Clustering in time of familial IBD separates ulcerative colitis from Crohn's disease.

BACKGROUND: The aim was to compare clustering of time at diagnosis and phenotype of inflammatory bowel disease (IBD) between affected parents and children and to explore generational differences in age at diagnosis (AAD) as well as the concordance of clinical characteristics. METHODS: Eighty-four affected pairs from 45 families were included from 5 counties in southeastern Norway between August 2003 and December 2006; 43 were sib-sib pairs and 39 parent-child pairs. Clinical data were obtained by phone interviews and by hospital records. RESULTS: The difference in median AAD was 17.0 years (P < 0.001) and 2.0 years (P = 0.29) in parent-child and sib-sib pairs, respectively. When the time interval between diagnosis in parent and child was split into 2 groups, below and above 5 years, 64% of pairs with ulcerative colitis (UC) offspring were diagnosed within 5 years, compared to 24% of pairs with Crohn's disease (CD) offspring (odds ratio [OR] = 5.7, 95% confidence interval [CI]: 1.4, 23.8). Concordance for smoking habits was low in 26 pairs with mixed disease (κ = 0.15), whereas patients with CD tended to be current smokers. CONCLUSIONS: Most of the children acquire their disease at an earlier time in life compared to their parents, suggesting genetic anticipation. The time interval between diagnosis of the parents and offspring was lower when the offspring developed UC compared to CD, which might reflect the influence of shared environment on the generational difference in AAD in UC families. This study confirmed the effect of smoking habits on IBD phenotype.

Familial aggregation in Crohn's disease and ulcerative colitis in a Norwegian population-based cohort followed for ten years.

BACKGROUND AND AIMS: To explore the change in risk among 1st degree relatives of ulcerative colitis (UC) and Crohn's disease (CD) for development of concordant disease in an incidence cohort followed for ten years. Furthermore, we wanted to compare familial and sporadic cases regarding clinical characteristics and the course of the disease. METHODS: This population-based study included 421 patients with UC and 197 with CD enrolled from 1990 to 1994. Clinical characteristics and the number of 1st degree relatives of the patients were recorded continuously during ten years. RESULTS: Age at diagnosis in CD patients (OR=0.95, 95% CI: 0.93-0.98) and cumulative relapse rate in UC patients (OR=4.91, 95% CI=1.16, 20.75) were significantly associated to familial clustering. Based on the calculated population prevalence of CD (262/100000) and UC (505/100000), the age-adjusted risk for development of concordant disease was 25.9 and 8.6 among siblings and parents of CD, respectively. In UC, the corresponding risks were 8.6 and 1.5. In the course of ten years the increase in risk was observed only among siblings (28%) and parents (97%) of UC, in contrast to no increase in CD. Moreover, the concordance for UC was high in three generations. CONCLUSIONS: Our study confirmed the importance of genetic influence on the development of CD. Within an observation period of ten years, the increased concordance and relapse rate in familial UC, might point to a larger genetic component in UC than previously suggested.

Ulcerative colitis: patient characteristics may predict 10-yr disease recurrence in a European-wide population-based cohort.

OBJECTIVES: Cumulative 10-yr relapse rates in ulcerative colitis (UC) of 70% to almost 100% have been reported in regional studies. The aim of this study was to determine the relapse rate in UC in a European population-based cohort 10 yr after diagnosis and to identify factors that may influence the risk of relapse. METHODS: From 1991 to 1993, 771 patients with UC from seven European countries and Israel were prospectively included in a population-based inception cohort and followed for 10 yr. A relapse was defined as an increase in UC-related symptoms leading to changes in medical treatment or surgery. The cumulative relapse rate, time to first relapse, and number of relapses in the follow-up period were recorded and possible causative factors were investigated. RESULTS: The cumulative relapse rate of patients with at least one relapse was 0.67 (95% CI 0.63-0.71). The time to first relapse showed a greater hazard ratio (HR) (1.2, CI 1.0-1.5) for women and for patients with a high level of education (1.4, CI 1.1-1.8). The number of relapses decreased with age, and current smokers had a lower relapse rate (0.8, CI 0.6-0.9) than nonsmokers. The relapse rate in women was 1.2 (CI 1.1-1.3) times higher than in men. An inverse relation was found between the time to the first relapse and the total number of relapses. CONCLUSION: In 67% of patients, there was at least one relapse. Smoking status, level of education, and possibly female gender were found to influence the risk of relapse.

Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations.

The first gene associated with Crohn disease (CD) has been identified as CARD15 (16q12). Three variants, R702W, G908R and 1007fsinsC are strongly and independently associated with the disease. A second gene, conveying a smaller risk for inflammatory bowel disease (IBD), has been identified as DLG5 (10q23). We assess the frequency of the CARD15 SNPs and of the R30Q mutation in DLG5 and their contribution to the development of CD in a cohort of unrelated IBD patients (151 CD, 325 ulcerative colitis (UC)) and healthy controls (236) from South-east Norway (IBSEN cohort). Genotype-based tests of population differentiation using 23 SNPs across CARD15, together with estimates of F(ST), indicated that the German and Norwegian background populations could be differentiated at the CARD15 locus. The Norwegian and German CD samples exhibited particularly strong differentiation at the three predisposing loci and those marking their background haplotype. There were significantly lower frequencies of the CARD15 SNPs and no significant association with CD in the Norwegian samples. Only a marginal association was observed for the subphenotypes ileitis and ileocolitis vs colitis (P=0.048). The population attributable risk percentage (PAR%) for CARD15 variants in the Norwegian cohort is the lowest reported for a European population (1.88%), except Iceland. Similarly, the DLG5 variant showed no association with CD or IBD, however, there was a negative correlation with stricture (P=0.035). The present results are consistent with an emerging pattern of a low frequency of the CARD15 variants in Northern countries where the prevalence of IBD is greatest.

Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study.

BACKGROUND: Crohn's disease is a heterogeneous disorder for which NOD2 (CARD 15) has been identified as a susceptibility gene. We investigate the relation between NOD2 genotype and phenotypic characteristics of patients with Crohn's disease. METHODS: Hypotheses about the relation between NOD2 genotype and Crohn's disease phenotype were generated retrospectively from a group of 446 German patients with this disorder. Positive findings (p<0.10) were verified in prospectively established cohorts of 106 German and 55 Norwegian patients with Crohn's disease. All patients were genotyped for the main coding mutations in NOD2, denoted SNP8, SNP12, and SNP13, with Taqman technology. FINDINGS: In the retrospective cohort, six clinical characteristics showed noteworthy haplotype association: fistulising, ileal, left colonic and right colonic disease, stenosis, and resection. In the German prospective cohort, these haplotype associations could be replicated for ileal (p=0.006) and right colonic disease (p < or =0.001). A similar trend was noted in the Norwegian patients. INTERPRETATION: We recorded a distinct relation between NOD2 genotype and phenotype of Crohn's disease. Test strategies with NOD2 variations to predict the clinical course of Crohn's disease could lead to the development of new therapeutic paradigms.