Junji Umeno

A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population

Ulcerative colitis is one of the principal forms of inflammatory bowel disease with complex manifestations. Although previous studies have indicated that there is a genetic contribution to the pathogenesis of ulcerative colitis, the genes influencing susceptibility to the disease have not been fully determined. To identify genetic factors conferring risk of ulcerative colitis, here we conducted a two-stage genome-wide association study and subsequent replication study using 1,384 Japanese individuals with ulcerative colitis and 3,057 control subjects. In addition to the expected strong association with the major histocompatibility complex (MHC) region, we identified three new susceptibility loci: the immunoglobulin receptor gene FCGR2A (rs1801274, P = 1.56 × 10−12), a locus on chromosome 13q12 (rs17085007, P = 6.64 × 10−8) and the glycoprotein gene SLC26A3 (rs2108225, P = 9.50 × 10−8). rs1801274 is a nonsynonymous SNP of FCGR2A that is reported to have a critical effect on receptor binding affinity for IgG and to be associated with other autoimmune diseases. Our findings provide insight into the molecular pathogenesis of ulcerative colitis.

A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population.

BACKGROUND & AIMS Crohns disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohns disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohns disease in the Japanese population. METHODS We performed a genome-wide association study with 372 individuals with Crohns disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohns disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. RESULTS We confirmed associations of Crohns disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10(-11); odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10(-9); odds ratio, 1.27). CONCLUSIONS In a genome-wide association study, we identified 2 new susceptibility loci for Crohns disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohns disease.

Meta‐analysis of published studies identified eight additional common susceptibility loci for Crohn's disease and ulcerative colitis

Background: Both ulcerative colitis (UC) and Crohns 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. Methods: 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. Results: 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. Conclusions: 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.

HLA-Cw*1202-B*5201-DRB1*1502 Haplotype Increases Risk for Ulcerative Colitis but Reduces Risk for Crohn's Disease

BACKGROUND & AIMS There are many genetic factors that are associated with both ulcerative colitis (UC) and Crohns disease (CD). However, genetic factors that have distinct effects on UC and CD have not been examined. METHODS We performed a comparative genome-wide association study (GWAS) and a replication study using data from 748 patients with UC and 979 with CD, selected from a Japanese population. We conducted high-resolution (4-digit) genotyping of human leukocyte antigen (HLA) alleles in patients with UC and CD and additional 905 healthy individuals (controls). We performed haplotype-based analysis using data from the GWAS and HLA alleles to associate them with UC or CD. RESULTS The comparative GWAS and the replication study identified significant associations in the major histocompatibility complex region at 6p21 with UC and CD (rs9271366, P = 1.6 × 10⁻⁷⁰; odds ratio [OR] = 4.44). Haplotype-based analysis in the major histocompatibility complex region showed that HLA-Cw*1202-B*5201-DRB1*1502 haplotype was significantly associated with increased risk of UC compared with CD (P = 1.1 × 10⁻³³; OR = 6.58), accounting for most of the associations observed in the GWAS. Compared with the controls, this HLA haplotype significantly increases susceptibility to UC (P = 4.0 × 10⁻²¹; OR = 2.65), but reduces risk for CD (P = 1.1 × 10⁻⁷; OR = 0.40). Distinct effects of this HLA haplotype on UC and CD were independent of other HLA alleles and haplotypes (P = 2.0 × 10⁻¹⁹ and P = 7.2 × 10⁻⁵, respectively). CONCLUSIONS The HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases susceptibility to UC but reduces risk for CD, based on a GWAS of a Japanese population.

Association study of 71 European Crohn's disease susceptibility loci in a Japanese population.

Background:A large-scale meta-analysis of a series of European genome-wide association studies revealed 71 susceptibility loci for Crohns disease (CD). However, it is not clear whether these susceptibility loci are also shared with Japanese populations. Methods:We genotyped 71 single-nucleotide polymorphisms (SNPs) comprising 1311 CD cases and 6585 controls of Japanese descent, and their associations with CD were evaluated using the Cochran–Armitage trend test. In addition, genotype–phenotype analyses were conducted on the SNPs showing associations with Japanese CD based on the Montreal classification. Results:Twenty-seven SNPs showed at least nominal association (P < 0.05) and 11 of them remained significant even after Bonferroni correction (P < 0.0007). Despite high statistical power, we could not find any association in 17 loci. Moreover, SNPs in 9 loci were rare or absent in the Japanese population. Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population. Genotype–phenotype analyses showed that rs3810936, a marker of TNFSF15, correlated with severe CD phenotypes. Conclusions:Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations.

Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis.

BACKGROUND Although some cases of collagenous colitis have been induced by lansoprazole (LPZ), the clinicopathologic features of LPZ-associated collagenous colitis have not been elucidated. OBJECTIVE To elucidate the clinical, endoscopic, and histopathologic features of LPZ-associated collagenous colitis. DESIGN Retrospective case study. PATIENTS The subjects were 13 patients with collagenous colitis diagnosed during a period from 2002 to 2007. MAIN OUTCOME MEASUREMENTS The colonoscopic and histopathologic findings were compared retrospectively between 9 cases of LPZ use (LPZ group) and 4 cases without the use of LPZ (non-LPZ group). RESULTS A colonoscopy revealed a linear mucosal defect more frequently in the LPZ group (7 of 9 cases [78%]) than in the non-LPZ group (0 of 4 cases [0%], P = .02). Friable mucosa was also noted in 4 patients (44%) in the LPZ group but none in the non-LPZ group. The colonoscopic finding in the non-LPZ group was either normal mucosa or nonspecific minimal abnormalities, whereas patients in the LPZ group had either a linear mucosal defect, mucosal bleeding, or both (P = .001). On histologic examination, the subepithelial collagen band was thicker in patients in the LPZ group than in those in the non-LPZ group (median 45 vs 26.3 mum). All patients in the LPZ group recovered from diarrhea after discontinuance of LPZ. LIMITATION A small number of patients. CONCLUSIONS Linear mucosal defects and friable mucosa may be characteristic colonoscopic findings in cases of LPZ-associated collagenous colitis.

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS).

Association study of the polymorphisms on chromosome 12p13 with atherothrombotic stroke in the Japanese population

Recent genome-wide association study using four prospective population-based cohorts identified two single-nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579, to be significantly associated with the incidence of atherothrombotic stroke. To examine the association of these SNPs with atherothrombotic stroke in the Japanese population, we carried out a case–control association study using a total of 3784 cases and 3102 controls. We also examined the effect of these SNPs on the subtypes of ischemic stroke. Association analysis was carried out using logistic regression model after adjustment of age, sex and cardiovascular risk factors. Rs12425791 was significantly associated with atherothrombotic stroke (P=0.0084, odds ratio (OR)=1.15). When we analyzed effects of rs12425791 on ischemic stroke subtypes, rs12425791 was significantly associated with both small-artery occlusion (P=0.015, OR=1.15) and large-artery atherosclerosis (P=0.024, OR=1.19). Rs11833579 showed no association with atherothrombotic stroke or its subtypes in our population. Our data suggest that rs12425791 on chromosome 12p13 is a genetic marker for atherothrombotic stroke in multiethnic population.

Gastric MALT lymphoma with t(14;18)(q32;q21) involving IGH and BCL2 genes that responded to Helicobacter pylori eradication

Four recurrent chromosomal translocations are recognised in mucosa-associated lymphoid tissue (MALT) lymphomas: t(11;18)/ API2-MALT1 , t(1;14)/ IGH - BCL10 , t(14;18)/ IGH - MALT1 and t(3;14)/ IGH - FOXP1 . In contrast, t(14;18)/ IGH - BCL2 , the genetic hallmark of follicular lymphoma, has been observed in only rare cases of MALT lymphoma. Oesophagogastroduodenoscopy revealed an ulcer in erythematous granular mucosa at the gastric corpus in a 55-year-old man. A diagnosis of MALT lymphoma was made on the basis of typical histological and immunohistochemical features of biopsy specimens: a diffuse infiltrate of centrocyte-like cells surrounding reactive lymphoid follicles and forming lymphoepithelial lesions, and a CD20+, IgD−, CD5−, CD10−, Bcl6−, cyclinD1− immunophenotype. Four months after the successful eradication of Helicobacter pylori , there was endoscopic regression with probable minimal residual disease detected by biopsy, but histological relapse was recognised 12 months after eradication. Interphase fluorescence in situ hybridisation revealed t(14;18)/ IGH-BCL2 , but not the translocations typically seen in MALT lymphoma. This is the first report of a gastric MALT lymphoma with t(14;18)/ IGH-BCL2 that responded to H pylori eradication. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is genetically characterised by the recurrent translocations t(11;18)(q21;q21)/ API2 - MALT1 , t(1;14)(p22;q32)/ BCL10 - IGH , t(14;18)(q32;q21)/ IGH - MALT1 and t(3;14)(p14;q32)/ FOXP1-IGH .1 2 Recent evidence suggests that at least some of these translocations may be associated with distinct clinicopathological features.1 3 The t(14;18)(q32;q21)/ IGH - BCL2 is found in the majority of follicular lymphomas and some diffuse large B-cell lymphomas.4 However, MALT lymphomas carrying this translocation are extremely rare and their clinical features are virtually unknown. A 55-year-old asymptomatic man underwent oesophagogastroduodenoscopy (OGD) as screening for gastric carcinoma. OGD revealed an open ulcer with surrounding granular erythematous mucosa in the upper corpus (fig 1A …

Impact of group IVA cytosolic phospholipase A2 gene polymorphisms on phenotypic features of patients with familial adenomatous polyposis

ObjectiveGroup IVA cytosolic phospholipase A2 (cPLA2α) plays a key role in tumorigenesis via generating arachidonic acids as the substrate of cyclooxygenase. The aim of this study was to elucidate the possible associations between cPLA2α gene polymorphisms and phenotypic features of patients with familial adenomatous polyposis (FAP).Patients and MethodsA tag single nucleotide polymorphisms (SNPs)-based genotype–phenotype association study of the cPLA2α gene was conducted in 73 Japanese patients from 59 families with FAP. Based on the HapMap database, seven tag SNPs of the cPLA2α gene were selected and genotyped by direct sequencing analysis. The genotype–phenotype association in relation to the adenomatous polyposis coli (APC) gene mutation was also assessed.ResultsThe single SNP analysis showed that rs3820185 C allele [odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2–4.9] and rs127446200 GG genotype (OR, 10.9; 95%CI, 1.6–69.8), were more frequent in patients with gastric fundic gland polyposis (FGP) than in those without. Rs12749354 C allele was more frequently found in patients with small intestinal adenoma (OR, 7.0; 95% CI, 1.5–30.4; p = 0.008). This association was also significant when adjusted for covariates (age, sex, and APC mutation) in a logistic regression analysis (adjusted OR, 7.4; 95% CI, 1.2–64.2; p = 0.027).ConclusionsThe cPLA2α gene may be a possible disease modifier gene in FAP.