Crohn's Disease Susceptibility Loci Research Articles

Sex-Dimorphic Analyses Identify Novel and Sex-Specific Genetic Associations in Inflammatory Bowel Disease.

Sex is an integral variable often overlooked in complex disease genetics. Differences between sexes have been reported in natural history, disease complications, and age of onset in inflammatory bowel disease (IBD). While association studies have identified >230 IBD loci, there have been a limited number of studies investigating sex differences underlying these genetic associations. We report the first investigation of sex-dimorphic associations via meta-analysis of a sex-stratified association study (34 579 IBD cases, 39 125 controls). In addition, we performed chromosome (chr) X-specific analyses, considering models of X inactivation (XCI) and XCI escape. Demographic and clinical characteristics were also compared between sexes. We identified significant differences between sexes for disease location and perianal complication in Crohn's disease and disease extent in ulcerative colitis. We observed genome-wide-significant sex-dimorphic associations (P < 5 × 10-8) at loci not previously reported in large-scale IBD genetic studies, including at chr9q22, CARMIL1, and UBASH3A. We identified variants in known IBD loci, including in chr2p15 and within the major histocompatibility complex on chr6, exhibiting sex-specific patterns of association (P < 5 × 10-7 in one sex only). We identified 3 chrX associations with IBD, including a novel Crohn's disease susceptibility locus at Xp22. These analyses identified novel IBD loci, in addition to characterizing sex-specific patterns of associations underlying sex-dimorphic associations. By elucidating the role of sex in IBD genetics, our study will help enhance our understanding of the differences between the sexes in IBD biology and underscores a need to move beyond conventional sex-combined analyses to appreciate the genetic architecture of IBD more comprehensively.

Paneth Cell Alterations in the Development and Phenotype of Crohn’s Disease

Pathogenesis of Crohn's disease (CD) involves immune and microbial dysregulation, induced by environmental factors in genetically susceptible individuals. There are believed to be multiple subtypes of CD, which contributes to its observed clinical heterogeneity. This concept has been reinforced by recognition of the complexity of the genetic, microbial, immune, and environmental factors that affect risk for CD. Paneth cells mediate immunity and maintain the small intestinal epithelium; defects in activities of these cells have been observed in high proportions of patients with CD, and are associated with a more aggressive CD phenotype. Paneth cells integrate complex genetic, immune, and environmental signals, therefore alterations in their function could lead to different subtypes of CD, as observed in studies in cohorts of primarily European descent. Subtypes of CD associated with Paneth cell function have been observed even among patients from different genetic backgrounds. We discuss genetic susceptibility loci for CD and how these affect Paneth cell activity.

Whole genome and exome sequencing of monozygotic twins discordant for Crohn's disease.

BackgroundCrohn’s disease (CD) is an inflammatory bowel disease caused by genetic and environmental factors. More than 160 susceptibility loci have been identified for IBD, yet a large part of the genetic variance remains unexplained. Recent studies have demonstrated genetic differences between monozygotic twins, who were long thought to be genetically completely identical.ResultsWe aimed to test if somatic mutations play a role in CD etiology by sequencing the genomes and exomes of directly affected tissue from the bowel and blood samples of one and the blood-derived exomes of two further monozygotic discordant twin pairs. Our goal was the identification of mutations present only in the affected twins, pointing to novel candidates for CD susceptibility loci. We present a thorough genetic characterization of the sequenced individuals but detected no consistent differences within the twin pairs. An estimate of the CD susceptibility based on known CD loci however hinted at a higher mutational load in all three twin pairs compared to 1,920 healthy individuals.ConclusionSomatic mosaicism does not seem to play a role in the discordance of monozygotic CD twins. Our study constitutes the first to perform whole genome sequencing for CD twins and therefore provides a valuable reference dataset for future studies. We present an example framework for mosaicism detection and point to the challenges in these types of analyses.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-564) contains supplementary material, which is available to authorized users.

O-025 Paneth Cell Phenotype Correlates with Genetics, Transcriptome Profile, Pathologic Hallmark and Predicts Clinical Outcome in Patients with Crohnʼs Disease

The identification of genetic susceptibility loci in Crohn's Disease (CD) represents an opportunity to define disease subtypes that could be utilized in the development of novel personalized therapies. The major challenges are that the CD susceptibility loci are numerous, complex and likely interact with undefined components of the environment. Paneth cells in the small intestine form part of the innate immunity and play crucial roles in CD pathogenesis. We have previously shown that the morphology of Paneth cell cytoplasmic antimicrobial granules can be used as a readout for host genetics and environmental exposure. We hypothesized that Paneth cell phenotypes could act as an integrative readout to define specific CD subtypes. We retrospectively analyzed 178 genotyped CD patients with small intestinal resections at 2 institutions. Uninvolved ileal sections were analyzed for transcriptional profiles by microarray and Paneth cell phenotype by lysozyme immunofluorescence (up to 250 crypts quantified/sample). The morphology of each individual Paneth cell was categorized. The sum of Paneth cells with abnormal lysozyme distribution was used to determine the patients' phenotype, with “bad” Paneth cell phenotype defined as ≥20% abnormal Paneth cells, and <20% defined as “good” Paneth cell phenotype. The patients' phenotypes were then correlated with genotype, pathologic features, transcriptional profiles, and time to recurrence after surgery. Among the 178 CD patients, 27 (15%) had bad Paneth cell phenotype. Patients with one or more CD-associated NOD2 susceptibility alleles had increased proportions of abnormal Paneth cells compared to those without NOD2 susceptibility alleles. Furthermore, there is an additive effect of CD-associated NOD2 susceptibility alleles and ATG16L1 T300A on Paneth cell abnormalities. We found that the cases with bad Paneth cell phenotype were more likely to be granuloma-poor (P = 0.0160). Bad Paneth cell phenotype was also associated with an altered transcriptional signature most strongly associated with immune activation pathways. Clinically, among the 121 patients who received adjuvant prophylactic therapy, those with bad Paneth cell phenotype showed shorter time to disease recurrence after surgery (median 10 months) compared to patients with good Paneth cell phenotype (median 14 months; P = 0.0198). The difference was not seen in patients who did not receive adjuvant prophylactic therapy. We also found that in the same patients, the Paneth cell phenotype in involved area was consistent with that in the uninvolved area (P = 0.0001). Finally, bioequivalence analysis showed that a minimum of 40 crypts in biopsy was sufficient for Paneth cell morphology analysis. Paneth cell phenotype is associated with patients' genetics, pathologic hallmark, and predicts clinical outcome. It can be used as a “hard” endpoint that can subdivide CD patients into clinically relevant groups. Defining the minimum crypt number required for Paneth cell phenotype analysis enables the use of routine biopsy material for further clinical studies.

ABO histo-blood group might modulate predisposition to Crohn's disease and affect disease behavior

Background and aimsABO encodes a glycosyltranferase which determines the major human histo-blood group. The FUT2 fucosyltransferase allows expression of ABO antigens on the gastrointestinal mucosa and in bodily secretions (secretor phenotype). A nonsense allele in FUT2 represents a susceptibility variant for Crohn's disease, and both the secretor and ABO blood group status affect the composition of the gut microbiota. Thus, we evaluated if variants in ABO might represent good candidates as Crohn's disease susceptibility loci. MethodsWe recruited two case–control cohorts, from Italy (n=1301) and Belgium (n=2331). Subjects were genotyped for one SNP in FUT2 and two variants in ABO. ResultsNo effect on Crohn's disease risk was detected for ABO variants, whereas an association was observed between the FUT2 polymorphism and Crohn's disease susceptibility in the Belgian sample, but not in the Italian cohort. The effect of histo-blood groups was evaluated using group O as the reference. Most non-O groups had odds ratios (ORs) higher than 1 in both cohorts, and combined analysis of the two samples indicated a predisposing effect for the A and B groups (OR=1.17, 95% CI: 1.02–1.32 and OR=1.33, 95% CI: 1.09–1.58, respectively). In Crohn's disease patients, the non-O blood group and the non-secretor status were associated with higher risk of developing a stricturing or penetrating disease. ConclusionsABO histo-blood group might confer susceptibility to Crohn's disease and modulate disease severity.

Multidimensional Prognostic Risk Assessment Identifies Association Between IL12B Variation and Surgery in Crohn’s Disease

The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.

Associations Between Genetic Variants in the IRGM Gene and Inflammatory Bowel Diseases in the Korean Population

Recent European ancestry genome-wide association studies have identified genetic variants of IRGM as significant susceptibility loci for Crohn's disease (CD). Therefore, we investigated whether genetic variants of IRGM confer genetic susceptibility to CD or ulcerative colitis (UC) and evaluated the genotype-phenotype associations in the Korean population. This study included 510 inflammatory bowel disease (IBD) patients (253 patients with CD and 257 with UC) and 520 healthy controls in Koreans. Initially, we performed direct sequencing analysis to identify unique IRGM single nucleotide polymorphisms (SNPs). Three selected haplotype-tagging SNPs and one risk locus (rs72553867, rs10065172, rs4958847, and rs12654043) within the IRGM were then geno-typed in patients and controls. IRGM SNP rs10065172 was significantly associated with CD susceptibility in terms of allelic frequency (P = 0.004; odds ratio [OR] = 1.42) and genotype frequency (dominant model, P = 0.008; OR = 1.62). We also found a relationship between SNP rs72553867 and CD susceptibility in the analysis of allelic frequency (P = 0.0117; OR = 0.67) and genotype frequency (dominant model, P = 0.002; OR = 0.55). In addition, we observed that the association of CD with rs10065172 became stronger in patients with younger age at diagnosis (≤ 20 years) or male gender. However, there was no significant association between the four SNPs and UC susceptibility. This is the first study to identify SNP rs10065172 and rs72553867 in IRGM as principal CD susceptibility loci in an Asian population.

PTGER4 Expression-Modulating Polymorphisms in the 5p13.1 Region Predispose to Crohn's Disease and Affect NF-κB and XBP1 Binding Sites

BackgroundGenome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes.Methodology/Principal FindingsA total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10−5; 0.76 [0.67–0.87]) and of rs7720838 (p = 6.91×10−4; 0.81 [0.71–0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10−7 for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.Conclusions/SignificanceWe confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.

Crohn's Disease Susceptibility Genes are Associated With Leprosy in the Vietnamese Population

A genomewide association study in Chinese patients with leprosy detected association signals in 16 single-nucleotide polymorphisms (SNPs) belonging to 6 loci, of which 4 are related to the NOD2 signaling pathway and are Crohn's disease susceptibility loci. Here, we studied these 16 SNPs as potential leprosy susceptibility factors in 474 Vietnamese leprosy simplex families. We replicated SNPs at HLA-DR-DQ, RIPK2, CCDC122-LACC1, and NOD2 as leprosy susceptibility factors in Vietnam. These results validated the striking overlap in the genetic control of Crohn's disease and leprosy.

A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300

ObjectiveGenome-wide association studies (GWAS) have identified multiple risk loci for Crohn's disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered...

Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5× 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53×10(-8), 11q13 near PRDX5, p(rs694739) = 3.71× 10(-09), 22q11 at YDJC, p(rs181359) = 8.02× 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99× 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and insilico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.

Genetic susceptibility to inflammation and colonic transit in lower functional gastrointestinal disorders: preliminary analysis

Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) coexist in some patients. We observed an association between Crohn's disease (CD) candidate gene TNFSF15 and IBS symptom phenotype. Three genes (TLR9, IL6, and CDH1) have been associated with postinfectious (PI)-IBS. Our aim was to preliminarily assess association between 30 susceptibility loci for CD, three genes associated with PI-IBS, and PARM1, with colonic transit in lower functional gastrointestinal disorders (FGID). A cohort of 665 persons was assembled in previous studies. TaqMan assay was used for all single nucleotide polymorphisms (SNPs) associated with the loci of interest. Data were analyzed for univariate associations with symptoms phenotype and colonic transit (nominal P values, uncorrected) using dominant and co-dominant genetic models. Carriers of the rs5743836 risk allele had increased odds for IBS-D (vs control, P = 0.02, uncorrected). Among the CD risk loci, rs7927894 (P = 0.007), rs7746082 (P=0.011), rs2872507 (P = 0.014), together with rs5743836 (P = 0.010) were univariately associated with colonic transit at 24 or 48 h. Specific tests for genetic interactions between loci revealed potential association of genes that influence neural, barrier, or mast cell function with colonic transit. Genetic variations that may influence local mucosal immune functions are univariately associated with altered colonic transit in lower FGID.

Defective innate immunity in inflammatory bowel disease: a Crohnʼs disease exclusivity?

This review summarizes the recent developments in support of the immunodeficiency model of Crohn's disease. The demonstration of impaired acute inflammation in Crohn's disease provides a novel mechanism for its pathogenesis, with diminished macrophage cytokine production and neutrophil recruitment leading to reduced bacterial clearance. The innate immune response may be further overwhelmed by other factors. The mucosal barrier in Crohn's patients is disrupted, with abnormal ultrastructure as well as antibacterial defensin deficiency. Specific bacterial agents may contribute and one promising candidate, adherent-invasive Escherichia coli, has recently been described. An interaction between Nod2 and the autophagy system has been elucidated, with direct consequences for bacterial clearance, and the most recent genome-wide association study meta-analysis has extended the number of Crohn's disease susceptibility loci to 71. The spectrum of congenital immunodeficiency disorders recognized to develop Crohn's-like inflammatory bowel disease is also expanding. Conversely, no specific immunodeficiency has so far been observed in ulcerative colitis, in which the defect appears to be failure of inflammation termination and resolution. Recent advances continue to highlight defects in innate immunity in Crohn's patients. Similar abnormalities may extend to other granulomatous disorders, but not diseases such as ulcerative colitis.

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

Intestinal inflammation arises from abnormal host-microbe interactions. The perturbations of homeostatic coexistence involve host genetic factors, barrier function, innate and adaptive immunity, as well as qualitative and quantitative changes in the composition of the microbiota. Dysbiosis toward selected micro-organisms and decreased complexity of commensal bacteria have been observed in patients with Crohn's disease and ulcerative colitis, but it is not clear whether the dysbiosis contributes to development of inflammatory bowel disease or is instead a consequence of the disease. Pathogens with virulence factors that allow them to breach the intestinal barrier and induce chronic inflammation might mediate the pathogenesis of these diseases. To identify new therapeutic approaches for inflammatory bowel disease, it is important to identify host susceptibility factors involved in the control of microbial infection, characterize potential pathogens, and eliminate them or block the expression of their virulence factors.

Genome-wide association studies and Crohn's disease

The development of genome-wide association scanning (GWAS) has revolutionized the search for genetic loci associated with complex diseases. Crohn's disease (CD), together with ulcerative colitis, has been a principal beneficiary of this technology with a recent meta-analysis from the International IBD Genetics Consortium increasing the number of confirmed CD susceptibility loci to 71. When one considers that prior to the development of GWAS only three susceptibility loci had been identified, the degree of progress becomes obvious. In this article we will summarize the principal discoveries that have been made in CD genetics and explain how these have contributed to our improved understanding of disease pathogenesis.

Meta-analysis of published studies identified eight additional common susceptibility loci for Crohnʼs disease and ulcerative colitis

Both ulcerative colitis (UC) and Crohn's disease (CD) have a complex etiology involving multiple genetic and environmental factors. Many genome-wide association studies (GWAS) and subsequent replication studies revealed that both diseases share some of the susceptibility loci; however, common genetic factors for both diseases are not fully elucidated. This study is aimed to identify the common genetic factors for CD and UC by a meta-analysis of published studies. We first reviewed the 10 GWAS for CD to select candidate single nucleotide polymorphisms (SNPs). Next, we performed a PubMed literature search up to June 30, 2010 and carried out a systemic review of published studies that examined the association of CD susceptibility loci in UC patients. Meta-analysis was carried out using the inverse variance-weighted method or the DerSimonian-Laird method after estimating the heterogeneity among the studies. The data for highly linked SNPs were combined. Finally, we performed a meta-analysis of 43 published studies in 45 SNPs located at 33 loci by using a total of 4852 to 31,125 subjects. We confirmed the association of 17 reported common susceptibility loci. Moreover, we found associations at eight additional loci: GCKR, ATG16L1, CDKAL1, ZNF365, LRRK2-MUC19, C13orf31, PTPN2, and SBNO2. The genetic risk of each locus was modest (odds ratios ranged from 1.05-1.22) except IL23R. These results indicate that CD and UC share many susceptibility loci with small genetic effect. Our data provide further understanding of the common pathogenesis between CD and UC.

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

Evidence for Significant Overlap between Common Risk Variants for Crohn's Disease and Ankylosing Spondylitis

BackgroundA multicenter genome-wide association scan for Crohn's Disease (CD) has recently reported 40 CD susceptibility loci, including 29 novel ones (19 significant and 10 putative). To gain insight into the genetic overlap between CD and ankylosing spondylitis (AS), these markers were tested for association in AS patients.Principal FindingsTwo previously established associations, namely with the MHC and IL23R loci, were confirmed. In addition, rs2872507, which maps to a locus associated with asthma and influences the expression of the ORMDL3 gene in lymphoblastoid cells, showed a significant association with AS (p = 0.03). In gut biopsies of AS and CD patients, ORMDL3 expression was not significantly different from controls and no correlation was found with the rs2872507 genotype (Spearman's rho: −0.067). The distribution of p-values for the remaining 36 SNPs was significantly skewed towards low p-values unless the top 5 ranked SNPs (ORMDL3, NKX2–3, PTPN2, ICOSLG and MST1) were excluded from the analysis.ConclusionsAssociation analysis using risk variants for CD led to the identification of a new risk variant associated with AS (ORMDL3), underscoring a role for ER stress in AS. In addition, two known and five potentially relevant associations were detected, contributing to common susceptibility of CD and AS.

Reply

In their comments on our recently published paper on the genome-wide association study of leprosy (N Engl J Med 2009;361:2609–2618), Watanabe and Chiba reviewed some existing experimental findings that are either supportive or objective for the molecular linkage between Leprosy and Crohn's disease (CD). Although they do recognize that leprosy and CD might share genetic signatures in innate immunity, they question the notion that the increased susceptibility to mycobacterial infections facilitates the development of CD in patients carrying NOD2 mutations. We agree that it is too early to claim that the same causal risk variants increase the susceptibility to both leprosy and CD, because causal variants for leprosy susceptibility within NOD2 are yet to be identified, and NOD2 causal variants for CD have not been shown to increase the susceptibility to mycobacterial infection. Furthermore, it is also worth pointing out that the association between NOD2 polymorphisms and CD has not been established in the Asian population (Gastroenterology 2002;123:86–91; Eur J Human Genet 2003;11:6–16; World J Gastroenterol 2008;14:4923–4927); and the association of NOD2 polymorphisms with leprosy has not been replicated in other populations (N Engl J Med 2010;362:1446–1447). Ethnic heterogeneity of genetic susceptibility to CD and leprosy has further complicated the interpretation of the shared genetic signatures in inner immunity between CD and leprosy. We also want to point out that, beside NOD2 and TNFSF15, C13orf31/CCDC122 at 13q14.11 has also been shown to be a susceptibility locus for CD (Nat Genet 2008;40:955–962), further enhancing the shared genetic signature between the 2 diseases. Functions of C13orf31 and CCDC122 are both unknown. Biological investigation of these genes will likely further illuminate the molecular linkage between the 2 diseases. Last, we want to comment that, although Toll-like receptor signaling, rather than NOD2 signaling, might be important for host defense against M tuberculosis (which is still debatable), NOD2 signaling clearly plays a very important role in host defense against M leprae, and our genome-wide association study of leprosy failed to reveal any association evidence within Toll-like receptor genes (N Engl J Med 2010;362:1446–1447). Card15 Polymorphisms in the Immunopathogenesis of Crohn's Disease and Mycobacterial Infectious DiseasesGastroenterologyVol. 139Issue 6PreviewZhang FR, Huang W, Chen SM, et al. Genomewide association study of leprosy. N Engl J Med 2009;361:2609–2618. Full-Text PDF

Genome-wide Profiling of Interleukin-4 and STAT6 Transcription Factor Regulation of Human Th2 Cell Programming

Dissecting the molecular mechanisms by which T helper (Th) cells differentiate to effector Th2 cells is important for understanding the pathogenesis of immune-mediated diseases, such as asthma and allergy. Because the STAT6 transcription factor is an upstream mediator required for interleukin-4 (IL-4)-induced Th2 cell differentiation, its targets include genes important for this process. Using primary human CD4(+) T cells, and by blocking STAT6 with RNAi, we identified a number of direct and indirect targets of STAT6 with ChIP sequencing. The integration of these data sets with detailed kinetics of IL-4-driven transcriptional changes showed that STAT6 was predominantly needed for the activation of transcription leading to the Th2 cell phenotype. This integrated genome-wide data on IL-4- and STAT6-mediated transcription provide a unique resource for studies on Th cell differentiation and, in particular, for designing interventions of human Th2 cell responses.