Sporadic Crohn's Disease Research Articles

Influence of familial forms of inflammatory bowel disease on the use of immunosuppressants, biological agents, and surgery in the era of biological therapies. Results from the ENEIDA project.

Familial inflammatory bowel disease (IBD) history is a controversial prognostic factor in IBD. We aimed to evaluate the impact of a familial history of IBD on the use of medical and surgical treatments in the biological era. Patients included in the prospectively maintained ENEIDA database and diagnosed with IBD after 2005 were included. Familial forms were defined as those cases with at least one first-degree relative diagnosed with IBD. Disease phenotype, the use of biological agents, or surgical treatments were the main outcomes. A total of 5263 patients [2627 Crohn's disease (CD); 2636 ulcerative colitis (UC)] were included, with a median follow-up of 31months. Of these, 507 (10%) corresponded to familial forms. No clinical differences were observed between familial and sporadic IBD forms except a lower age at IBD diagnosis and a higher rate of males in familial forms of UC. In CD, the proportions of patients treated with thiopurines (54.4% vs 46.7%; P = .015) and survival time free of thiopurines (P = .009) were lower in familial forms. No differences were found regarding the use of biological agents. Concerning surgery, a higher rate of intestinal resections was observed in sporadic CD (14.8% vs 9.9%, P = .027). No differences were observed in UC. In the era of biological therapies, familial and sporadic forms of IBD show similar phenotypes and are managed medically in a similar way; whether these is due to lack of phenotypical differences or an effect of biological therapies is uncertain. What is already known on this topic: IBD's etiopathogenesis points to an interaction between environmental and genetic factors, being familial history a controversial prognostic factor. Biological agents use and need for surgery regarding familial or sporadic forms of IBDs present conflicting results. What this study adds: Familial and sporadic forms of IBD have similar phenotypes and are managed medically and surgically in a similar way. How this study might affect research, practice or policy: Familial aggregation should not be considered a factor associated with more aggressive disease.

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.

Hospital Admissions, Biological Therapy, and Surgery in Familial and Sporadic Cases of Inflammatory Bowel Disease: A Population-Based Cohort Study 1977-2011.

Easily accessible predictors of disease course in inflammatory bowel disease (IBD) are scarce, and it remains largely unknown whether a family history of IBD predicts the course of Crohn's disease (CD) and ulcerative colitis (UC). We aimed to compare the course of disease in familial and sporadic cases of IBD in a nationwide cohort study. From national registries, covering a population of 8,295,773 individuals, we obtained information on date and year of diagnosis of IBD cases, gender, age, and family ties. Using Cox regression, we estimated hazard ratios for IBD-related hospitalization, biological treatment, and surgery in familial versus sporadic cases of IBD. A total of 27,886 IBD cases, including 1006 IBD-relative pairs, were followed-up for up to 16 years, totaling 164,979 person-years. We observed no difference in risk of hospital admissions between familial and sporadic cases of IBD. However, patients with familial CD had significantly higher risk of major surgery than sporadic CD cases after 2 years of disease duration (hazard ratio, 1.62; 95% confidence interval, 1.26-2.07). Also, sensitivity analysis suggested a slightly reduced time from diagnosis to first tumor necrosis factor-α inhibitor treatment among familial CD and UC cases as compared with sporadic cases. We found only minor differences in surgery rates and tumor necrosis factor exposure, between familial and sporadic cases of IBD. These findings may represent purely social rather than functional effects, which is consoling for newly diagnosed CD or UC patients with a family history of IBD.

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.

Familial clustering of Crohnʼs disease in Israel: Prevalence and association with disease severity

There is limited data addressing the severity of Crohn's disease (CD) in patients with a family history of inflammatory bowel disease (IBD) compared to sporadic cases. We investigated the familial occurrence of IBD and its correlation with disease behavior in CD patients attending the Israeli IBD Foundation meeting using a structured questionnaire. The study group consisted of 181 CD patients with a total of 825 1(st) degree relatives. Positive family history for IBD in a 1(st) degree relative was reported in 30 patients (16%). Nine out of the 360 parents (2.5%) had IBD (4 CD, 5 UC). There were 17 siblings with IBD (15 CD, 2 UC) out of 351 (4.8%). Ten out of 114 (8.8%) offsprings had IBD (6 CD, 4 UC). When two siblings were affected, their respective age of disease onset was strikingly concordant (r = 0.76, p = 0.008). There was no difference between sporadic and familial CD patients in the age of disease onset, the location of disease, proportion of smokers or percentage of Ashkenazi origin. Furthermore, similar proportions of sporadic and familial patients underwent intestinal surgery, had penetrating or obstructive complications or were treated by immunomodulators and/or biologics. There was also no difference in the reported percentage of time with active disease or the number of flare-ups. The prevalence of familial disease among Jewish CD patients in Israel is at the high range of the rate found in other ethnicities. Having a positive family history of IBD has no impact on the severity of the disease.

Smoking and inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD) result from genetic and environmental factors. Never smoking and formerly smoking increase the risk of UC, whereas smoking exacerbates the course of CD. We sought to define the age-dependent effects of smoking on the development of UC and CD in familial and sporadic cohorts. University of Chicago patients diagnosed with UC or CD between 1990 and 2002 were surveyed about their tobacco use relative to their diagnosis. Smoking trends were used to estimate age-dependent odds ratios and the attributable risks of smoking in the IBD cohort compared to in the general population. One thousands and thirteen patients were included in the study: 245 with sporadic UC; 216 with sporadic CD; 249 with familial UC; and 303 with familial CD. Being an ex-smoker conferred an increased risk for UC in the 25-44 age group in both the sporadic and familial cohorts, but not in the 45-64 age group in the familial UC cohort. Furthermore, there was no difference in tobacco use between patients with sporadic CD and the general population, although there was a significant increase in smoking in younger patients with familial CD. Ex-smokers make up an increasing percentage of older patients diagnosed with UC, accounting for more than 35% of the attributable risk of late onset (>45 years) UC and a large component of the second peak in diagnosis. Current smokers account for a large percentage of patients diagnosed at a younger age with familial CD but not with sporadic CD. Families with IBD should be counseled that early tobacco use significantly increases the risk of developing CD or, if an ex-smoker, UC at a young age.

Incidence of Crohn’s disease and CARD15 mutation in a small township in Sicily

The incidence of Crohn's disease (CD) has been shown to be lower in Southern than in Northern Europe. Data on the frequency of the NOD2/CARD15 mutations for Mediterranean area are very scant. To determine the incidence of CD from 1979 to 2002 in a township in Sicily together with the allele frequency of NOD2/CARD15 mutations in patients, family members and controls, and to determine the allele frequency of these mutations in sporadic CD from other areas of Sicily in comparison with a control population. Casteltermini is a small town close to Agrigento (Sicily) with a population of 9,130 inhabitants. All the diagnoses of inflammatory bowel disease (IBD) made from 1979 to 2002 were obtained through the local health authority. NOD2/CARD15 mutations were studied in 23 out of the 29 patients with CD in Casteltermini, in 60 family members and in 64 controls. NOD2/CARD15 was also studied in 80 sporadic cases of CD disease among Sicilians outside Casteltermini and 118 healthy controls. From 1979 to 2002, 29 patients with CD and 13 patients with ulcerative colitis (UC) were registered. The 6-year mean incidence of CD ranged from 8.0 to 17 new cases for every 100,000 inhabitants, whereas the mean incidence of UC ranged from five new cases to 7.8 for every 100,000 inhabitants. The allele frequencies of NOD2/CARD15 mutations (L1007finsC, G908R, R702W) were 8.7, 4.3 and 8.7%, respectively, in CD cases; 5.0, 4.2 and 3.1% in family members; 1.6, 2.3 and 3.1% in controls. In sporadic Sicilian CD patients outside Casteltermini the allele frequency was 7.5, 8.1, 6.2% whereas in control population it was 3.3, 1.6, 1.6%. A high incidence of CD compared with UC was observed in this small town in Southern Italy. The frequency of NOD2/CARD15 mutations in CD is similar to other Caucasian population studied so far.

Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease

Abnormal barrier function may be genetically determined in Crohn's disease. To examine the role of abnormal intestinal permeability in genetic predisposition in multiplex vs. sporadic Crohn's disease families. Intestinal permeability was measured in patients, relatives and partners by means of lactulose/mannitol test. Healthy subjects from the hospital staff served as controls. CARD15 mutations were investigated in sporadic and familial Crohn's disease patients and in a group of blood donors. The median lactulose/mannitol ratio was increased significantly in Crohn's disease patients vs. their relatives [0.03 (0.01-0.24) vs. 0.01 (0.003-0.19), P=0.005]. The percentage of abnormal tests was significantly higher in familial vs. sporadic first-degree relatives of Crohn's disease patients (29% vs. 11%, P=0.0281). Abnormal permeability occurred significantly more frequent in patients with familial Crohn's disease carrying the frameshift mutation. The frameshift mutation 3020 insC was associated with increased permeability in 75% in the multiplex and in 61% of the sporadic CD patients. One partner had abnormal lactulose/mannitol ratio. Conclusion Intestinal permeability is raised in Crohn's disease patients and relatives, with higher rates in familial vs. sporadic healthy relatives. CARD15 mutations are associated with abnormal permeability in ileal Crohn's disease.

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.

Crohn Disease: Frequency and Nature of CARD15 Mutations in Ashkenazi and Sephardi/Oriental Jewish Families

Crohn disease (CD), an inflammatory bowel disease, is a multifactorial trait with the highest frequency in Ashkenazi Jewish (AJ) individuals of Central European origin. Recently, three common predisposing CARD15 mutations (R702W, G908R, and 1007fs) and a polymorphism (P268S) were identified. To determine whether CARD15 mutations account for the higher prevalence of CD in AJ individuals, the haplotypes and allele frequencies of the common mutations and variants were assessed in 219 members of 50 AJ and 53 members of 10 Sephardi/Oriental Jewish (SOJ) multiplex families with CD, in 36 AJ patients with sporadic CD, and in 246 AJ and 82 SOJ controls. A higher frequency of CARD15 mutations was found in AJ patients from multiplex families with CD from Central (44.0%) versus Eastern (24.0%) Europe, especially for G908R and 1007fs, and in SOJ patients (34.5%) compared with AJ (10.1%) or SOJ (5.4%) controls. Contrary to expectation, the frequency of the common mutations was slightly lower in AJ patients with CD (30.1%) than in SOJ patients with CD (34.5%). The 702W allele was associated with both the P268 and 268S alleles. CARD15 mutation frequencies were greater in affected sib pairs than in sporadic CD cases but actually decreased in families with three or more affected sibs, raising the possibility of genetic heterogeneity. Similarly, our linkage evidence on chromosome 16 was diminished in the families with three or more affected sibs compared with sib pairs. Screening the CARD15 gene for rare variants revealed five novel changes (D113N, D357A, I363F, L550V, and N852S) of which N852S occurred only in AJ individuals and may be disease predisposing. Also, there was no evidence for increased risk associated with the recently described IVS(+158) single-nucleotide polymorphism. Although the AJ controls appear to have a higher frequency of CARD15 mutations than the SOJ controls, it is unlikely that this difference fully explains the excess frequency of CD in the AJ population.

Low prevalence of NOD2 variants in Dutch cohort of sporadic Crohn's disease

Low prevalence of NOD2 variants in Dutch cohort of sporadic Crohn's disease

CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population.

We have previously reported strong evidence for linkage between IBD1 and Crohn's disease (CD) in Australian Crohn's disease families. Three risk alleles for Crohn's disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (-/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR-RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohn's disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohn's disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three-fold increase in risk for Crohn's disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohn's disease. While the three risk alleles influence susceptibility to Crohn's disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.

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%.

CARD15 Genetic Variation in a Quebec Population: Prevalence, Genotype-Phenotype Relationship, and Haplotype Structure

The caspase recruitment domain gene (CARD15) was recently identified as the underlying gene associated with the IBD1 locus that confers susceptibility to Crohn disease (CD). CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD. We collected a cohort of 231 patients with CD and 71 healthy control individuals from the Canadian province of Quebec, to determine the prevalence of these sequence variants in an independent population. Clinical records of all patients were systematically reviewed, and detailed phenotypic information was obtained. All patient DNA samples were genotyped for the three variants, thus enabling an analysis of genotype-phenotype correlations. In this cohort, 45.0% of patients with CD carried at least one variant in the CARD15 gene, compared with 9.0% of control individuals (P<10-7). Allele frequencies of Arg702Trp, Gly908Arg, and Leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with CD, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Importantly, CARD15 mutants were seen with equal frequency in patients with familial and sporadic CD. Analysis of the relationship between genotype and phenotype convincingly demonstrates that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P<.001). Moreover, we were able to determine the haplotype structure surrounding this disease gene by genotyping 45 single-nucleotide polymorphisms (SNPs) in a 177-kb region that contained the CARD15 gene. This structure helps clarify the history of these causal mutations. Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone.

Familial and Sporadic Inflammatory Bowel Disease: Comparison of Clinical Features and Serological Markers in a Genetically Homogeneous Population

Background: The familial occurrence of inflammatory bowel disease (IBD) and the clinical features of familial and sporadic IBD in the genetically homogeneous Finnish population are evaluated. Methods: 257 patients with Crohn disease (CD) and 436 with ulcerative colitis (UC) participated in the study. They were asked whether IBD was present (familial IBD) or absent (sporadic IBD) in their first-degree relatives. Data on the clinical course of the disease were collected from the patient records. Antibodies to Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) were determined from serum samples. Results: Affected first-degree relatives were found in 15.6% of patients with CD and in 13.8% of patients with UC. In familial cases, CD was more often located in the ileum (38% versus 21%) and less often in the ileocolon (35% versus 50%) ( P < 0.05) than in sporadic cases. A greater percentage of CD patients than UC patients were smokers (47% versus 13%; P < 0.01). An elevated level of IgA and/or IgG antibodies for ASCA was found more often in CD patients than in UC patients (59% versus 14%; P < 0.01), while pANCA were found more often in UC than in CD patients (48% versus 12%; P < 0.01). The combination of pANCA-ASCA + yielded a sensitivity, specificity and positive predictive value of 48%, 92% and 90%, respectively, for CD, and the combination of pANCA + ASCAof 55%, 94% and 90%, respectively, for UC. Conclusions: The percentage of familial IBD cases in Finland is comparable to that reported elsewhere in Europe. No important clinical differences between patients with familial and sporadic forms of the disease were found. ASCA is associated with both familial and sporadic CD and pANCA with UC, but low sensitivity diminishes their value as a serological marker of IBD or as a differential diagnostic test between CD and UC.

Genes and Microbes Linked at Last

Genes and Microbes Linked at Last

Familial expression of anti-Saccharomyces cerevisiae Mannan antibodies in Crohn's disease and ulcerative colitis: a GISC study.

Recent studies in familial Crohn's disease (CD) have suggested that anti-Saccharomyces cerevisiae mannan antibodies (ASCAs) may represent a new specific marker of genetic susceptibility. In this study we aimed to assess the importance of ASCAs by comparing their presence in a large number of patients with sporadic and familial occurrence of CD or ulcerative colitis (UC) and their unaffected relatives. Serum samples from 96 patients with sporadic CD, 97 patients with sporadic UC, and 50 unrelated healthy controls were tested for ASCAs by a standard ELISA method. Moreover, 73 families with two or more members affected by CD and/or UC were recruited. From these families 58 CD patients, 84 UC patients, and 216 unaffected first degree relatives were investigated. ASCAs were detected in 34 of 96 patients with sporadic CD (35%, p < 0.01 vs controls), 11 of 97 patients with sporadic UC (12%), and two of 50 controls (4%). ASCAs were significantly (p < 0.04) more frequent in patients with familial CD (55%) and familial UC (25%) than in sporadic cases. Moreover, ASCAs were found in 25% of unaffected relatives, and this rate did not significantly differ in CD, UC, and mixed families (28%, 26%, and 22%, respectively). In this study we confirm that ASCAs occur particularly frequently in CD patients, especially with the presence of a positive family history. However, they are also significantly increased in UC patients with a family history and in a considerable number of unaffected relatives of inflammatory bowel disease families, irrespective of the characteristics of their families (UC, CD, mixed, ASCA positive, and ASCA negative). The presence of ASCAs in unaffected relatives might point toward a genetic predisposition to either CD or UC.

Anti-Saccharomyces Cerevisiae Antibodies (ASCA), Phenotypes of IBD, and Intestinal Permeability: A Study in IBD Families

Serologic markers anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies with perinuclear staining (pANCA) have been proposed to study the immunopathogenesis of IBD. Their measurement may allow better phenotyping of the disease and the detection of subclinical disease. To test the hypothesis that serological markers identify an immunologic trait related to disease susceptibility. We also wanted to test the hypothesis that ASCA is a marker related to abnormal tissue permeation by common antigens. We studied the prevalence of pANCA and ASCA in a large cohort of sporadic and familial inflammatory bowel diseases and their unaffected relatives and spouses. Kinetics of ASCA was studied and the relationship between ASCA and 51Cr-EDTA intestinal permeation was investigated. ASCA was associated with sporadic Crohn's disease (CD) (63%), with Crohn's patients belonging to pure CD families (62%) and also with their unaffected family members (21%). pANCA was associated with UC (58%). The prevalence of ASCA in CD patients belonging to mixed families was strikingly low (33%). ASCA was a stable marker throughout the disease and was not related to an increased small intestinal permeability. ASCA is strongly associated with familial CD in Belgium, and 21% of healthy family members also display the marker. The association is much weaker in patients belonging to mixed families. ASCA is a stable marker and is not a secondary phenomenon due to increased intestinal permeability.