Mortality in patients with Crohn’s disease in Örebro, Sweden 1963–2010

Some studies have suggested a reduced life expectancy in patients with Crohn’s disease (CD) compared with the general population. The evidence, however, is inconsistent. Prompted by such studies, we studied survival of CD patients in Örebro county, Sweden. From the medical records, we identified all patients diagnosed with CD during 1963–2010 with follow-up to the end of 2011. We estimated: overall survival, net and crude probabilities of dying from CD, relative survival ratio (RSR), and excess mortality rate ratios (EMRR) at 10-year follow-up. The study included 492 patients (226 males, 266 females). Median age at diagnosis was 32 years (3–87). Net and crude probabilities of dying from CD increased with increasing age and were higher for women. Net survival of patients aged ≥60 at diagnosis was worse for patients diagnosed during 1963–1985 (54%) than for patients diagnosed during 1986–1999 (88%) or 2000–2010 (93%). Overall, CD patients’ survival was comparable to that in the general population [RSR = 0.98; 95% CI: (0.95–1.00)]. However, significantly lower than expected survival was suggested for female patients aged ≥60 diagnosed during the 1963–1985 [RSR = 0.47 (0.07–0.95)]. The adjusted model suggested that, compared with diagnostic period 1963–1985, disease-related excess mortality declined during 2000–2010 [EMRR = 0.36 (0.07–1.96)]; and age ≥60 at diagnosis [EMRR = 7.99 (1.64–39.00), reference: age 40–59], female sex [EMRR = 4.16 (0.62–27.85)], colonic localization [EMRR = 4.20 (0.81–21.88), reference: ileal localization], and stricturing/penetrating disease [EMRR = 2.56 (0.52–12.58), reference: inflammatory disease behaviour] were associated with poorer survival. CD-related excess mortality may vary with diagnostic period, age, sex and disease phenotype.Key summaryThere is inconsistent evidence on life expectancy of patients with Crohn’s diseaseCrohn’s disease-specific survival improved over time.Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn’s disease-related mortality. There is inconsistent evidence on life expectancy of patients with Crohn’s disease Crohn’s disease-specific survival improved over time. Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn’s disease-related mortality.</p

Allele frequencies of the polymorphism rs2241057 in the <i>CYP26B1</i> gene in patients with inflammatory bowel disease <i>vs</i>. healthy controls.

<p>Chi-square test used for <i>P</i>-values. Odds ratio and confidence interval estimated using 2×2 contingency tables. CD =  Crohn’s disease, UC =  Ulcerative colitis, C =  minor allele, T =  major allele. OR =  odds ratio, CI =  95% confidence interval.^* Uncorrected P-value/FDR corrected P-value.</p

Polymorphism in the Retinoic Acid Metabolizing Enzyme CYP26B1 and the Development of Crohn’s Disease

<div><p>Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn’s disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the <i>CYP26B1</i> rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the <i>CYP26B1</i> polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.</p></div

Clinical characteristics of patients with inflammatory bowel disease.

<p>CD =  Crohn’s disease, UC =  Ulcerative colitis.</p

Genotype frequencies of the polymorphism <i>rs2241057</i> in the <i>CYP26B1</i> gene for patients with Crohn’s disease and healthy controls, displayed for sub phenotypes and clinical features.

<p>Chi-square test used for <i>P</i>-values unless otherwise stated. Odds ratio and confidence interval estimated using 2×2 contingency tables. C =  minor allele, T =  major allele. OR =  odds ratio, CI =  95% confidence interval. ^*Patients with combination of two locations are excluded in this overview, ^† Fisher’s two tailed exact test used.</p

Allele frequencies of the polymorphism <i>rs2241057</i> in the <i>CYP26B1</i> gene for patients with Crohn’s disease versus healthy controls, displayed for sub phenotypes and clinical features.

<p>Chi-square test used for <i>P</i>-values unless otherwise stated. Odds ratio and confidence interval estimated using 2×2 contingency tables. C =  minor allele, T =  major allele. OR =  odds ratio, CI =  95% confidence interval. ^*Patients with combination of two locations are excluded in this overview, ^† Fisher’s two tailed exact test used.</p

Genotype frequencies of the polymorphism rs2241057 in the <i>CYP26B1</i> gene in patients with inflammatory bowel disease <i>vs</i>. healthy controls.

<p>Chi-square test used for <i>P</i>-values. Odds ratio and confidence interval estimated using 2×2 contingency tables. CD =  Crohn’s disease, UC =  Ulcerative colitis, C =  minor allele, T =  major allele. OR =  odds ratio, CI =  95% confidence interval. ^* Uncorrected P-value/FDR corrected P-value.</p

Taxonomic assignments in metagenome and metaproteome datasets.

<p>Relative abundance (log scale) of genera in (<b>A</b>) metagenomic datasets, determined by reference genome alignments and (<b>B</b>) metaproteomic datasets, determined by HMRG PSMs. Error bars represent standard error of the mean of the samples from Healthy (3 MG, 4 MP), ICD (5 MG, 6 MP) and CCD (2 MG/MP). Asterisks indicate genera that were statistically lower in relative abundance in ICD compared to Healthy (q-values of 0.0030, 0.0041, 0.0041, 0.0040 for <i>Faecalibacterium Roseburia, Coprococcus</i> and <i>Dialaster</i>, respectively). <i>Subdolidogranulum</i> was not included in the HMRG database, so it is not shown in the metaproteome. Grey bars  =  Healthy, Blue bars  =  CCD, Red bars  =  ICD. standard error of the mean.</p

Metaproteome differences between mean Healthy and mean ICD COG frequencies.

<p>To determine statistically significant differences between categories, White's non-parametric t-test was used with bootstrapping and Storey FDR multiple test correction. 95% upper and lower confidence intervals are shown. Red and grey bars indicate COG categories that are higher in ICD or Healthy metaproteomes, respectively; Asterisks indicate COG categories that were significantly different between ICD and healthy (q-value<0.05).</p

Comparison of protein expression levels across disease categories.

<p>(<b>A</b>) Boxplots depicting the distribution of the fraction of the metagenomes with PSMs. Boxes indicate 25^th, 50^th and 75^th percentile, with whiskers representing 10^th and 90^th percentile points. (<b>B</b>) Gene family richness as measured by the number of KEGG Orthologous group (KO) matches in the metagenomic dataset. Grey  =  Healthy, Blue  =  CCD, Red  =  ICD.</p