Dunecan Massey

Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease

We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohns disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohns disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 × 10−5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10−17), 16q22 (CDH1 and CDH3; P = 2.8 × 10−8) and 7q31 (LAMB1; P = 3.0 × 10−8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

Investigation of Crohn's Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

BACKGROUND & AIMS Identifying shared and disease-specific susceptibility loci for Crohns disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. METHODS We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. RESULTS Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. CONCLUSIONS Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.

Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease.

The era of genome-wide association (GWA) scanning has shed new light on the genetic basis of common disease and nowhere is this better illustrated than Crohn’s disease (CD). CD is a chronic debilitating inflammatory bowel disease characterized by stricturing and fistula formation. Mainstays of current therapy are immune suppression and surgery. The pathogenesis of CD is poorly understood, but it has long been recognized that both genetic susceptibility and bacterial antigens play important roles. A variety of intracellular bacteria have been postulated to trigger CD, but the evidence for any one organism is equivocal. The current consensus is that commensal gut bacteria provide the drive for CD-related inflammation. Three GWA scans undertaken in the last 6 months have identified 10 new loci demonstrating highly significant and replicated association with CD. Two of the strongest hits implicate genes IRGM and ATG16L1, which encode proteins thought to be critical to the autophagy pathway. The critical next step is functional characterization of the CD-associated genetic variants in IRGM and ATG16L. It seems highly plausible that variation in these genes holds the key to understanding exactly which bacteria drive the intestinal inflammation of CD and the mechanism by which they do this. Addendum to: Sequence Variants in the Autophagy Gene IRGM and Multiple Other Replicating Loci Contribute to Crohns Disease Susceptibility M. Parkes, J.C. Barrett, N.J. Prescott, M. Tremelling, C.A. Anderson, S.A. Fisher, R.G. Roberts, E.R. Nimmo, F.R. Cummings, D. Soars, H. Drummond, C.W. Lees, S.A. Khawaja, R. Bagnall, D.A. Burke, C.E. Todhunter, T. Ahmad, C.M. Onnie, W. McArdle, D. Strachan, G. Bethel, C. Bryan, C.M. Lewis, P. Deloukas, A. Forbes, J. Sanderson, D.P. Jewell, J. Satsangi, J.C. Mansfield, Wellcome Trust Case Control Consortium, L. Cardon and C.G. Mathew Nat Genet 2007; 39:830-2

Use of sirolimus (rapamycin) to treat refractory Crohn's disease

We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn’s disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn’s disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn’s disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn’s disease symptoms with the Harvey–Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn’s disease.

Mucosal genome-wide methylation changes in inflammatory bowel disease†

Background: DNA methylation constitutes a key epigenetic mechanism by which cells regulate gene transcription. Among its roles are the dynamic regulation of gene expression, for example, as part of an evolving immune response, and cell differentiation in specialized tissues. Here our aim was to study the impact of differences in methylation patterns in the intestine with regard to inflammatory bowel disease (IBD) susceptibility and activity. Methods: Having extracted DNA from rectal biopsies, we conducted genome‐wide methylation profiling using the HumanMethylation27 BeadChip microarray to identify genes showing evidence of differential methylation between cases of ulcerative colitis and Crohns disease and healthy controls. Selected methylation signals were validated in an independent replication panel by pyrosequencing. Correlation with gene expression was sought by quantitative real‐time polymerase chain reaction (RT‐PCR). Results: Multiple genes showed significant evidence of differential methylation, several appearing in both ulcerative colitis and Crohns disease comparisons including THRAP2, FANCC, GBGT1, DOK2, TNFSF4, TNFSF12, and FUT7. Many more than expected by chance overlapped with genes previously implicated as playing a role in IBD susceptibility in genome‐wide association scans, including CARD9, ICAM3, and IL8RB (P < 0.001). Correlation between methylation and gene expression was identified for selected transcripts. Conclusions: Consistent differences in DNA methylation between IBD cases and controls at regulatory sites within these genes suggest that their altered transcription contributes to IBD pathogenesis. (Inflamm Bowel Dis 2012;)

Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population

Background: Identification of Crohns disease (CD)‐associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. Methods: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. Results: TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01–1.41) P = 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR = 1.44 (95% CI 1.23–1.68) P = 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499–3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. Conclusions: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease‐causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies.

Genetics of inflammatory bowel disease: clues to pathogenesis

INTRODUCTION OR BACKGROUND It has long been recognized from epidemiological data that inflammatory bowel diseases (IBD), Crohns disease (CD) and ulcerative colitis (UC), have a strong genetic predisposition, interacting with unknown environmental drivers to render susceptible individuals at risk for relapsing intestinal inflammation. Substantial progress has been made in the last 2 years in characterizing the susceptibility genes involved. SOURCES OF DATA The recent acceleration in understanding has resulted from the use of new technologies of genome-wide association scanning in large panels of cases and controls. AREAS OF AGREEMENT Genome scans have robustly identified 11 susceptibility genes and loci and highlighted a number of new, previously unsuspected pathways as playing an important role in IBD pathogenesis-including the IL23 pathway in IBD overall and specific aspects of innate immunity (particularly NOD2 and the autophagy genes ATG16L1 and IRGM) in CD. AREAS OF CONTROVERSY The next challenge is to identify specific causal variants at each of the confirmed susceptibility loci and then characterize their biological impact on gene expression and function of the protein product. GROWING POINTS To date, most attention has focused on CD. A recent meta-analysis has increased the number of confirmed susceptibility loci to 32-more than for any other common disease to date. Attention is now turning to the use of the same techniques in UC to identify new, disease-specific genes and understand areas of overlap. AREAS TIMELY FOR DEVELOPING RESEARCH This review explores genetic clues to the pathogenesis of IBD derived from the growing list of confirmed IBD susceptibility genes, and briefly elaborates some of the important themes and overlaps that are becoming evident both within IBD and also with other complex diseases.

Genetic association between NLRP3 variants and Crohn's disease does not replicate in a large UK panel

Background: NLRP3 (formerly known as CIAS1 or NALP3) encodes a key component of the inflammasome and is a strong candidate gene for Crohns disease (CD) susceptibility. A recent study reported significant and internally replicated association between CD and six single nucleotide polymorphisms (SNPs) in a regulatory region 5.3 kb downstream of NLRP3. Independent replication is required to verify these findings. Methods: In all, 1298 CD cases and 1244 healthy controls were genotyped for the six SNPs using Taqman. Single locus, haplotype, and subphenotype analyses were conducted using logistic regression‐based methods and PLINK, respectively. Results: No significant associations were found, either on single locus, subphenotype, or haplotype analysis. Conclusions: Given our high (>90%) power to replicate findings from the index study, our data suggest either a much smaller effect size for the association between NLRP3 and CD susceptibility than previously reported or the possibility of a false‐positive result in the index study. Further studies in other populations are required to determine what role, if any, NLRP3 variants play in CD susceptibility. (Inflamm Bowel Dis 2011;)

Stomal Cytomegalovirus Infection Following Intestinal Transplant

Intravenous antiviral therapy was started for increasing cytomegalovirus (CMV) titers 6 months after this 61-year-old man underwent small intestine/liver transplantation for Crohn’s disease with short-bowel syndrome and cirrhosis secondary to nonalcoholic steatohepatitis. The ileostomy appeared grossly abnormal with ulceration, edema, and friability (left), although at endoscopy the ileum was macroscopically normal (center). Because of concerns about bowel obstruction, the stoma was refashioned, with the resection specimen demonstrating histological features of CMV infection (right) limited to the stoma and not including the proximal ileum and no evidence of recurrent Crohn’s disease or rejection. Similar features developed shortly thereafter in the refashioned stoma and improved with ongoing antiviral therapy; there was no need for further surgery.