Sporadic Crohn's Disease Patients Research Articles

P1109 Differences of Clinical Phenotype Between Familial and Sporadic Crohn's Disease in East China

Abstract Background Family history is one of the strongest risk factors for Crohn's disease (CD) while few studies have focused on whether family history influences the clinical features, disease course, and severity of CD. There is still controversy about the difference between sporadic and familial CD. This study aimed to compare the phenotypic features of familial CD with sporadic CD in Chinese populations. Methods We included 2,043 patients diagnosed with CD. Familial CD was defined as CD patients having one or more first-, second-, third-, fourth-degree or above relatives with CD. Sporadic CD patients hospitalized during the same period were matched 1:3 by age and gender. Differences in clinical characteristics, phenotype distributions, extra-intestinal manifestations, and complications at diagnosis, as well as treatment regimens and surgeries, were compared between familial and sporadic CD. Results A total of 55 familial CD and 165 sporadic CD were identified. The familial CD was associated with a higher rate of past appendectomy history (20.00% vs 6.67%, P=0.009), more intestinal perforation at onset (12.73% vs 3.03%, P=0.012), more anal lesion (85.45% vs 68.48%, P=0.023) and gastrointestinal perforation (14.55% vs 5.45%, P=0.040) at diagnosis, higher rate of past intestinal surgery history (50.91% vs 29.70%, P=0.007), more number of intestinal surgeries (1.50[IQR 1.00-2.00] vs 1.00[IQR 1.00-1.00], P=0.037), longer duration of follow-up (54.00 months[IQR 21.50-125.00] vs 41.00 months[IQR 14.00-79.00], P=0.017), lower rate of taking biologicals for current maintenance (61.82% vs 76.97%, P=0.043), lower tendency to upgrade to biologicals during follow-up (69.09% vs 85.37%, P=0.013), higher possibility to experience gastrointestinal obstruction (23.64% vs 11.52%, P=0.047) and abdominal abscess during follow-up (9.09% vs 2.42%, P=0.045). Conclusion Familial CD is associated with a more aggressive clinical phenotype compared with sporadic CD.

ELISA Serology for Antibodies Against Chlamydia trachomatis in Crohn's Disease.

BackgroundRecently we reported IgA anti-Chlamydia antibodies in patients with Crohn’s disease (CD), in particular in four patients from a single family of six with CD.MethodsWe studied sera from four cohorts from the north of France. These were identified as: EPIMAD (80 pediatric onset CD and 20 pediatric onset ulcerative colitis), MINOTOR (148 adult onset sporadic CD and 50 adult onset ulcerative colitis), Grande Famillies (50) and matched controls for the Grande Famillies cohort (49). Sera were tested using commercial anti-Chlamydia trachomatis (LGV2:434) IgG and IgA human enzyme-linked immunosorbent assay (ELISA) kits. Cutoff for positivity was 11.0 standard units.ResultsPatients with sporadic CD, unaffected first degree relatives from multiplex families and ulcerative colitis patients had no greater serologic reactivity than controls. However, multiplex families’ patients had twice as many positives as the other groups: for IgG 20% vs. 8%; for IgA 20% vs. 10%.ConclusionsThough not attaining statistical significance, the data showed that familial CD patients had greater exposure to C. trachomatis than sporadic CD patients, supporting our earlier results from one family from the north of France. More specific serologic tests based on outer membrane proteins will need to be employed against the various Chlamydia species with zoonotic potential.

Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study.

BackgroundGenetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.MethodsExome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.ResultsFrom the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play mutiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1. ConclusionsWe have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

Similar clinical characteristics of familial and sporadic inflammatory bowel disease in South Korea

To investigate differences of clinical characteristics and disease courses between familial and sporadic inflammatory bowel disease (IBD) patients. We obtained clinical data on Crohn's disease (CD) (n = 691) and ulcerative colitis (n = 1113) from a tertiary referral medical center between 2005 and 2012. Seventeen patients (2.5%) with CD and 27 patients (2.4%) with ulcerative colitis (UC) were identified as having a familial history of IBD, including the first and second degree relatives. For each control case, three times the number of age-, sex-, and diagnosis year-matched CD and UC patients, without a family history of IBD, were randomly selected in this case control study. There were no significant differences in age or main symptom at diagnosis, extraintestinal manifestation, location/extent, behavior of disease activity, number of hospitalizations, number of operations, operation type, number of relapses, or oral medical treatment between familial and sporadic CD and UC patients. Median (min-max) follow-up periods after diagnosis of familial CD and sporadic CD patients were 84 (24-312) and 36 (8-240) mo, respectively (P = 0.008). Familial CD patients more frequently used anti-tumor necrosis factor (TNF) antibodies compared to sporadic CD patients (17.6% vs 0%, P = 0.014). In conclusion, a family history of IBD does not seem to be an important predictive factor affecting clinical characteristics or disease course even if there is a more frequent use of anti-TNF antibodies in familial CD patients compared to sporadic CD patients.

Variants of CARD15 are Associated with an Aggressive Clinical Course of Crohn's Disease-An IG-IBD Study

Three major variants of the CARD15 gene confer susceptibility to Crohn's disease (CD). Whether or not these variants correlate with specific clinical features of the disease is under evaluation. We investigated the possible association of CARD15 variants with specific clinical characteristics, including the occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), in a large cohort of inflammatory bowel disease (IBD) patients and their unaffected relatives. Three hundred and sixteen CD patients (156 with positive family history), 408 ulcerative colitis (UC) patients (206 with positive family history), 588 unaffected relatives, and 205 unrelated healthy controls (HC) were studied. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated and correlated to age at diagnosis, gender, family history, localization, extraintestinal manifestations, previous resective surgery, stenosing/fistulizing pattern, ANCA, and ASCA. Compared to HC, the frequencies of all three variants in CD were significantly increased: 8.7% versus 4.1% for R702W (p < 0.006), 7.3% versus 2.7% for G908R (p < 0.002), 9.3% versus 0.7% for L1007finsC (p < 0.00001). At least one risk allele was found in 38.2% (p < 0.0001, compared to HC), 13.7% (NS), and 15.1% of CD, UC, and HC, respectively. The L1007finsC risk allele was also significantly increased in unaffected relatives of familial (9.5%; p < 0.00001), and sporadic CD (9%; p < 0.00001), compared to HC (0.7%). Sixteen healthy relatives, carriers of two risk alleles, were asymptomatic after 5-8 yr of follow-up. CD carriers of at least one variant were younger (p= 0.03), more likely to have ileal localization (p= 0.0001), stenosing pattern (p= 0.01), previous resective surgery (p= 0.0001), and presence of ASCA (p= 0.0001). No difference in SNPs frequency between familial and sporadic cases of CD was found. In our population, both familial and sporadic CD patients carrying at least one major variant of CARD15 had an aggressive clinical course.

Variation at NOD2/CARD15 in familial and sporadic cases of Crohn's disease in the Ashkenazi Jewish population.

Recent reports indicate that allelic variants in NOD2/CARD15 are associated with Crohn's disease (CD) susceptibility, and that homozygosity or compound heterozygosity at this locus for any of three recently defined sequence variants confers a greatly increased risk of CD. These sequence changes include two missense mutations, R702W and G908R, and a frameshift insertion, 1007insC. The aim of this study was to determine the frequency of these NOD2/CARD15 variants in familial and sporadic CD patients in the Ashkenazi population and to determine their effects on disease susceptibility and age of disease onset (AOO). Allele and genotype frequencies of these three variants were determined in 481 CD patients of Jewish descent and 110 Jewish controls; 169 patients had a family history of CD, and 312 were "sporadic" cases. Variants were detected by polymerase chain reaction using allele-specific primers labeled with fluorescent dye. Familial cases had a significantly higher frequency of the G908R variant than sporadic cases (0.127 vs 0.059, p = 0.0003) and correspondingly, a significantly higher proportion of homozygotes and compound heterozygotes (11.8% vs 4.5%, p = 0.0027). Homozygotes and compound heterozygotes had an OR for CD of 14.6 for familial cases and 5.1 for sporadic cases. There was no increased risk of CD for simple heterozygotes. The AOO was significantly lower for CD patients who were homozygotes and compound heterozygotes for NOD2/CARD15 (17.5 vs 22.4 yr, p = 0.04), but only for familial cases. NOD2/CARD15 contributes more to CD susceptibility in familial cases than in sporadic cases, and to an earlier AOO. There is no increased risk of CD for individuals carrying only a single copy of these NOD2/ CARD15 variants, whereas individuals carrying two copies have a 5-15-fold increased risk. The penetrance of the NOD2/CARD15 mutations was estimated at less than 1%.

The relationship between heritability and smoking habits in Crohn's disease. Italian Cooperative Study Group.

In Crohn's disease (CD), the relationship between genetic predisposition and smoking has not been well defined. The aim of this study was to compare the smoking habits at the time of the diagnosis of CD patients having familial occurrence of inflammatory bowel disease (IBD) with those of some control groups. In a multicenter study, 136 CD patients with a relative with IBD, 272 healthy controls matched for sex and age, 500 CD patients without familial occurrence of IBD, and 84 ulcerative colitis patients (UC) with familial occurrence of IBD were personally interviewed about their smoking habits. In addition, data for 35 healthy siblings of patients with familial CD were collected by interviewing the patients' relatives. The prevalence of smokers was found significantly higher in CD patients with a family history for IBD than in healthy controls and in familial UC patients (OR 2.28 CI 1.5-3.48 and OR 5.81 CI 3.15-10.75, respectively). No significant difference was found either in the percentage of smokers or in the number of cigarettes smoked per day between familial and sporadic CD patients. Among all siblings of CD patients, 72% of affected siblings and 34% of healthy siblings were smokers, concordant with their relatives. In CD patients with familial occurrence of IBD, the percentage of smokers is elevated. It is possible that in a genetically predisposed population, smoking could be an important environmental factor in determining CD or expressing this disease instead of UC.