Inflammatory bowel disease in a Swedish twin cohort: A long-term follow-up of concordance and clinical characteristics
ABSTRACT In 1988, we reported the first twin study in inflammatory bowel disease. The aim of the current study was to follow up these twins regarding new cases of inflammatory bowel disease and Crohn's disease characteristics using the Vienna classification.
The official Swedish population register and the cause of death register were used to search for the twins. All living patients were interviewed.
Three monozygotic twins earlier classified as healthy had been diagnosed with inflammatory bowel disease (ulcerative colitis, n = 2; Crohn's disease, n = 1). Retrospectively, all 3 were symptomatic at the original survey. This changed the pair concordance in monozygotic twins from 6.3% to 18.8% in ulcerative colitis and from 44.4% to 50.0% in Crohn's disease. A high degree of concordance regarding age at diagnosis, disease location at diagnosis and during the course, and disease behavior was found in concordant monozygotic twin pairs with Crohn's disease. Seven of 9 pairs were identical in 3 or more of these disease characteristics compared with an expected number of 1.5 (P = 0.000076).
This study confirms that the genetic influence is stronger in Crohn's disease than in ulcerative colitis. A remarkable phenotype similarity within concordant pairs with Crohn's disease was found using the Vienna classification.
- SourceAvailable from: Sebastian Zeissig
[Show abstract] [Hide abstract]
- "This might be obvious in the context of the genetic association of XBP1 variants with IBD reported here, but we speculate that environmental factors may also impair XBP1 function (and hence the ER stress response). Monozygotic twin studies have highlighted the importance of as yet unknown environmental and/or epigenetic factors in the development of IBD (Halfvarson et al., 2003). One might speculate that microbial-or food-derived XBP1 inhibitors could interfere with the pathways described herein, particularly in a genetically susceptible host, thus contributing to the development of intestinal inflammation. "
ABSTRACT: Inflammatory bowel disease (IBD) has been attributed to aberrant mucosal immunity to the intestinal microbiota. The transcription factor XBP1, a key component of the endoplasmic reticulum (ER) stress response, is required for development and maintenance of secretory cells and linked to JNK activation. We hypothesized that a stressful environmental milieu in a rapidly proliferating tissue might instigate a proinflammatory response. We report that Xbp1 deletion in intestinal epithelial cells (IECs) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell dysfunction and an epithelium that is overly reactive to inducers of IBD such as bacterial products (flagellin) and TNFalpha. An association of XBP1 variants with both forms of human IBD (Crohn's disease and ulcerative colitis) was identified and replicated (rs35873774; p value 1.6 x 10(-5)) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IECs, thus linking cell-specific ER stress to the induction of organ-specific inflammation.Cell 10/2008; 134(5):743-56. DOI:10.1016/j.cell.2008.07.021 · 33.12 Impact Factor
[Show abstract] [Hide abstract]
- "For example, polymorphisms in pattern recognition receptors, such as CARD15/NOD2 that recognize microbial components, have highlighted the importance of the microbiota in pathogenesis of CD (Sartor et al., 2006). The genetic influence is also supported by higher concordance rates (approximately 50%) for CD occurrence in monozygotic twins (Halfvarson et al., 2003; Jess et al., 2005; Orholm et al., 2000; Tysk et al., 1988). Still, approximately 50% of identical twin pairs are discordant for CD (i.e. one is diseased and one is healthy) demonstrating that environmental factors are also important for disease incidence (Halfvarson et al., 2006; Loftus et al., 2004). "
ABSTRACT: Increasing evidence suggests that a combination of host genetics and the composition of the gut microbiota are important for development of Crohn's disease (CD). Our aim was to study identical twins with CD to determine microbial factors independent of host genetics. Fecal samples were studied from 10 monozygotic twin pairs with CD (discordant n=6 and concordant n=4) and 8 healthy twin pairs. DNA was extracted, 16S rRNA genes were PCR amplified and T-RFLP fingerprints generated using general bacterial and Bacteroides group-specific primers. The microbial communities were also profiled based on their percentage G+C contents. Bacteroides 16S rRNA genes were cloned and sequenced from a subset of the samples. The bacterial diversity in each sample and similarity indices between samples were estimated based on the T-RFLP data using a combination of statistical approaches. Healthy individuals had a significantly higher bacterial diversity compared to individuals with CD. The fecal microbial communities were more similar between healthy twins than between twins with CD, especially when these were discordant for the disease. The microbial community profiles of individuals with ileal CD were significantly different from healthy individuals and those with colonic CD. Also, CD individuals had a lower relative abundance of B. uniformis and higher relative abundances of B. ovatus and B. vulgatus. Our results suggest that genetics and/or environmental exposure during childhood, in part, determine the gut microbial composition. However, CD is associated with dramatic changes in the gut microbiota and this was particularly evident for individuals with ileal CD.The ISME Journal 08/2008; 2(7):716-27. DOI:10.1038/ismej.2008.37 · 9.27 Impact Factor
[Show abstract] [Hide abstract]
- "Such an aggregate of CD within this small community would result in the extremely high prevalence of 2,400/100,000 inhabitants. A detailed investigation showed that patients had commonly bathed in a pool polluted with Coliform bacteria . However, caution is needed in interpreting these results. "
ABSTRACT: A rapid increase in the incidence of Crohn's disease and ulcerative colitis in developed countries, the occurrence of Crohn's disease in spouses, and a lack of complete concordance in monozygotic twins are strong arguments for the role of environmental factors in inflammatory bowel disease (IBD). Research in the field of environmental factors in IBD is based upon epidemiological (geographical and case-control), clinical and experimental studies. The role of two environmental factors has clearly been established in IBD. Smoking is a risk factor for Crohn's disease and a protective factor for ulcerative colitis; appendectomy is a protective factor for ulcerative colitis. Many other environmental factors for IBD have been investigated, including infectious agents, diet, drugs, stress and social status. They are detailed in the present review. Among them, atypical Mycobacteria, oral contraceptives and antibiotics could play a role in Crohn's disease. To date, three hypotheses associate environmental factors with the pathophysiology of IBD (loss of tolerance of intestinal immune system towards commensal bacterial flora): the hygiene, infection and cold chain hypotheses. Much work remains to be done to identify risk factors for IBD. Research identifying environmental factors that might cause a predisposition to IBD is useful. It may lead to disease prevention in subjects who are genetically predisposed and disease improvement in patients.Gastroentérologie Clinique et Biologique 30(6-7):859-67. · 1.14 Impact Factor