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Inflammatory bowel disease in twins: studies of genetics and environmental factors
Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aetiology of inflammatory bowel disease (IBD) is unknown but considered to be caused by interplay of genetic and environmental factors.

The aims of this thesis were to study the influence of genetics and environmental factors in aetiology, disease phenotype and levels of Anti-Saccharomyces cerevisiae antibodies (ASCA), as well as to assess whether CARD15/NOD2 polymorphisms explain the influence of genetics in these aspects.

Twin pairs, where at least one twin in each pair had been hospitalized for IBD, were identified using a combination of the Swedish twin registry and the Swedish Hospital Discharge Register. Twin pairs with confirmed IBD were invited to take part in a questionnaire-based study on environmental factors and studies on ASCA and CARD 15/NOD2 polymorphisms.

The follow-up of the old Swedish twin group showed fairly stable concordance rates. A high degree of concordance regarding age at diagnosis, disease location and behaviour was seen in concordant monozygotic twin pairs with Crohn's disease (CD).

The three "classical" CARD15/NOD2 polymorphisms were infrequent in Swedish CD twins and healthy controls, but seemed to be more common among concordant than discordant monozygotic twins with CD.

No increased occurrence of ASCA was observed in healthy twin siblings in discordant monozygotic twin pairs, but a high degree of concordance in ASCA titres was seen in concordant monozygotic twin pairs with CD. ASCA were not associated with CARD15/NOD2.

Including both Swedish and Danish twins, associations between recurrent gastrointestinal infections up to age 20 years and both ulcerative colitis (UC) and CD were observed, whereas coffee and egg consumption was associated with UC only. Swimming in lakes in contrast with swimming pools, sea and rivers was also associated with UC.

These results confirm a stronger genetic influence in CD than in UC and suggest that genetic factors are important not only in acquiring the disease but also in determining disease characteristics of CD. The CARD15/NOD2 variants contribute, but do not fully explain concordance of CD and support the hypothesis that concordant monozygotic twins are under an increased load of susceptibility genes. Furthermore, the results question the concept of ASCA as a marker of genetic susceptibility for CD and we propose that ASCA are a marker of a response to an environmental antigen and that specific gene(s) other than CARD15/NOD2 determine the level of response and perhaps also specific phenotypic characteristics. The results also indicate, that markers of possible infectious events during childhood/adolescence and dietary factors may influence the risk of IBD. In addition, previous reported associations between smoking and IBD were confirmed.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2005. , 76 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 909
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-30042Local ID: 15498ISBN: 91-852-9919-7 (print)OAI: oai:DiVA.org:liu-30042DiVA: diva2:250862
Public defence
2005-09-30, Wilandersalen, Universitetssjukhuset i Örebro, Örebro, 09:00 (English)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-03Bibliographically approved
List of papers
1. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics
Open this publication in new window or tab >>Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics
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2003 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 124, no 7, 1767-1773 p.Article in journal (Refereed) Published
Abstract [en]

Background & Aims:

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.

Methods:

The official Swedish population register and the cause of death register were used to search for the twins. All living patients were interviewed.

Results:

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).

Conclusions:

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33375 (URN)10.1016/S0016-5085(03)00385-8 (DOI)19390 (Local ID)19390 (Archive number)19390 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
2. CARD15/NOD2 polymorphisms do not explain concordance of Crohn's disease in Swedish monozygotic twins
Open this publication in new window or tab >>CARD15/NOD2 polymorphisms do not explain concordance of Crohn's disease in Swedish monozygotic twins
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2005 (English)In: Digestive and Liver Disease, ISSN 1590-8658, E-ISSN 1878-3562, Vol. 37, no 10, 768-772 p.Article in journal (Refereed) Published
Abstract [en]

Background.

CARD15/NOD2 polymorphisms are associated with Crohn's disease. There is a high concordance for disease and disease phenotype in monozygotic twin pairs with Crohn's disease.

Aim.

We studied CARD15/NOD2 polymorphisms in a Swedish, population-based cohort of monozygotic twins with Crohn's disease to assess whether these variants explain disease concordance.

Subjects and methods.

Twenty-nine monozygotic twin pairs (concordant n = 9, discordant n = 20) with Crohn's disease and 192 healthy controls were investigated for the CARD15/NOD2 variants Arg702Trp, Gly908Arg and Leu1007fsinsC.

Results.

CARD15/NOD2 mutations were found in 5/38 (13%) twins with Crohn's disease, corresponding to a total allele frequency of 6.6%. Only 2/9 concordant twin pairs carried any of the variants and the remaining seven were wild type genotype. The total allele frequency was 4.4 times higher (95% confidence interval 1.0–21.5, p = 0.06) in concordant twins than in discordant ones, 11.1% versus 2.5%. In healthy controls the total allele frequency was 2.6%.

Conclusions.

CARD15/NOD2 polymorphisms contribute but do not alone explain concordance of Crohn's disease in monozygotic twins and, at least in a Swedish population, other polymorphisms are required. The low occurrence of CARD15/NOD2 mutations in the study and other Northern European populations suggests that these variants are of less importance in Northern Europe.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33366 (URN)10.1016/j.dld.2005.05.005 (DOI)19381 (Local ID)19381 (Archive number)19381 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
3. Anti-Saccharomyces cerevisiae antibodies in twins with inflammatory bowel disease
Open this publication in new window or tab >>Anti-Saccharomyces cerevisiae antibodies in twins with inflammatory bowel disease
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2005 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 54, no 9, 1237-1243 p.Article in journal (Refereed) Published
Abstract [en]

Background and aims: An increased occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) is reported in unaffected members of families with Crohn’s disease. Whether ASCA is a familial trait due to genetic factors or is caused by exposure to environmental factors is unknown. To assess the genetic influence of ASCA we studied its occurrence in a twin population.

Patients and methods: ASCA were analysed in 98 twin pairs with inflammatory bowel disease and were related to clinical phenotype and CARD15/NOD2 genotype.

Results: ASCA were more common in Crohn’s disease than in ulcerative colitis (40/70 (57%) twins v 5/43 (12%) twins). Associations with ileal Crohn’s disease, stricturing/penetrating behaviour, and young age, but not CARD15/NOD2 were confirmed. ASCA were found in 1/20 (5%) healthy siblings in discordant monozygotic pairs with Crohn’s disease compared with 7/27 (26%) in discordant dizygotic pairs. Using the intraclass correlation coefficient (ICC), no agreement in ASCA titres was observed in discordant twin pairs with Crohn’s disease, in monozygotic (ICC = −0.02) or dizygotic (ICC = −0.26) pairs. In contrast, strong agreement was seen within concordant monozygotic twin pairs with Crohn’s disease (ICC = 0.76).

Conclusions: These findings question the concept of ASCA as a marker of genetic susceptibility for Crohn’s disease. The agreement in ASCA titres within concordant monozygotic twin pairs with Crohn’s disease, suggests that the level of increase is genetically determined. We propose that ASCA are a marker of a response to an environmental antigen and that a specific gene(s) other than CARD15/NOD2 determines the level of response and perhaps also specific phenotypic characteristics.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33369 (URN)10.1136/gut.2005.066860 (DOI)19384 (Local ID)19384 (Archive number)19384 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
4. Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population
Open this publication in new window or tab >>Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population
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2006 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 12, no 10, 925-933 p.Article in journal (Refereed) Published
Abstract [en]

Background: Genetics and environmental factors are implicated in the etiology of inflammatory bowel disease (IBD). We studied environmental factors in a population-based Swedish-Danish twin cohort using the co-twin control method.

Subjects and Methods: A questionnaire was sent to 317 twin pairs regarding markers of exposures in the following areas: infections/colonization and diet as well as smoking, appendectomy, and oral contraceptives. Odds ratios (OR) were calculated by conditional logistic regression. When confounding appeared plausible, multivariate conditional logistic regression was added. The questions were also divided into topic groups, and adjustment was made for multiple testing within each of the groups.

Results: The response rate to the questionnaire was 83%. In consideration of the study design, only discordant pairs were included (Crohn's disease [CD], n = 102; ulcerative colitis [UC], n > = 125). Recurrent gastrointestinal infections were associated with both UC (OR, 8.0; 95% confidence interval [CI], 1.0–64) and CD (OR, 5.5; 95% CI, 1.2–25). Hospitalization for gastrointestinal infections was associated with CD (OR, 12; 95% CI, 1.6–92). Smoking was inversely associated with UC (OR, 0.4; 95% CI, 0.2–0.9) and associated with CD (OR, 2.9; 95% CI, 1.2–7.1).

Conclusions: The observed associations indicate that markers of possible infectious events may influence the risk of IBD. Some of these effects might be mediated by long-term changes in gut flora or alterations in reactivity to the flora. The influence of smoking in IBD was confirmed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37491 (URN)10.1097/01.mib.0000228998.29466.ac (DOI)36385 (Local ID)36385 (Archive number)36385 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved

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