Role of ASCA and the NOD2/CARD15 mutation Gly908Arg in predicting increased surgical costs in Crohn's disease patients: a project of the European Collaborative Study Group on Inflammatory Bowel Disease.

BACKGROUND: NOD2/CARD15, the first identified susceptibility gene in Crohn's disease (CD), is associated with ileal stenosis and increased frequency of surgery. Anti-Saccharomyces cerevisiae antibody (ASCA), a serological marker for CD, is associated with ileal location and a high likelihood for surgery. We hypothesized that the presence of ASCA and NOD2/CARD15 mutations could predict increased health care cost in CD. METHODS: CD patients in a prospectively designed community-based multinational European and Israeli cohort (n = 228) followed for mean 8.3 (SD 2.6) years had blood drawn for measurement of ASCA (IgG, IgA), Arg702Trp, Gly908Arg, and Leu1007fsinsC. Days spent in the hospital and the costs of medical and surgical hospitalizations and medications were calculated. RESULTS: The median duration of surgical hospitalizations was longer in Gly908Arg-positive than -negative patients, 3.5 and 1.5 days/patient-year (P < 0.01), and in ASCA-positive than -negative patients, 1.1 and 0 days/patient-year (P < 0.001). Median surgical hospitalization cost was 1,580 euro/patient-year in Gly908Arg-positive versus 0 euro/patient-year in -negative patients (P < 0.01), and 663 euro/patient-year in ASCA-positive versus 0 euro/patient-year in -negative patients (P < 0.001). Differences in cost of medications between groups were not significant. The effect of Gly908Arg was expressed in countries with higher Gly908Arg carriage rates. ASCA raised surgical costs independently of the age at diagnosis of disease. Arg702Trp and Leu1007fsinsC did not affect the cost of health care. CONCLUSIONS: Since CD patients positive for Gly908Arg and ASCA demonstrated higher health care costs, it is possible that measurement of Gly908Arg and ASCA at disease diagnosis can forecast the expensive CD patients.

NOD2/CARD15 mutations in Croatian patients with Crohn's disease: prevalence and genotype-phenotype relationship.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with variations in localization and behaviour. Mutations in the NOD2/CARD15 gene on chromosome 16q have been implicated in the pathogenesis of the disease and three main sequence variants, all single nucleotide polymorphisms (SNPs), have been identified in North American and European populations. AIMS AND METHODS: As no data exist in the Croatian population, we consecutively collected a cohort of 136 CD patients and 91 healthy controls to determine the prevalence of NOD2/CARD15 mutations and their association with phenotypic expression of the disease. All patients and controls were genotyped for Arg702Trp (Hugot SNP8), Gly908Arg (Hugot SNP12), and Leu1007fsinsC (Hugot SNP13) and allele frequencies were compared between the Crohn's patients and controls. The correlation of NOD2/CARD15 genotypes with the phenotypic expression of Crohn's disease was further assessed by logistic regression analysis. RESULTS: NOD2/CARD15 variants were found in 38/136 CD patients (27.9%) compared to 10/91 (10.9%) healthy controls (P = 0.0022). Allele frequencies in patients with CD were 13.97%, 4.4% and 11.76%, respectively, for SNP8, 12 and 13, compared to 5.49%, 1.12% and 4.40% in controls (P = 0.041, P = 0.162, P = 0.055). Six CD patients carried double mutations and, remarkably, we identified two homozygous mutants amongst the healthy control group. Surgery over the course of the disease and a younger age at onset of the disease were significantly more frequent in patients who were carriers of NOD2/CARD15 mutations. CONCLUSIONS: This report on NOD2/CARD15 mutations in Croatian patients with CD demonstrates that this gene is also implicated in susceptibility to CD in the Croatian population. Phenotypic association showed a younger age at diagnosis and a higher need for surgery in patients carrying NOD2/CARD15 mutations. However, the prevalence is somewhat lower compared to other reports, likely due to a more prominent colonic inflammation.

Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD.

BACKGROUND & AIMS: Three years after the identification of NOD2/CARD15, 2 more genes for inflammatory bowel diseases (IBDs) were reported. The carnitine/organic cation transporter (OCTN) on 5q31 (IBD5) is associated with Crohn's disease (CD) and DLG5 (10q23), a member of membrane-associated guanylate kinase (MAGUK) family, with IBD. We studied mutation prevalence, assessed phenotypic expression, and performed conditional analysis to examine evidence for gene-gene interactions. METHODS: A cohort of 2032 individuals was genotyped for disease-associated OCTN and DLG5 variants, including 981 patients with IBD (CD, n = 769; ulcerative colitis, n = 186; indeterminate colitis, n = 26) followed up at a tertiary IBD center. For 373 patients, DNA from both parents was available (cohort 1) for transmission disequilibrium testing analysis; case-control analysis was performed in 608 patients and 305 controls (cohort 2). RESULTS: There was no distortion of transmission toward affected offspring for any of the variant alleles. Case-control analysis also failed to shown an association. A higher frequency of DLG5 113A was observed in CARD15-positive patients (12.2%) compared with CARD15-negative patients (8.7%; P = .033). The OCTN-TC risk haplotype was associated with penetrating disease (odds ratio, 1.474; 95% confidence interval, 1.028-2.114; P = .035). For DLG5, there were no associations with a particular phenotype. CONCLUSIONS: DLG5 and OCTN do not play a role in the susceptibility to IBD, CD, or ulcerative colitis in the Flemish population but play a role in the phenotypic expression of the disease. OCTN variants were associated with perianal and penetrating CD. More studies in independent populations are urgently needed to assess the validity of DLG5 and OCTN in the pathogenesis of IBD.

Transmission of CARD15 (NOD2) variants within families of patients with inflammatory bowel disease.

OBJECTIVES: Three single nucleotide polymorphisms (SNPs) in CARD15 have been independently associated with Crohn's disease (CD). Since nothing is known about the transmission of these variants within families, this was the subject of our study in Flemish patients with inflammatory bowel disease (IBD) and their healthy relatives. METHODS: A cohort of 1,670 individuals (570 CD, 173 UC, 165 healthy controls, 762 first-degree unaffected relatives of CD patients) was genotyped for Arg702Trp, Gly908Arg, and Leu1007fsinsC. Mutant allele and carrier frequencies were compared between groups. Segregation patterns were compared using a bivariate Dale model. RESULTS: The carrier prevalence of CARD15 variants for CD patients was 46.3%, compared to 20.6% for healthy controls and 22.0% for ulcerative colitis (UC) patients (both p < 0.0001). An increased carriage rate of CARD15 variants was observed in unaffected relatives of CD patients (37.3%; p < 0.0001 vs controls), although this was significantly lower than in the CD patients (p = 0.001). Paternal transmission gave a 5.17-fold higher chance for the child to develop the disease compared to maternal transmission (95% CI [1.59, 16.78]; p = 0.0063). UC patients belonging to mixed IBD families carried significantly more mutations (42.3%) compared to other UC patients (18.4%) (p < 0.01). CONCLUSIONS: Maternal transmission of the CARD15 variant allele is associated with a lower proportion of affected individuals compared to paternal transmission. Therefore, maternal transmission does not carry an increased risk of transmission as does paternal transmission. The increased mutation carriage in unaffected siblings of CD patients and in UC patients belonging to mixed families suggests that other factors than CARD15 contribute to the eventual disease expression.

Pancreatic autoantibodies in inflammatory bowel disease.

BACKGROUND: Autoantibodies against exocrine pancreas (PABs) have been reported to be specific for Crohn's disease (CD), albeit at a low prevalence (30%). We studied PABs in patients with inflammatory bowel disease (IBD), unaffected family members, and control subjects. METHODS: A Belgian study cohort of 575 subjects, including 289 IBD patients (CD, 169 patients; ulcerative colitis [UC], 120 patients), 108 unaffected first-degree relatives, 78 subjects with non-IBD gastrointestinal disorders (gastrointestinal control subjects [GIcos]), and 100 healthy control subjects (Hcos), were tested for PAB by a standardized indirect immunofluorescence method. RESULTS: The prevalence of PABs in this study cohort was 32% for CD, 23.3% for UC, and 22.2% for their unaffected family members (all P < 0.001), compared with 1.3% for GIcos and 0% for Hcos. Two staining patterns could be observed: an intracellular pattern (IC); and an extracellular pattern (EC). The EC was significantly more prevalent in CD patients compared with UC patients (P = 0.014), and higher titers of this pattern were found in CD patients (P = 0.01). Both PAB patterns were negatively associated with stricturing disease behavior of CD (P = 0.021). The IC was associated with familial CD (P = 0.0009) and familial UC (P = 0.0003). CONCLUSIONS: The prevalence of PAB found in CD patients in this study was similar to that cited in previous reports. In contrast to these reports, we also found an increased prevalence of PABs in patients with UC and in unaffected first-degree relatives of IBD patients. We observed two main staining patterns, both of which were present in IBD and were associated with specific phenotypes of the disease.