRF1, PDLIM, and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.

van Bodegraven AA, Curley CR, Hunt KA, Monsuur AJ, Linskens RK, Onnie CM, Crusius JB, Annese V, Latiano A, Silverberg MS, Bitton A, Fisher SA, Steinhart AH, Forbes A, Sanderson J, Prescott NJ, Strachan DP, Playford RJ, Mathew CG, Wijmenga C, Daly MJ, Rioux JD, van Heel DA. · Department of Gastroenterology, VU University Medical Centre, Amsterdam, The Netherlands. · Gastroenterology. · Pubmed #17087940 No free full text.

Abstract: BACKGROUND & AIMS: Common germline genetic variation in the 3' region of myosin IXB (MYO9B) has been associated recently with susceptibility to celiac disease, with a hypothesis that MYO9B variants might influence intestinal permeability. These findings suggested the current study investigating a possible further role for MYO9B variation in inflammatory bowel disease. METHODS: Eight single-nucleotide polymorphisms (SNPs) were selected to tag common haplotypes from the 35-kb 3' region of MYO9B. These included the strongest celiac disease-associated variants reported in a Dutch cohort. These SNPs were studied in 3 independently collected and genotyped case-control cohorts of European descent (UK, Dutch, and Canadian/Italian), comprising in total 2717 inflammatory bowel disease patients (1197 with Crohn's disease, 1520 with ulcerative colitis) and 4440 controls. RESULTS: Common variation in MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis P = 1.9 x 10(-6); odds ratio, 1.2), with the same alleles showing association as reported for celiac disease. CONCLUSIONS: MYO9B genetic variants predispose to inflammatory bowel disease. Interestingly, rs1545620 is a nonsynonymous variant leading to an amino acid change (Ala1011Ser) in the third calmodulin binding IQ domain of MYO9B. Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn's disease also was observed. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.

Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA. · Science. · Pubmed #17068223 links to  free full text

Abstract: The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Maunder RG, Greenberg GR, Hunter JJ, Lancee WJ, Steinhart AH, Silverberg MS. · Department of Psychiatry, Mount Sinai Hospital, Toronto, Canada. · Am J Gastroenterol. · Pubmed #17029612 No free full text.

Abstract: INTRODUCTION: Studies of psychological factors in ulcerative colitis (UC) have produced inconsistent findings. This study sought to determine whether perinuclear antineutrophil cytoplasmic antibody (pANCA) demarcates subtypes which differ with respect to psychobiological interactions. METHODS: In 148 outpatients with UC, the strength of the relationship between current UC disease activity and psychological distress was assessed. pANCA was determined by ELISA and immunofluorescence, disease activity was determined by symptoms, physical examination, and endoscopy using the St. Mark's index, and depressive symptoms and health anxiety were measured with self-report scales. Pearson correlations between disease activity and depressive symptoms and between disease activity and health anxiety were calculated. RESULTS: In 74 pANCA negative subjects, the relationship between disease activity and measures of psychological distress was significant for disease activity-depression (partial correlation = 0.48, p < 0.001) and for disease activity-health anxiety (partial correlation = 0.64, p < 0.001), whereas in 74 pANCA positive subjects, no relationships were found (disease activity-depression: partial correlation = 0.18, p= 0.14; disease activity-health anxiety: partial correlation = 0.20, p= 0.09). The differences in the strength of correlation between pANCA positive and pANCA negative subjects were statistically significant for both disease activity-depression (z = 2.0, p= 0.02) and activity-health anxiety (z = 3.3, p < 0.001). CONCLUSIONS: pANCA status demarcates psychobiologically distinct subtypes of UC, such that the absence of pANCA is associated with greater psychobiological interaction. These findings have implications for clinical care and understanding the pathophysiology of intestinal inflammation.

Satsangi J, Silverberg MS, Vermeire S, Colombel JF. · Gstrointestinal Unit, Western General Hospital, University of Edinburg, UK. · Gut. · Pubmed #16698746 links to  free full text

Abstract: In recent years, investigators have readdressed the complex issues involved in the classification of inflammatory bowel diseases. In 2003, a Working Party of investigators with an interest in the issues involved in disease subclassification was formed with the aim of summarising recent developments in disease classification and establishing an integrated clinical, molecular, and serological classification of inflammatory bowel disease. The results of the Working Party were reported at the 2005 Montreal World Congress of Gastroenterology. Here we highlight the key issues that have emerged from discussions of the Montreal Working Party and the relevance to clinical practice and research activities.

Nguyen GC, Torres EA, Regueiro M, Bromfield G, Bitton A, Stempak J, Dassopoulos T, Schumm P, Gregory FJ, Griffiths AM, Hanauer SB, Hanson J, Harris ML, Kane SV, Orkwis HK, Lahaie R, Oliva-Hemker M, Pare P, Wild GE, Rioux JD, Yang H, Duerr RH, Cho JH, Steinhart AH, Brant SR, Silverberg MS. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Am J Gastroenterol. · Pubmed #16696785 No free full text.

Abstract: OBJECTIVES: Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. METHODS: Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. RESULTS: African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts. CONCLUSIONS: There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.

Achkar JP, Dassopoulos T, Silverberg MS, Tuvlin JA, Duerr RH, Brant SR, Siminovitch K, Reddy D, Datta LW, Bayless TM, Zhang L, Barmada MM, Rioux JD, Steinhart AH, McLeod RS, Griffiths AM, Cohen Z, Yang H, Bromfield GP, Schumm P, Hanauer SB, Cho JH, Nicolae DL. · Center for Inflammatory Bowel Disease, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH, USA. · Am J Gastroenterol. · Pubmed #16542294 No free full text.

Abstract: OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus Jr EV, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF. · Mount Sinai Hospital, Toronto, Canada. · Can J Gastroenterol. · Pubmed #16151544 No free full text.

Abstract: The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Pierik M, Yang H, Barmada MM, Cavanaugh JA, Annese V, Brant SR, Cho JH, Duerr RH, Hugot JP, McGovern DP, Paavola-Sakki P, Radford-Smith GL, Pavli P, Silverberg MS, Schreiber S, Taylor KD, Vlietinck R, Anonymous00395. · Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #15674107 No free full text.

Abstract: BACKGROUND AND AIMS: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 x smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. PATIENTS AND METHODS: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. RESULTS: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P </= 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). CONCLUSIONS: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4.

Karban AS, Okazaki T, Panhuysen CI, Gallegos T, Potter JJ, Bailey-Wilson JE, Silverberg MS, Duerr RH, Cho JH, Gregersen PK, Wu Y, Achkar JP, Dassopoulos T, Mezey E, Bayless TM, Nouvet FJ, Brant SR. · Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Room B136, Baltimore, MD 21231, USA. · Hum Mol Genet. · Pubmed #14613970 links to  free full text

Abstract: Nuclear Factor-kappaB (NF-kappaB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-kappaB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the -94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047-0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The -94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to -94insATTG but not to -94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.

Silverberg MS, Mirea L, Bull SB, Murphy JE, Steinhart AH, Greenberg GR, McLeod RS, Cohen Z, Wade JA, Siminovitch KA. · Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Inflamm Bowel Dis. · Pubmed #12656131 No free full text.

Abstract: The aim of this study was to identify major histocompatibility complex alleles associated with the development and clinical features of inflammatory bowel disease (IBD). Genotyping at the human leukocyte antigen (HLA) DRB1 and DQB1 loci was performed on individuals from 118 Caucasian IBD sibling pair families and on 216 healthy controls. Both population- and family-based association tests were used to analyze data obtained on the entire study population and on clinical subgroups stratified by diagnosis, ethnicity, and disease distribution. HLA DRB1*0103 was significantly associated with IBD (OR = 6.0, p = 0.0001) in a case-control analysis of non-Jewish IBD-affected individuals. This association was apparent among both Crohn's disease (OR = 5.23, p = 0.0007) and ulcerative colitis (OR = 7.9, p = 0.0001) patients and was confirmed in the non-Jewish IBD population by results of family-based association analysis using the transmission disequilibrium test. HLA DQB1*0501 was also associated with IBD (OR = 1.64, p = 0.02) in the non-Jewish population. but statistically significant association of this allele with disease was not detected for Crohn's disease and ulcerative colitis separately. No significant associations were identified among the Jewish patients. In the non-Jewish IBD families, IBD was as strongly associated with the DRB1*0103 DQB1*0501 haplotype as with the DRB1*0103 allele alone. The carrier frequency of the DRB1*0103 allele was found to be 10-fold higher in Crohn's disease patients with pure colonic involvement than in healthy controls (38.5% vs. 3.2%; p = 0.0002). These data demonstrate the association of the HLA DRB1*0103 allele with both Crohn's disease and ulcerative colitis and with large intestine-restricted disease in non-Jewish IBD patients and therefore identify HLA DRB1*0103 as a potentially important contributor to disease susceptibility and to expression of colonic involvement in IBD.

Silverberg MS, Daly MJ, Moskovitz DN, Rioux JD, McLeod RS, Cohen Z, Greenberg GR, Hudson TJ, Siminovitch KA, Steinhart AH. · Department of Medicine, Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Canada. · Gut. · Pubmed #11709510 links to  free full text

Abstract: BACKGROUND: Linkage data have now identified several inflammatory bowel disease (IBD) susceptibility loci but these data have not been consistently replicated in independent studies. One potential explanation for this is the possibility that patients enrolled in such studies may have been erroneously classified with respect to their diagnosis. AIMS: To determine the rate and type of misclassification in a large population of individuals referred for participation in an IBD genetics study and to examine the effect of diagnostic misclassification on the power to detect linkage. METHODS: The medical records of 1096 patients entered into an IBD genetics programme were reviewed using standardised diagnostic criteria. The original patient reported diagnoses were changed, if necessary, based on review, and the reasons for the change in diagnosis were recorded. To evaluate the effect of misclassification on linkage results, simulations were created with Gensim and analysed using Genehunter to evaluate a model for IBD inheritance. RESULTS: Sixty eight of 1096 (6.2%) individuals had a change in diagnosis from that originally reported. The majority of changes were patients with either Crohn's disease or ulcerative colitis who were determined not to have IBD at all. The principal reasons for changes to the original diagnosis were discordance between the patients' subjective reports of diagnosis and actual clinical history, endoscopic, or pathological results; a change in disease pattern over time; and insufficient information available to confirm the original diagnosis. A 10% misclassification rate resulted in 28.4% and 40.2% loss of power to detect a true linkage when using a statistical model for a presumed IBD locus with lambda(s) values of 1.8 and 1.3, respectively. CONCLUSIONS: Diagnostic misclassification occurs in patients enrolled in IBD genetic studies and frequently involves assigning the diagnosis of IBD to non-affected individuals. Even low rates of diagnostic misclassification can lead to significant loss of power to detect a true linkage, particularly for loci with modest effects as are likely to be found in IBD.