I-Abstract I.1-Objectives- To grossly evaluate colonic abnormalities within the Manitoba population by determining prevalence according to; age, gender, body mass index, body weight, body length, colon length, and fecal weight. I.2-Methods- A population study of 67 medico-legal autopsies from two major teaching hospitals was performed, examining the colon for abnormalities. The colon was resected just proximal to the ileocecal valve and just distal to the recto-sigmoid junction. Once the specimen was detached it was weighed with the autopsy scale opened and the feces removed. The specimen was patted dry and re-weighed. The specimen was laid on a blue specimen photograph board where the length was measured from the cecum to terminal sigmoid/rectum and photographed digitally. The specimen was then evaluated for any abnormalities. The specimen was then placed back into the body. I.3-Results Of the 67 colons assessed, 66% had an abnormality, of which 37.3% had diverticular disease and 24% had polyps, the two most common diseases. Age was the only significant factor (p=0.004) in this study affecting prevalence. The prevalence of multiple polyps was 63% with colon length being the only significant factor (p=0.0265) in this study affecting prevalence. I.4-Conclusions A progressive risk of increased abnormality formation is noted with age. Diverticular disease and polyps have similar prediction factors and disease prevalence. Many factors are suggested in the literature to influence the prediction of abnormalities, however only age was determined to be significant in this study. Multiplicity of polyps in the colon is significantly related to colon length. / October 2007

I-Abstract I.1-Objectives- To grossly evaluate colonic abnormalities within the Manitoba population by determining prevalence according to; age, gender, body mass index, body weight, body length, colon length, and fecal weight. I.2-Methods- A population study of 67 medico-legal autopsies from two major teaching hospitals was performed, examining the colon for abnormalities. The colon was resected just proximal to the ileocecal valve and just distal to the recto-sigmoid junction. Once the specimen was detached it was weighed with the autopsy scale opened and the feces removed. The specimen was patted dry and re-weighed. The specimen was laid on a blue specimen photograph board where the length was measured from the cecum to terminal sigmoid/rectum and photographed digitally. The specimen was then evaluated for any abnormalities. The specimen was then placed back into the body. I.3-Results Of the 67 colons assessed, 66% had an abnormality, of which 37.3% had diverticular disease and 24% had polyps, the two most common diseases. Age was the only significant factor (p=0.004) in this study affecting prevalence. The prevalence of multiple polyps was 63% with colon length being the only significant factor (p=0.0265) in this study affecting prevalence. I.4-Conclusions A progressive risk of increased abnormality formation is noted with age. Diverticular disease and polyps have similar prediction factors and disease prevalence. Many factors are suggested in the literature to influence the prediction of abnormalities, however only age was determined to be significant in this study. Multiplicity of polyps in the colon is significantly related to colon length.

I-Abstract I.1-Objectives- To grossly evaluate colonic abnormalities within the Manitoba population by determining prevalence according to; age, gender, body mass index, body weight, body length, colon length, and fecal weight. I.2-Methods- A population study of 67 medico-legal autopsies from two major teaching hospitals was performed, examining the colon for abnormalities. The colon was resected just proximal to the ileocecal valve and just distal to the recto-sigmoid junction. Once the specimen was detached it was weighed with the autopsy scale opened and the feces removed. The specimen was patted dry and re-weighed. The specimen was laid on a blue specimen photograph board where the length was measured from the cecum to terminal sigmoid/rectum and photographed digitally. The specimen was then evaluated for any abnormalities. The specimen was then placed back into the body. I.3-Results Of the 67 colons assessed, 66% had an abnormality, of which 37.3% had diverticular disease and 24% had polyps, the two most common diseases. Age was the only significant factor (p=0.004) in this study affecting prevalence. The prevalence of multiple polyps was 63% with colon length being the only significant factor (p=0.0265) in this study affecting prevalence. I.4-Conclusions A progressive risk of increased abnormality formation is noted with age. Diverticular disease and polyps have similar prediction factors and disease prevalence. Many factors are suggested in the literature to influence the prediction of abnormalities, however only age was determined to be significant in this study. Multiplicity of polyps in the colon is significantly related to colon length.

Background/Objectives: The possible relationship between smoking and risk of colonic diverticulosis has been suggested by recent epidemiological studies, although the results were inconsistent. This meta-analysis was conducted to summarize all available data. Methods: A comprehensive literature review was conducted using the MEDLINE and EMBASE databases through May 2017 to identify all studies that compared the risk of colonic diverticulosis among current and former smokers versus nonsmokers. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. Results: Of 465 potentially eligible articles, three prospective cohort studies with 130,520 participants met the eligibility criteria and were included in the meta-analysis. The risk of colonic diverticulosis in current smokers was significantly higher than nonsmokers with the pooled risks ratio of 1.46 (95% confidence interval [CI], 1.13-1.89). However, the risk of colonic diverticulosis in former smokers was not significantly higher than nonsmokers with the pooled risk ratio of 1.13 (95% CI, 0.88-1.44). Conclusions: A significantly increased risk of colonic diverticulosis among current smokers is demonstrated in this study.

Hospital readmission rates are being used to indicate quality of care by healthcare facilities in recent years. Increase in incidence and hospitalizations of patients with diverticular disease (DD) has caused burden to hospital resources. High fiber diets have been a part of the recommended therapy for patients to reduce symptoms and complications of DD. Analysis of the effect of high fiber diet education on hospital readmission of patients with a diagnosis of DD (N=68) was conducted. Chi-square analysis determined that high fiber diet education was not associated with readmission (x2=0.567, P=0.452). T-tests determined that men were more likely to be readmitted than women (P=0.029). A higher BMI was also observed in patients who were readmitted compared to those not readmitted (P=0.006). While high fiber diet education was not associated with readmission, males and patients with a higher BMI were significantly associated with hospital readmission.

A doença diverticular dos cólons (DDC) é relacionada à civilização, industrialização e à dieta. Estudos fisiológicos demonstraram que uma pressão intraluminal elevada, bem como alterações estruturais adquiridas da parede intestinal parecem ser fator decisivo, que se intensificam com o envelhecimento. Estas alterações podem ser causadas por alterações no tecido muscular e tecido conjuntivo relacionados ao metabolismo do colágeno e elastina, que presumivelmente pode ser geneticamente determinada. Sabe-se que pacientes com desordens genéticas do gene da elastina (ELN), como a estenose aórtica supravalvar e a cutis laxa, podem manifestar hérnia, diverticulose e disfunção urinária. Recentemente, foi demonstrado mutação pontual no exon 20 do ELN em pacientes com hérnia inguinal. No presente estudo investigamos o polimorfismo do exon 20 do ELN em 14 pacientes com DDC e 26 controles. A presença de mutação foi verificada por eletroforese conformacional de fita simples e sequenciamento automático. Demonstramos bandas anormais em alguns pacientes, que representaram uma mutação não conservativa: substituição de um nucleotídeo (AGT->GGT) no códon 422 do gene da ELN em cinco pacientes com DDC. Nenhum indivíduo controle estudado apresentou este tipo de mutação. Observamos uma associação significante (P=0,003) desta mutação com o desenvolvimento da DDC e risco relativo 3,89 vezes maior (intervalo de confiança de 95%: 2,21-6,83) dos indivíduos com esta mutação desenvolver DDC. Esta mutação troca Serina, um aminoácido não polar, por glicina, um aminoácido neutro, alterando a estrutura hidrofóbica da elastina e secundariamente a estrutura da fibra elástica. Esta alteração pode promover perda da complacência da parede intestinal e o desenvolvimento de divertículo / Colonic diverticular disease (CDD) is related to civilization, industrialization and diet. Physiological studies demonstrated that increased intraluminal pressures as well as acquired structural changes of the intestinal wall seem to be decisive factors, which intensify during ageing. These changes may be due to alterations of the musculare and connective tissues and are related to collagen and elastin metabolism, which presumably can be genetically determined. It is known that patients with genetic disorders of elastin gene (ELN), such as supravalvular aortic stenosis and cutis laxa, may also manifest hernias, diverticulosis and bladder dysfunction. Recently, punctual mutations were demonstrated in ELN exon 20 of inguinal hernia patients. In the the present study, the polymorphism ELN exon 20 was tested in 14 patients with CDD and in 26 controls. Mutations were sought by singlestrand conformation polymorphism and by automatical sequence. An abnormal band was demonstrated in some patients, representing a missense mutation: a single nucleotide substitution (AGT->GGT) was detected in codon 422 in five patients with CDD. There is a substituion of serine, a nonpolar amino acid, by glycine, na uncharged one. No controls showed this punctual mutation(P=0,003), and the odds ratio for development of CDD was 3.33 (95% confidence interval:1,98-5,62). As a consequence of this substitution, the hydrophobic structure of elastin and of elastic fiber may promote a loss of compliance of the intestinal wall and development of diverticula

A doença diverticular dos cólons (DDC) é relacionada à civilização, industrialização e à dieta. Estudos fisiológicos demonstraram que uma pressão intraluminal elevada, bem como alterações estruturais adquiridas da parede intestinal parecem ser fator decisivo, que se intensificam com o envelhecimento. Estas alterações podem ser causadas por alterações no tecido muscular e tecido conjuntivo relacionados ao metabolismo do colágeno e elastina, que presumivelmente pode ser geneticamente determinada. Sabe-se que pacientes com desordens genéticas do gene da elastina (ELN), como a estenose aórtica supravalvar e a cutis laxa, podem manifestar hérnia, diverticulose e disfunção urinária. Recentemente, foi demonstrado mutação pontual no exon 20 do ELN em pacientes com hérnia inguinal. No presente estudo investigamos o polimorfismo do exon 20 do ELN em 14 pacientes com DDC e 26 controles. A presença de mutação foi verificada por eletroforese conformacional de fita simples e sequenciamento automático. Demonstramos bandas anormais em alguns pacientes, que representaram uma mutação não conservativa: substituição de um nucleotídeo (AGT->GGT) no códon 422 do gene da ELN em cinco pacientes com DDC. Nenhum indivíduo controle estudado apresentou este tipo de mutação. Observamos uma associação significante (P=0,003) desta mutação com o desenvolvimento da DDC e risco relativo 3,89 vezes maior (intervalo de confiança de 95%: 2,21-6,83) dos indivíduos com esta mutação desenvolver DDC. Esta mutação troca Serina, um aminoácido não polar, por glicina, um aminoácido neutro, alterando a estrutura hidrofóbica da elastina e secundariamente a estrutura da fibra elástica. Esta alteração pode promover perda da complacência da parede intestinal e o desenvolvimento de divertículo / Colonic diverticular disease (CDD) is related to civilization, industrialization and diet. Physiological studies demonstrated that increased intraluminal pressures as well as acquired structural changes of the intestinal wall seem to be decisive factors, which intensify during ageing. These changes may be due to alterations of the musculare and connective tissues and are related to collagen and elastin metabolism, which presumably can be genetically determined. It is known that patients with genetic disorders of elastin gene (ELN), such as supravalvular aortic stenosis and cutis laxa, may also manifest hernias, diverticulosis and bladder dysfunction. Recently, punctual mutations were demonstrated in ELN exon 20 of inguinal hernia patients. In the the present study, the polymorphism ELN exon 20 was tested in 14 patients with CDD and in 26 controls. Mutations were sought by singlestrand conformation polymorphism and by automatical sequence. An abnormal band was demonstrated in some patients, representing a missense mutation: a single nucleotide substitution (AGT->GGT) was detected in codon 422 in five patients with CDD. There is a substituion of serine, a nonpolar amino acid, by glycine, na uncharged one. No controls showed this punctual mutation(P=0,003), and the odds ratio for development of CDD was 3.33 (95% confidence interval:1,98-5,62). As a consequence of this substitution, the hydrophobic structure of elastin and of elastic fiber may promote a loss of compliance of the intestinal wall and development of diverticula

Molekulargenetische Feinanalyse der Cutis laxa assoziierten Kandidatengene ELN und FBLN5 bei der Divertikelerkrankung. Bei Unterformen der Cutis laxa, einer genetisch heterogenen Gruppe von Bindegewebserkrankungen, fanden sich Mutationen des Elastin-Gens und des Fibulin-5-Gens ursächlich für die Erkrankung. Bei diesen Unterformen kommt es gehäuft zum Auftreten einer Divertikelerkrankung. Es wurden Einzelnukleotid-Polymorphismen (SNPs) in diesen Genen genotypisiert und auf eine Risikoassoziation mit der Divertikelerkrankung getestet. Mit Hilfe von statistischen Analysen wurde die Genotyp- und Allelfrequenz zwischen Personen, die an Divertikulose oder Divertikulitis erkrankt sind, mit denen gesunder Personen aus der Kontrollgruppe verglichen. Falls eine genetische Variante die kausale Ursache der Divertikulose oder Divertikulitis sein sollte oder mit einer kausalen Variante im Kopplungsungleichgewicht stehen sollte, dann wäre ein signifikanter Unterschied der Genotyp- bzw. Allelfrequenzen zwischen Patienten mit Divertikulose und Personen ohne Divertikel zu erwarten. In die Fallgruppe konnten insgesamt 2.871 Patienten mit Divertikelerkrankung eingeschlossen werden. Die Kontrollgruppe umfasste 1.167 Personen. Untersucht wurden 77 SNPs des ELN-Gens und 123 SNPs der stromabwärts angrenzenden Region inklusive des Nachbargens LIMK1. Zwölf dieser SNPs erreichten jeweils die Signifikanzschwelle (p-Wert < 0,05). Die Signifikanz der Ergebnisse konnte auch in der Bonferroni-Korrektur für multiples Testen bestätigt werden. Somit ergab die Untersuchung der SNPs für das ELN- und LIMK1-Gen eine Assoziation zum Auftreten einer Divertikulose. Allerdings war eine genaue Diskriminierung zwischen dem Kandidatengen ELN und dessen Nachbargen LIMK1 nicht möglich, da das Assoziationssignal beide Gene überspannte. Die Ergebnisse der gewebespezifischen Genexpressionsanalyse legen nahe, dass der SNP rs34208922 im 3´UTR Bereich des ELN-Genes signifikant mit alternativem Spleißen (sQTL) des Genes ELN assoziiert ist. Es wurden 315 repräsentative SNPs des FBLN5-Gens untersucht. Es konnte kein Zusammenhang zwischen der Divertikelerkrankung und den genetischen Varianten im FBLN5-Gen nachgewiesen werden.:Abkürzungsverzeichnis 4 Abbildungsverzeichnis 8 Tabellenverzeichnis 9 1. Einleitung 10 1.1 Definitionen der Divertikelerkrankung 10 1.2 Divertikulose des Kolons 12 1.2.1 Epidemiologie 12 1.2.2 Anatomische Voraussetzungen 13 1.2.3 Lokalisation 15 1.2.4 Klinik 15 1.2.5 Diagnostik 17 1.2.6 Therapie 17 1.3 Divertikulitis 17 1.3.1 Klinik 19 1.3.2 Diagnostik 20 1.3.3 Therapie 21 1.4 Ätiologie und Risikofaktoren der Divertikulose 23 1.4.1 Beeinflussbare Risikofaktoren 23 1.4.2 Nicht-beeinflussbare Risikofaktoren 27 1.5 Möglicher Einfluss genetischer Risikofaktoren auf die Divertikelerkrankung 31 1.5.1 Familiäre Risikofaktoren 32 1.5.2 Assoziation der Divertikulose mit genetischen Erkrankungen 34 1.5.3 Mögliche Kandidatengene für die Divertikulose 39 1.5.4 Bereits bekannte Risikogene für die Divertikulose 39 1.5.5 Die Gene ELN und FBLN5 40 1.5.6 Komplexe genetische Erkrankungen 42 1.5.7 Hypothesengesteuerte Studien - Kandidatengenstudien 44 1.5.8 Einzelnukleotid-Polymorphismus 45 2. Zielsetzung 47 3. Material und Methoden 48 3.1 Patientenrekrutierung 48 3.1.1 Überregionale Patientenrekrutierung 50 3.1.2 Rekrutierungsplattform PopGen 50 3.1.3 Ein und Ausschlusskriterien für das Patientenkollektiv 51 3.2 Datenschutz und Ethik 53 3.3 Genotypisierung 54 3.3.1 Labortechnische Methoden - DNA-Extraktion 54 3.3.2 Labortechnische Methoden - Genotypisierungsverfahren 55 3.3.3 Imputation der Daten 56 3.4 Kandidatengenansatz 57 3.5 Genetische Assoziationsstudien 58 3.6 Metaanalysen 59 3.7 Kopplungsungleichgewicht 59 3.8 Odds-Ratio 60 3.9 Chi-Quadrat-Test 61 3.10 Power-Schätzung 62 3.11 Bonferroni-Korrektur 62 4. Ergebnisse 64 4.1 Demographie des Patientenkollektivs 64 4.2 Ergebnisse der Analyse der ELN-Genregion 69 4.2.1 Genetische Varianten des ELN-Gens und ihre Assoziation zur Transkriptionsrate und zum alternativen Spleißen 73 4.3 Ergebnisse der Analyse des FBLN5-Gens 75 5. Diskussion 79 5.1 Gegenwärtiger Kenntnisstand zu identifizierten Risikoloci der Divertikelerkrankung 79 5.2 Ergebnisse für die Analysen der Kandidatengene ELN und FBLN5 80 5.2.1 Quantitative Trait Locus 85 5.3 Limitationen der Untersuchung 87 5.4 Ausblick und medizinethische Schlussfolgerungen 89 6. Zusammenfassung 92 6.1 Hintergrund 92 6.2 Zielsetzung 92 6.3 Material und Methoden 93 6.4 Ergebnisse 93 6.5 Diskussion 94 7. English summary 96 7.1 Background 96 7.2 Objective 96 7.3 Material and methods 97 7.4 Results 97 7.5 Discussion 98 8. Literaturverzeichnis 99 9. Anlagen 121 9.1 Anlage 1: Fragebogen der Fallgruppe 122 9.2 Anlage 2: Einverständniserklärung und Merkblatt 133 9.3 Anlage 3: Fragebogen der Kontrollgruppe 135 9.4 Anlage 4: Ergebnisse der Assoziationsanalyse des Gens ELN 143 9.5 Anlage 5: Ergebnisse der Assoziationsanalyse des Gens FBLN5 148 9.6 Anlage 6: Bekannte Risikoloci für die Divertikelerkrankung 156 Danksagung Erklärung zur Eröffnung des Promotionsverfahrens Erklärung zur Einhaltung rechtlicher Vorschriften Verzeichnis der wissenschaftlichen Veröffentlichungen