BACKGROUND/AIMS: The aim of this study was to identify the profile of rare variants associated with Crohn's disease (CD) using whole exome sequencing (WES) analysis of Korean children with CD and to evaluate whether genetic profiles could provide information during medical decision making. METHODS: DNA samples from 18 control individuals and 22 patients with infantile, very-early and early onset CD of severe phenotype were used for WES. Genes were filtered using panels of inflammatory bowel disease (IBD)-associated genes and genes of primary immunodeficiency (PID) and monogenic IBD. RESULTS: Eighty-one IBD-associated variants and 35 variants in PID genes were revealed by WES. The most frequently occurring variants were carried by nine (41%) and four (18.2%) CD probands and were ATG16L2 (rs11235604) and IL17REL (rs142430606), respectively. Twenty-four IBD-associated variants and 10 PID variants were predicted to be deleterious and were identified in the heterozygous state. However, their functions were unknown with the exception of a novel p.Q111X variant in XIAP (X chromosome) of a male proband. CONCLUSIONS: The presence of many rare variants of unknown significance limits the clinical applicability of WES for individual CD patients. However, WES in children may be beneficial for distinguishing CD secondary to PID.
Asian Continental Ancestry Group/genetics ; Carrier Proteins/genetics ; Child ; Child, Preschool ; Crohn Disease/*genetics ; *Exome ; Female ; Genetic Predisposition to Disease ; *Genetic Variation ; Humans ; Immunologic Deficiency Syndromes/genetics ; Infant ; Male ; Phenotype ; Receptors, Interleukin-17/genetics ; Republic of Korea ; Sequence Analysis, DNA/*methods ; X-Linked Inhibitor of Apoptosis Protein/genetics

OBJECTIVETo assess the association of inflammatory bowel disease with polymorphisms and haplotypes of Fucosyltransferase 3 (FUT3) gene.

METHODSA total of 389 patients with ulcerative colitis (UC), 274 patients with Crohn's disease (CD), and 492 controls were collected. Three single nucleotide polymorphisms (SNPs) of the FUT3 gene (rs28362459, rs3745635 and rs3894326) were determined by direct sequencing. Linkage disequilibrium and haplotype analysis were performed using a Haploview 4.2 software.

RESULTSCompared with the controls, the allele and genotype distributions of FUT3 gene did not significantly differ between the UC and CD groups (all P>0.05). By stratified analysis, the mutant allele (A) and genotype (GA+AA) of the FUT3 gene (rs3745635) were significantly increased in the UC group with distal colitis compared with the controls (P<0.01, P<0.05, respectively). The mutant allele (G) and genotype (TG+GG) of the FUT3 gene (rs28362459) as well as the mutant allele (A) of FUT3(rs3745635) were significantly increased in patients with ileocolonic CD and ileal CD as compared with the controls (P<0.05, P<0.01, P<0.05, respectively). The frequency of mutant allele (G) of FUT3(rs28362459) was higher in stricturing CD patients than in the controls (P<0.05). In addition, the three polymorphic loci of FUT3 gene were shown in complete linkage disequilibrium [rs3894326/rs3745635 (D'=1.0, r2=0.017), rs3894326/rs28362459 (D'=0.937, r2=0.311), rs3745635/rs28362459 (D'=0.944, r2=0.448)]. However, the frequency of each haplotype was not significantly different between the UC and CD groups compared with the controls (all P>0.05).

CONCLUSIONFUT3 (rs3745635) mutation may increase the risk of distal colitis. FUT3 (rs28362459 and rs3745635) mutations may engender the increased risk of ileocolonic and ileal CD. Moreover, FUT3 (rs28362459) polymorphism may influence the incidence of stricturing CD.

Adult ; Alleles ; Colitis, Ulcerative ; enzymology ; genetics ; Crohn Disease ; enzymology ; genetics ; Female ; Fucosyltransferases ; genetics ; Gene Frequency ; Genetic Predisposition to Disease ; genetics ; Genotype ; Haplotypes ; Humans ; Inflammatory Bowel Diseases ; enzymology ; genetics ; Linkage Disequilibrium ; Logistic Models ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA ; Young Adult

OBJECTIVETo assess the associations of death receptor DR4 and DR5 gene polymorphisms with Crohn's disease (CD).

METHODSA total of 295 CD patients and 490 healthy controls were recruited. Three single nucleotide polymorphisms (SNPs) of the DR4 (rs13278062, rs20575) and DR5 (rs1047266) genes were determined with a SNaPshot method. Unconditional logistic regression analysis was carried out for determining the allelic and genotypic differences of the three SNPs between CD patients and the controls, as well as the influence of the DR4 and DR5 gene polymorphisms on the clinical features of CD patients. Linkage disequilibrium and haplotype analysis were calculated by haplotype 4.2 and R language software. A gene-gene interaction model was established to analyze whether the three SNPs can exert a synergistic effect on the susceptibility to CD.

RESULTSThe mutant allele (T) and genotype (GT+TT) of DR4 (rs13278062) were increased among CD patients compared to the controls (37.12% vs. 32.04%, P = 0.040, 95%CI: 1.010-1.550; 62.71% vs. 54.90%, P = 0.032, 95%CI: 1.028-1.855, respectively). However, the allelic and genotypic frequencies of DR4 (rs20575) and DR5 (rs1047266) did not differ between the two groups (all P > 0.05). Based on the Montreal Classification Standards, the CD patients were stratified by locations and behaviors of the disease. After multiple comparison correction (P < 0.0125), compared to ileocolonic CD patients respectively, the mutant allele (T) and genotype (GT+TT) of the rs13278062 polymorphism were significantly increased in colonic CD patients (41.04% vs. 25.64%, P = 0.002, 95%CI: 0.315-0.778; 66.04% vs. 41.03%, P = 0.001, 95%CI: 0.196-0.655, respectively) and terminal ileum CD patients (41.44% vs. 25.64%, P = 0.002, 95%CI: 0.311-0.762; 74.77% vs. 41.03%, P < 0.001, 95%CI: 0.126-0.437, respectively). In comparison to penetrating CD patients, the mutant allele (T) and genotype (GT+TT) of DR4 (rs13278062) were significantly decreased in stricturing CD patients (32.29% vs. 48.91%, P = 0.007, 95%CI: 0.300-0.828; 57.29% vs. 86.96%, P = 0.001, 95%CI: 0.078-0.520, respectively). A similar conclusion was drawn for the mutant genotype (GT+TT) of DR4 (rs13278062) in non-stricturing, non-penetrating CD patients (58.82% vs. 86.96%, P = 0.001, 95%CI: 0.086-0.536). Haplotype analysis indicated that the CT haplotype formed by rs20575 and rs13278062 was increased in CD patients compared to the controls (37.1% vs. 31.8%, P = 0.029, OR=1.279, 95%CI: 1.022-1.600). The outcome of a gene-gene interaction model indicated that the mutant genotype (GT+TT) of DR4 (rs13278062) and mutant genotype (CT+TT) of DR5 (rs1047266) may play a negatively synergistic role in CD patients (B = - 0.483, OR = 0.617, P = 0.030).

CONCLUSIONThe rs13278062 polymorphism of the DR4 gene not only can confer an increased risk for CD, but may also influence the location of the lesions and the disease behaviors. The CT haplotype formed by rs20575 and rs13278062 may be an independent risk factor for CD. Furthermore, the mutant genotype (GT+TT) of DR4 (rs13278062) and mutant genotype (CT+TT) of DR5 (rs1047266) may exert a negative synergistic effect on CD.

Adult ; Crohn Disease ; genetics ; Epistasis, Genetic ; Female ; Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; genetics

OBJECTIVETo investigate the association between TaqI, BsmI, and ApaI polymorphisms of vitamin D receptor (VDR) gene and pediatric Crohn's disease (CD) in China.

METHODSNineteen children with CD were selected as a case group, and 122 healthy children who underwent physical examination were selected as a control group. Serum 25-hydroxyvitamin D3 [25(OH)D3] levels were measured using ELISA. The TaqI, BsmI, and ApaI polymorphisms of VDR gene were determined by gene sequencing, and the two groups were compared in terms of genotype and allele frequencies.

RESULTSThe case group had significantly lower serum 25(OH)D3 levels than the control group (17.3±2.4 ng/mL vs 26.9±2.1 ng/mL; P<0.05). There were no significant differences in the frequencies of genotypes and alleles of TaqI, BsmI, and ApaI polymorphisms between the case and control groups (P>0.05).

CONCLUSIONSChildren with CD have low serum 25(OH)D3 levels. TaqI, BsmI, and ApaI polymorphisms of VDR gene may not be associated with susceptibility to CD among the Chinese population.

Adolescent ; Calcifediol ; blood ; Child ; Child, Preschool ; Crohn Disease ; blood ; genetics ; Female ; Humans ; Male ; Polymorphism, Single Nucleotide ; Receptors, Calcitriol ; genetics ; Sequence Analysis, DNA

Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized by multiple gastrointestinal hamartomatous polyps and mucocutaneous pigmentation. Peutz-Jeghers syndrome has an incidence of approximately 1 in 25,000 to 300,000 births. Crohn's disease is a chronic inflammatory bowel disease that typically manifests as regional enteritis with its incidence ranging from 3.1 to 14.6 cases per 100,000 person-years in North America. Herein, we report a case of a 30-year-old male patient who had both Peutz-Jeghers syndrome and Crohn's disease. We believe that this is the first case in Korea and the second report in the English literatures on Peutz-Jeghers syndrome coincidentally accompanied by Crohn's disease.
Adult ; Crohn Disease/complications/*diagnosis/pathology ; Endoscopy, Gastrointestinal ; Humans ; Intestinal Obstruction/etiology ; Intestinal Perforation/etiology ; Intestinal Polyps/pathology/surgery ; Male ; Peutz-Jeghers Syndrome/complications/*diagnosis/genetics ; Protein-Serine-Threonine Kinases/genetics

Herpes simplex virus (HSV) is a recognized cause of gastrointestinal infection in immunodeficient patients. Although a few cases of HSV gastritis and colitis in immunocompromised patients have been reported, there are no reports of HSV duodenitis in patients with Crohn's disease (CD). A 74-year-old female was admitted with general weakness and refractory epigastric pain. She had been diagnosed with CD three years ago. Esophagogastroduodenoscopy (EGD) revealed diffuse edematous and whitish mucosa with multiple erosions in the duodenum. Considering the possibility of viral co-infection, cytomegalovirus (CMV) immunohistochemical staining, PCR, and cultures of duodenal biopsies were performed, all of which were negative with the exception of the isolation of HSV in culture. After administration of intravenous acyclovir for 1 week, follow-up EGD showed almost complete resolution of the lesions and the patient's symptoms improved. In CD patients with refractory gastrointestinal symptoms, HSV, as well as CMV, should be considered as a possible cause of infection, so that the diagnosis of viral infection is not delayed and the appropriate antiviral treatment can be initiated.
Acyclovir/therapeutic use ; Aged ; Antiviral Agents/therapeutic use ; Crohn Disease/complications/*diagnosis/virology ; DNA, Viral/analysis ; Duodenitis/complications/*diagnosis ; Endoscopy, Digestive System ; Female ; Herpes Simplex/*diagnosis/drug therapy/virology ; Humans ; Intestinal Mucosa/pathology ; Polymerase Chain Reaction ; Simplexvirus/genetics/*isolation & purification

The innate immune response in patients who develop inflammatory bowel disease (IBD) may be abnormal. However, the exact role of Toll-like receptors (TLRs) / CD14 gene in the pathogenesis of IBD has not been fully elucidated. We aimed to investigate the association between polymorphisms of TLR1, 2, 4, 6, and CD14 gene and susceptibility to IBD in Korean population. A total 144 patients of IBD (99 patients with ulcerative colitis, 45 patients with Crohn's disease) and 178 healthy controls were enrolled. Using a PCR-RFLP, we evaluated mutations of TLR1 (Arg80Thr), TLR2 (Arg753Gln and Arg677Trp), TLR4 (Asp299Gly and Thr399Ile), TLR6 (Ser249Pro) genes and the -159 C/T promoter polymorphism of CD14 gene. No TLR polymorphisms were detected in Korean subjects. T allele and TT genotype frequencies of CD14 gene were significantly higher in IBD patients than in healthy controls. In subgroup analysis, T allelic frequency was higher in pancolitis phenotype of ulcerative colitis. In Korean population, the promoter polymorphism at -159 C/T of the CD14 gene is positively associated with IBD, both ulcerative colitis and Crohn's disease.
Adult ; Aged ; Alleles ; Antigens, CD14/*genetics ; Asian Continental Ancestry Group/*genetics ; Colitis, Ulcerative/genetics ; Crohn Disease/genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Inflammatory Bowel Diseases/*genetics ; Male ; Middle Aged ; Phenotype ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Republic of Korea ; Toll-Like Receptor 1/genetics ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 6/genetics ; Toll-Like Receptors/*genetics

OBJECTIVETo observe the effects of Huangqi Jiegeng Decoction (HJD) and Huangqi Huanglian Decoction (HHD) on the intercellular adhesion molecule-I (ICAM-1) content in the lung and colon of rats with Crohn's disease (CD).

METHODSTotally 56 rats were used to establish the CD rat model using TNBS water solution/absolute alcohol enema (with the model successful rate of 63.0%). Seven rats randomly selected from 35 successfully modeled rats and from the normal group were recruited as the model group and the normal group before intervention. The rest 28 successfully modeled rats were randomly divided into the model group, the Western medicine group (treated with salazosulfapyridine at 0.4 g/kg), the HJD group (20.5 g/kg), and the HHD group (20.8 g/kg), 7 in each group. Another 7 normal rats were recruited as the normal group. Equal volume of pure water was given to rats in the normal group and the model group by gastrogavage, twice daily, for 3 successive weeks. The protein and mRNA expressions of ICAM-1 in the lung and colon tissues were determined before and after intervention using Western blot and RT-PCR.

RESULTSCompared with the normal control group, the protein and mRNA levels of ICAM-1 in the colon tissue, and the mRNA level of ICAM-1 in the lung tissue increased (P< 0.01, P<0.05). After intervention the protein and mRNA levels of ICAM-1 in the colon tissue and the lung tissue increased (P<0.01) in the model group. Compared with the model group at the same time point, the protein and mRNA levels of ICAM-1 in the colon tissue and the lung tissue decreased in each medication group after intervention (P<0.01, P<0.05). Compared with the Western medicine group, the protein level of ICAM-1 in the lung tissue decreased more significantly in the HJD group (P<0.05). The protein level of ICAM-1 in the colon tissue also decreased in the HHD group (P<0.05).

CONCLUSIONSHHD and HJD both could down-regulate the over-expressed ICAM-1 in the lung and colon tissues of CD rats. HHD was prominent in inhibiting the adherence of colonic inflammatory cells and attenuating local immunopathological injury. HJD was prominent in attenuating inflammation and injury in the lung, and preventing pulmonary fibrosis.

Animals ; Colon ; metabolism ; Crohn Disease ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Intercellular Adhesion Molecule-1 ; genetics ; metabolism ; Lung ; metabolism ; Male ; RNA, Messenger ; genetics ; Rats ; Rats, Wistar

Although the incidence and prevalence rates of IBD in Korea are still lower than Western populations, they have been increasing rapidly during the past decades. Crohn's disease (CD) tends to run in families because it is thought to be related to genetic susceptibility coupled with environmental factors. A large number of monozygotic and dizygotic twin pairs with inflammatory bowel disease have been reported in western countries. The population relative risk in first-degree relatives is considered to be about equal in both Koreans and westerners. To our best knowledge, there is no report in monozygotic twins with CD in Korea. This case report is the first documented occurrence of concordant CD occurring in monozygotic twins in Korea.
Adolescent ; Antimetabolites/therapeutic use ; Azathioprine/therapeutic use ; Colonoscopy ; Crohn Disease/*diagnosis/drug therapy/genetics ; Diseases in Twins/*diagnosis/drug therapy/genetics ; Humans ; Male ; Pedigree ; Tomography, X-Ray Computed ; Twins, Monozygotic/*genetics

Although the incidence and prevalence rates of IBD in Korea are still lower than Western populations, they have been increasing rapidly during the past decades. Crohn's disease (CD) tends to run in families because it is thought to be related to genetic susceptibility coupled with environmental factors. A large number of monozygotic and dizygotic twin pairs with inflammatory bowel disease have been reported in western countries. The population relative risk in first-degree relatives is considered to be about equal in both Koreans and westerners. To our best knowledge, there is no report in monozygotic twins with CD in Korea. This case report is the first documented occurrence of concordant CD occurring in monozygotic twins in Korea.
Adolescent ; Antimetabolites/therapeutic use ; Azathioprine/therapeutic use ; Colonoscopy ; Crohn Disease/*diagnosis/drug therapy/genetics ; Diseases in Twins/*diagnosis/drug therapy/genetics ; Humans ; Male ; Pedigree ; Tomography, X-Ray Computed ; Twins, Monozygotic/*genetics