Ulcerative Colitis: Rotter JI

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.

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Michelsen KS, Thomas LS, Taylor KD, Yu QT, Mei L, Landers CJ, Derkowski C, McGovern DP, Rotter JI, Targan SR. · Inflammatory Bowel Disease Center & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. · PLoS One. · Pubmed #19262684 links to  free full text

Abstract: BACKGROUND: The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts. METHODOLOGY AND PRINCIPAL FINDINGS: Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P< or =0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcgammaR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype. CONCLUSIONS AND SIGNIFICANCE: These findings suggest that TL1A gene variation exacerbates induction of TL1A in response to FcgammaR stimulation in Jewish CD patients and this may lead to chronic intestinal inflammation via overwhelming T cell responses. Thus, TL1A may provide an important target for therapeutic intervention in this subgroup of IBD patients.

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).

Saruta M, Targan SR, Mei L, Ippoliti AF, Taylor KD, Rotter JI. · Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California 90048, USA. · Inflamm Bowel Dis. · Pubmed #18942751 No free full text.

Abstract: BACKGROUND: TNF-alpha and IL-1 have been associated with mucosal inflammation in both Crohn's disease (CD) and ulcerative colitis (UC). Innate immune defects have been associated with CD, specifically CARD15/NOD2. Recently, Toll-like receptor 8 (TLR8) signaling has been shown to enhance generation of both cytokines. Interestingly, TLR8 is located on the X chromosome and inflammatory bowel disease (IBD) has been associated with abnormalities of the X chromosome. The aim was to test whether TLR8 haplotypes are associated with IBD. METHODS: Subjects (735 CD, 343 UC, 245 controls) were genotyped. Single nucleotide polymorphisms (SNPs) were chosen to tag common Caucasian haplotypes. RESULTS: Both "risk (H4)" and "protective (H1)" TLR8 haplotypes were observed associated with CD in females. Eighteen percent of CD females had H4 compared with 9% of controls (P = 0.02). Fifty-nine percent of CD females had H1 compared with 72% of controls (P = 0.01). H1 was also negatively associated with UC in females (59% of UC, 72% of controls P = 0.03). Diplotype analysis of CD, UC, and all IBD in females revealed that 2 protective haplotypes (H1/H1) had a markedly diminished odds ratio, 0.4-0.5. The presence of a risk haplotype (H4 / not H1) had a significantly increased odds ratio, 2.0-2.2. Thus, the risk for IBD was 4-5 times higher in females with 1 risk haplotype than with the protective/protective diplotype. CONCLUSIONS: TLR8 is an X-linked IBD susceptibility gene with both common predisposing and protecting haplotypes. These associations further emphasize the importance of genetic variation in innate immunity as determinants, not only of CD, but of UC as well.

McGovern DP, Taylor KD, Landers C, Derkowski C, Dutridge D, Dubinsky M, Ippoliti A, Vasiliauskas E, Mei L, Mengesha E, King L, Pressman S, Targan SR, Rotter JI. · Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Inflamm Bowel Dis. · Pubmed #18720471 No free full text.

Abstract: BACKGROUND: Despite recent advances the majority of inflammatory bowel disease (IBD) susceptibility 'genes' remain undiscovered. Recent data suggest that autoimmune conditions may 'share' susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens. METHODS: We genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls. RESULTS: The most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002). CONCLUSIONS: These findings support the significance of the epithelial barrier in IBD pathogenesis.

Fleshner P, Ippoliti A, Dubinsky M, Vasiliauskas E, Mei L, Papadakis KA, Rotter JI, Landers C, Targan S. · Division of Colon and Rectal Surgery, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #18378498 No free full text.

Abstract: BACKGROUND & AIMS: Acute pouchitis (AP) and chronic pouchitis (CP) are common after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. The aim of this study was to assess associations of preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti-CBir1 flagellin on AP or CP development. METHODS: Patients were assessed prospectively for clinically and endoscopically proven AP (antibiotic responsive) or CP (antibiotic-dependent or refractory to antibiotic therapy). Sera from 238 patients were analyzed for ANCA and anti-CBir1 using an enzyme-linked immunosorbent assay. pANCA(+) patients were substratified into high-level (>100 EU/mL) and low-level (<100 EU/mL) groups. RESULTS: After a median follow-up period of 47 months, 72 patients (30%) developed pouchitis. Pouchitis developed in 36% of pANCA(+) patients versus 16% of pANCA(-) patients (P = .005), 46% of anti-CBir1(+) patients versus 26% of anti-CBir1(-) patients (P = .02), and 54% of 35 pANCA(+)/anti-CBir1(+) patients versus 31% of 136 pANCA(+)/anti-CBir1(-) patients (P = .02). AP developed in 37 pANCA(+) patients (22%) versus 6 pANCA(-) patients (9%) (P = .02), and 12 anti-CBir1(+) patients (26%) versus 31 anti-CBir1(-) patients (16%) (P = .1). Although AP was not influenced by pANCA level, AP was seen in 38% of low-level pANCA(+)/anti-CBir1(+) patients versus 18% low-level pANCA(+)/anti-CBir1(-) patients (P = .03). CP was seen in 29% of high-level pANCA(+) patients versus 11% of low-level pANCA(+) patients (P = .03). CONCLUSIONS: Both pANCA and anti-CBir1 expression are associated with pouchitis after IPAA. Anti-CBir1 increases the incidence of AP only in patients who have low-level pANCA expression, and increases the incidence of CP only in patients who have high-level pANCA expression. Diverse patterns of reactivity to microbial antigens may manifest as different forms of pouchitis after IPAA.

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.

Melmed GY, Fleshner PR, Bardakcioglu O, Ippoliti A, Vasiliauskas EA, Papadakis KA, Dubinsky M, Landers C, Rotter JI, Targan SR. · Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Dis Colon Rectum. · Pubmed #18085333 links to  free full text

Abstract: PURPOSE: Approximately 5 to 10 percent of patients undergoing ileal pouch-anal anastomosis with a diagnosis of ulcerative colitis are subsequently diagnosed with Crohn's disease. Preoperative predictors for Crohn's disease post-ileal pouch-anal anastomosis have not been prospectively defined. METHODS: A total of 238 consecutive patients with ulcerative colitis or indeterminate colitis undergoing ileal pouch-anal anastomosis were prospectively enrolled into a longitudinal database. Clinical factors were assessed perioperatively. Serum drawn preoperatively was assayed for anti-Saccharomyces cerevisiae, antiouter membrane porin-C, anti-CBir1, and perinuclear antineutrophil cytoplasmic antibody using enzyme-linked immunosorbent assay. Crohn's disease was defined by small bowel inflammation proximal to the ileal pouch or a perianal fistula identified at least three months after ileostomy closure. Predictors were assessed in a multivariate Cox proportional hazards model to predict the rate of Crohn's disease after ileostomy closure. RESULTS: Sixteen patients (7 percent) were diagnosed with Crohn's disease; median time to Crohn's disease was 19 (range, 1-41) months. Significant factors for postoperative Crohn's disease after ileal pouch-anal anastomosis included family history of Crohn's disease (hazard ratio, 8.4; 95 percent confidence interval, 2.96-24.1; P < 0.0001) and anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity (hazard ratio, 3.14; 95 percent confidence interval, 1.1-9.81; P = 0.04). Crohn's disease developed in only 8 of 198 patients (4 percent) without these predictors vs. 8 of 40 patients (20 percent) in those with at least one of these factors (P = 0.002). The cumulative risk of Crohn's disease among patients with two risk factors (67 percent) was higher than in patients with either risk factor (18 percent) or neither risk factor (4 percent, P < 0.001). CONCLUSIONS: Patients with ulcerative colitis and indeterminate colitis with a family history of Crohn's disease or preoperative anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity are more likely to be diagnosed with Crohn's disease after ileal pouch-anal anastomosis.

Picornell Y, Mei L, Taylor K, Yang H, Targan SR, Rotter JI. · Medical Genetics Institute, Cedars-Sinai Medical Center Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #17663424 links to  free full text

Abstract: BACKGROUND: Inflammatory bowel disease (IBD) is a clinically and, likely, genetically heterogeneous group of disorders. A recent report suggests that genetic variations in the TNFSF15 gene contribute to the susceptibility of IBD in both Japanese and Caucasian populations. The aim was to confirm the association between TNFSF15 high- and low-risk haplotypes and IBD in a Caucasian population. METHODS: Five single-nucleotide polymorphisms (SNPs) that comprise the 2 common haplotypes were genotyped in 599 Caucasian patients with Crohn's disease (CD), 382 Caucasian patients with ulcerative colitis (UC), and 230 ethnically matched healthy controls, including both Jews and non-Jews. RESULTS: The previously reported 'risk' haplotype was not associated with CD or UC (88.2% in CD cases versus 88.3% in controls, P = 0.96; 88.1% in UC cases versus 88.3% in controls, P = 0.78). We did, however, observe an increased frequency of the "protective" haplotype in non-Jewish controls for both CD and UC (38.8% CD cases versus 50% controls, P = 0.01; 37.3% UC cases versus 50% controls, P = 0.01) with no such effect observed in the Jewish samples. There was an interactive effect between ethnicity and the protective haplotype in CD (P = 0.04). CONCLUSIONS: We observed a protective haplotype, consisting of the minor alleles for all 5 markers, to have a higher frequency in the non-Jewish controls than in CD and UC. Of further interest, the haplotype frequency was in the opposite direction in our Jewish case-control panels (both CD and UC), leading us to conclude 1) that TNFSF15 is indeed an IBD susceptibility gene, and 2) the disease susceptibility is ethnic-specific.

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.

Dubinsky MC, Wang D, Picornell Y, Wrobel I, Katzir L, Quiros A, Dutridge D, Wahbeh G, Silber G, Bahar R, Mengesha E, Targan SR, Taylor KD, Rotter JI, Anonymous00160. · Department of Pediatrics, Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #17309073 links to  free full text

Abstract: BACKGROUND: The IL-23 receptor (IL-23R) has been found to be associated with small bowel Crohn's disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL-23R is associated with IBD in children. The aim was to examine the association of IL-23R with susceptibility to IBD in pediatric patients. METHODS: DNA was collected from 609 subjects (151 CD and 52 ulcerative colitis [UC] trios). Trios were genotyped for the R381Q SNP of the IL-23R gene and SNP8, SNP12, SNP13, of the CARD15 gene using Taqman. The transmission disequilibrium test (TDT) was used for association to disease using GENEHUNTER 2.0. RESULTS: The rare allele of R381Q SNP was present in 2.7% of CD and 2.9% UC probands. The CARD15 frequency was 31.5% (CD) and 18% (UC). The IL-23R allele was negatively associated with inflammatory bowel disease (IBD): the R381Q SNP was undertransmitted in children with IBD (8 transmitted [T] versus 27 untransmitted [UT]; P = 0.001). This association was significant for all CD patients (6 T versus 19 UT; P = 0.009), especially for non-Jewish CD patients (2 T versus 17 UT; P = 0.0006). TDT showed a borderline association for UC (2 T versus 8 UT; P = 0.06). As expected, CARD15 was associated with CD in children by the TDT (58 T versus 22 UT P = 0.00006), but not with UC. CONCLUSIONS: The protective IL-23R R381Q variant was particularly associated with CD in non-Jewish children. Thus, the initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD.

Papadakis KA, Yang H, Ippoliti A, Mei L, Elson CO, Hershberg RM, Vasiliauskas EA, Fleshner PR, Abreu MT, Taylor K, Landers CJ, Rotter JI, Targan SR. · Cedars-Sinai Inflammatory Bowel Disease Center, Los Angeles, California, USA. · Inflamm Bowel Dis. · Pubmed #17260364 links to  free full text

Abstract: BACKGROUND: Antibody reactivity to microbial antigens correlates with distinct Crohn's disease (CD) phenotypes such as fistulizing or fibrostenosing disease. We examined the association between anti-CBir1 and clinical phenotypes and NOD2 variants in a large cohort of adult CD patients. METHODS: Sera and genomic DNA were collected from 731 patients with CD and tested for immune responses to I2, CBir1, oligomannan, and outer membrane porin C (OmpC) and the 3 most common CD-associated NOD2 variants. RESULTS: Anti-CBir1 reactivity was significantly associated with fibrostenosis (FS), internal penetrating (IP) disease phenotypes, small bowel (SB) involvement, and SB surgery but negatively associated with ulcerative colitis (UC)-like CD. Multivariate logistic regression analysis showed that anti-CBir1 was independently associated with FS and UC-like CD irrespective of the antibody reactivity to I2, oligomannan, or OmpC, but not with SB involvement or SB surgery. The magnitude of anti-CBir1 reactivity, when added to the quantitative response toward the other 3 CD-associated antigens, enhances the discrimination of FS, IP, UC-like CD, and SB involvement, but not SB surgery. Finally, although the frequency of anti-CBir1 was similar in patients with none versus at least 1 NOD2 variant, the quantitative response to CBir1 flagellin was significantly higher in patients with CD carrying at least 1 NOD2 variant versus those carrying no variants (median anti-CBir1 titer 33.39 versus 28.36, respectively; P = 0.01). CONCLUSIONS: Anti-CBir1 serum reactivity in CD patients is independently associated with FS and complicated SB CD. Quantitative, but not qualitative, response to CBir1 is also significantly associated with the CD-associated NOD2 variants.

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.

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.

Mei L, Targan SR, Landers CJ, Dutridge D, Ippoliti A, Vasiliauskas EA, Papadakis KA, Fleshner PR, Rotter JI, Yang H. · Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Gastroenterology. · Pubmed #16618402 No free full text.

Abstract: BACKGROUND & AIMS: Crohn's disease (CD) is a genetically complex disorder with strong familial aggregation. Pathogenesis appears to involve dysregulation of the immune response to endogenous bacteria. Anti-Escherichia coli outer membrane porin C (anti-OmpC) expression reflects an exaggerated response to commensal bacteria and occurs with higher frequency in CD. The aim of this study was to determine whether there is familial aggregation and genetic determination of anti-OmpC expression in CD families. METHODS: Study groups consisted of 787 CD patients, 389 ulcerative colitis (UC) patients, 619 unaffected relatives, and 216 healthy controls. Serum anti-OmpC was detected by enzyme-linked immunosorbent assay. RESULTS: CD patients had a greater percentage of anti-OmpC than UC patients and healthy controls. Anti-OmpC expression was more frequent in unaffected relatives from CD-only or mixed families, compared with healthy controls (P = .002 and .0001, respectively), and it was more frequent in UC patients from mixed families than those from UC-only families (P = .02). There was a significant familiality in anti-OmpC expression: P = .02 for qualitative concordance and P < .0001 for quantitative intraclass correlation. The heritability estimate for anti-OmpC level was .39 (P < .0001). CONCLUSIONS: Anti-OmpC is a heritable immunophenotype. Increased anti-OmpC expression in the unaffected family members of CD patients suggests that anti-OmpC may be an immunologic risk marker for CD. That UC patients in mixed families had a higher response to OmpC than those in UC-only families indicates pathophysiologic heterogeneity within UC.

Yang H, Ohmen JD, Ma Y, Bentley LG, Targan SR, Fischel-Ghodsian N, Rotter JI. · Department of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles 90048, USA. · Genet Med. · Pubmed #11256672 No free full text.

Abstract: PURPOSE: The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) are chronic intestinal disorder of unknown etiology. Genetic factors play an important role in the pathogenesis of these diseases, but with a complex pattern of inheritance. A number of genome-wide scans have identified several putative susceptibility loci for both CD and UC, including a locus on chromosome 12 reported in a set of British families. We aim to evaluate the linkage between CD or UC and this chromosome 12 locus in an independent set of U.S. Caucasian families (36% being of Ashkenazi Jewish origin). METHODS: Microsatellite markers along chromosome 12 spaced at approximately 10 cm intervals were used to test the putative loci in CD only families (65 sib pairs from 46 families). Regions with positive linkage for CD were then tested in a panel of UC and mixed families (44 sib pairs from 29 families). Two point linkage analysis was performed with SIBPAL. Multipoint linkage analysis was carried out with MAPMAKER/SIBS. RESULTS: We observed evidence of linkage between the region on chromosome 12 and Crohn's disease, because there was a significant excess of allele sharing in CD sib pairs (pi = 0.62, p = 0.0004 from two-point linkage; and logarithm of the odds score (LOD) = 2.0 from multipoint linkage). However, we did not observe the same linkage in UC and mixed families (p = 0.48; not significant [ns]). CONCLUSION: Our data provided further evidence that the region on chromosome 12 is likely to contain a gene predisposing to CD.

Trachtenberg EA, Yang H, Hayes E, Vinson M, Lin C, Targan SR, Tyan D, Erlich H, Rotter JI. · Children's Hospital Oakland Research Institute, Oakland, CA, USA. · Hum Immunol. · Pubmed #10689124 No free full text.

Abstract: Ulcerative colitis (UC) and Crohn's disease (CD) are the clinical entities comprising idiopathic inflammatory bowel disease (IBD). Previous studies on the association of IBD and human leukocyte antigen (HLA) class II genes suggested a role for HLA in this disease. Here we present HLA class II (DRB1, DQB1, DQA1, DPB1) allele and haplotype distributions determined using the polymerase chain reaction and sequence-specific oligonucleotide probe methods. A total of 578 UC and CD Caucasian patients and controls from Jewish (Ashkenazi) and non-Jewish populations was examined. Our previously reported association of DR1-DQ5 with CD was attributable to DRB1*0103. A dramatic association with IBD and the highly unusual DRB1*0103-DQA1*0501-DQB1*0301 haplotype (OR = 6.6, p = 0.036) was found. The more common DR1 haplotype, DRB1*0103-DQA1*0101-DQB1*0501, was also associated with IBD (OR = 3.1, p = 0.014), a result suggesting that interaction between DR and DQ may determine the extent of disease risk. Our previously reported association of DR2 with UC was attributable to DRB1*1502 (OR = 2.6, p = 0.006). At the DPB1 locus, a significant association of DPB1*0401 with CD was observed for the combined populations (OR = 1.85, p = 0.007). These observations indicate that some class II alleles and haplotypes confer susceptibility to both UC and CD, implying common immunogenetic mechanisms of pathogenesis, while others confer risk to only one of these diseases, and illustrate the value of DNA HLA typing in disease susceptibility analyses.

Ma Y, Ohmen JD, Li Z, Bentley LG, McElree C, Pressman S, Targan SR, Fischel-Ghodsian N, Rotter JI, Yang H. · Parke-Davis Laboratory for Molecular Genetics (PDLMG), Alameda, California, USA. · Inflamm Bowel Dis. · Pubmed #10579120 No free full text.

Abstract: Chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD. From four genome-wide scans, putative susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4, 6, 7, 10, and 12 for IBD, have been identified. Several other groups, including ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of this study is to identify other potential susceptibility loci for CD with a genome-wide search approach. In our sample of 222 individuals from 46 families (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we observed a novel locus with suggestive linkage [multipoint logarithm of the odds score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition, suggestive linkage was observed in our Jewish families at chromosome 17q21-q23 (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The syntenic regions of the latter locus are mapped within two putative loci on mouse chromosomes 11 and 18, which were identified in a mouse IBD model induced by dextran sulfate sodium (29). Our preliminary results provide potential evidence for several susceptibility loci contributing to the risk of CD. The observation of man-mouse synteny may accelerate the identification of CD susceptibility gene(s) on human chromosome 5.

Tountas NA, Casini-Raggi V, Yang H, Di Giovine FS, Vecchi M, Kam L, Melani L, Pizarro TT, Rotter JI, Cominelli F. · Division of Gastroenterology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA. · Gastroenterology. · Pubmed #10500062 No free full text.

Abstract: BACKGROUND & AIMS: The role of the interleukin (IL)-1 receptor antagonist (IL-1ra) in predisposing an individual to inflammatory bowel disease (IBD) is controversial. This study aimed to determine the association between intron 2 IL-1ra polymorphism and IBD by performing a multiethnic case-control study and to assess its functional significance. METHODS: A total of 236 patients with ulcerative colitis (UC), 196 patients with Crohn's disease (CD), and 338 ethnically matched control patients treated at LAC-USC and Cedars-Sinai Medical Centers and the University of Milan Medical Center were genotyped for a variable length polymorphism in intron 2 of the IL-1ra gene (IL-1RN). Total IL-1ra protein production rates in peripheral blood mononuclear cells (PBMCs) were correlated with carriage of allele 2 of the IL-1RN gene (IL-1RN*2). RESULTS: In the LAC-USC group, UC patients (n = 60) had an increased frequency of at least 1 copy of IL-1RN*2 compared with controls (n = 129) (70% vs. 33%; P < 0.01; odds ratio [OR], 4.7). The frequency of IL-1RN*2 carriage in the Cedars-Sinai group was 59% in UC, 45% in CD, and 42% in controls (P < 0.01; OR, 2.0). A significant difference was observed only in the Jewish subgroup (P = 0.003; OR, 5.0). The association was not detected in UC or CD patients treated at the University of Milan. The ORs of 4.7 and 5.0 appear to be the highest reported in any UC population for any genetic markers. Further, carriage of IL-1RN*2 was associated with decreased production of total IL-1ra protein in cultured PBMCs from both UC patients and controls. CONCLUSIONS: These results provide further evidence that IL-1ra is important in the predisposition to UC, there may be genetic or pathogenetic heterogeneity between different ethnic groups, and UC and CD are genetically distinct diseases.

Swallow DM, Vinall LE, Gum JR, Kim YS, Yang H, Rotter JI, Mirza M, Lee JC, Lennard-Jones JE. · No affiliation provided · J Med Genet. · Pubmed #10636731 links to  free full text

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