Development and psychometric testing of inflammatory bowel disease fatigue (IBD-F) patient self-assessment scale.

BACKGROUND AND AIMS: Fatigue is one of the main symptoms of inflammatory bowel disease (IBD) and is frequently reported by people in both active and quiescent disease. Many different fatigue assessment scales have been used to measure fatigue, but none has been developed or tested in IBD. This study aimed to develop a fatigue scale specific to the needs and experiences of people with IBD. METHODS: A five-step sequential mixed method design was used: a qualitative phase to assess patients' experience of fatigue and its impact on their lives, and four mixed qualitative-quantitative phases to refine the scale and to assess its psychometric properties. RESULTS: 567 people participated in five phases. The resulting questionnaire has 3 sections: 5 questions assessing frequency and severity of fatigue; 30 questions rating the experience and impact of fatigue; and a free-text section asking for patients' comments and additional issues related to fatigue. Initial validation suggests that the questionnaire has good face and content validity, acceptable to excellent test-retest stability (ICC 0.74 for Section 1 and 0.83 for Section 2) and a high degree of internal consistency (Cronbach's alpha>0.9). CONCLUSIONS: Participants in the study confirmed that fatigue in IBD is burdensome. Items generated and refined by people with IBD-fatigue reflect their experience and form the basis of this new IBD-fatigue scale, which is psychometrically robust with reliability estimates which fall within statistically acceptable ranges. The scale can be used by patients and practitioners to assess severity and impact of fatigue in people with IBD.

Healthcare professionals' perceptions of fatigue experienced by people with IBD.

BACKGROUND AND AIMS: Fatigue is one of the top complaints of people with inflammatory bowel disease (IBD); however this is often not addressed in clinical consultations. This study aimed to gain an understanding of healthcare practitioners' (HCPs) perception of IBD fatigue as experienced by people with IBD. METHODS: Descriptive phenomenology was conducted with 20 HCPs who work with people with IBD. In-depth semi-structured interviews were audio recorded and transcribed verbatim. Colazzi's framework was used to analyse data. RESULTS: Three themes and several sub-themes were identified. The main themes were: the phenomenon of fatigue as perceived by HCPs; the impact of fatigue on patients' lives; and the methods used by HCPs to deal with fatigue. Fatigue was identified as an important, but difficult and frustrating, symptom to understand. HCPs reported that fatigue impacts on the emotional, private and public aspects of patients' functioning, however there were few methods suggested on how to assess and manage the fatigue. Many expressed frustration at not being able to help more. CONCLUSIONS: The study identified a gap in HCPs' knowledge and their understanding of the complexity of IBD fatigue and the full impact that IBD fatigue has on people's lives. There is a need for more research-generated evidence to enhance our understanding of the concept and the factors associated with IBD fatigue. Advances in the assessment and management of this complicated and poorly understood clinical symptom are needed in order to help enable HCPs to provide better quality care to people affected by IBD and IBD fatigue.

Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis.

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.

Genetic association between NLRP3 variants and Crohn's disease does not replicate in a large UK panel.

BACKGROUND: NLRP3 (formerly known as CIAS1 or NALP3) encodes a key component of the inflammasome and is a strong candidate gene for Crohn's disease (CD) susceptibility. A recent study reported significant and internally replicated association between CD and six single nucleotide polymorphisms (SNPs) in a regulatory region 5.3 kb downstream of NLRP3. Independent replication is required to verify these findings. METHODS: In all, 1298 CD cases and 1244 healthy controls were genotyped for the six SNPs using Taqman. Single locus, haplotype, and subphenotype analyses were conducted using logistic regression-based methods and PLINK, respectively. RESULTS: No significant associations were found, either on single locus, subphenotype, or haplotype analysis. CONCLUSIONS: Given our high (>90%) power to replicate findings from the index study, our data suggest either a much smaller effect size for the association between NLRP3 and CD susceptibility than previously reported or the possibility of a false-positive result in the index study. Further studies in other populations are required to determine what role, if any, NLRP3 variants play in CD susceptibility.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population.

BACKGROUND: Identification of Crohn's disease (CD)-associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. METHODS: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. RESULTS: TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01-1.41) P = 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR = 1.44 (95% CI 1.23-1.68) P = 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499-3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. CONCLUSIONS: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease-causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies.

IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease.

BACKGROUND & AIMS: Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn's disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15. METHODS: Eight single nucleotide polymorphism markers in IL23R tested in the North American study were genotyped in 1902 cases of Crohn's disease (CD), 975 cases of ulcerative colitis (UC), and 1345 controls using MassARRAY. Data were analyzed using chi(2) statistics, and subgroup association was sought. RESULTS: A highly significant association with CD was observed, with the strongest signal at coding variant Arg381Gln (allele frequency, 2.5% in CD vs 6.2% in controls [P = 1.1 x 10(-12)]; odds ratio, 0.38; 95% confidence interval, 0.29-0.50). A weaker effect was seen in UC (allele frequency, 4.6%; odds ratio, 0.73; 95% confidence interval, 0.55-0.96). Analysis accounting for Arg381Gln suggested that other loci within IL23R also influence IBD susceptibility. Within CD, there were no subphenotype associations or evidence of interaction with CARD15. CONCLUSIONS: This study shows an association between IL23R and all subphenotypes of CD with a smaller effect on UC. This extends the findings of the North American study, providing clear evidence that genome-wide association scanning can successfully identify true complex disease genes.

Complex insertion/deletion polymorphism in NOD1 (CARD4) is not associated with inflammatory bowel disease susceptibility in East Anglia panel.

BACKGROUND AND AIMS: Genetic association between inflammatory bowel disease (IBD) and NOD1 (CARD4) has recently been reported. This gene has structural similarity to NOD2 (CARD15), a confirmed susceptibility gene for Crohn"s disease (CD). The NOD1 association was strongest at novel complex indel ND1 + 32656. Our aim was to ascertain the contribution of ND1 + 32656 variants to IBD in a large independent United Kingdom dataset and to identify any subphenotype association within CD and ulcerative colitis (UC). METHODS: The presence of the ND1 + 32656 variant in our panel was confirmed by direct resequencing in 96 cases. One thousand three hundred seventy unrelated white IBD subjects (671UC, 645 CD, 54 indeterminate) and 760 regionally matched controls were then genotyped for the ND1 + 32656 variant. Data were analyzed by logistic regression methods within STATA software. RESULTS: There was no association between ND1 + 32656 and IBD in our panel. There was no heterogeneity between UC and CD, nor within the CD subgroup when conditioned by subphenotype or the presence of NOD2 variants. CONCLUSIONS: There was no overall evidence of association between IBD and the reported NOD1 susceptibility variant ND1 + 32656 in our panel. The discrepancy with the earlier report may reflect a smaller effect size than previously predicted, a false-positive result in the index study, or population heterogeneity.

Genetic variants in TNF-alpha but not DLG5 are associated with inflammatory bowel disease in a large United Kingdom cohort.

BACKGROUND: Genetic variants in DLG5, which encodes a scaffolding protein on chromosome 10q23, and tumor necrosis factor (TNF)-alpha, encoding a proinflammatory cytokine on chromosome 6p, have recently been reported to be associated with inflammatory bowel disease (IBD). We studied these variants to seek evidence of association with IBD in a large independent dataset. METHODS: We genotyped 1104 unrelated white IBD subjects-496 with Crohn's disease, 512 with ulcerative colitis, and 96 with indeterminate colitis from the Cambridge/Eastern (UK) panel-and 760 healthy control subjects for DLG5_113G/A, DLG5_4136C/A, TNF-857C/T, and TNF-1031T/C polymorphisms. Known Crohn's disease-predisposing variants in CARD15/NOD2 were also genotyped to permit analysis for reported epistatic interactions. RESULTS: : TNF-857 was shown to be associated with IBD overall (P = 0.0079). A formal interaction test showed that TNF-857 is associated equally with ulcerative colitis and Crohn's disease. Neither of the DLG5 alleles, however, was associated with IBD (P = 0.32 and 0.35). Subgroup analysis also failed to show evidence of association between either DLG5 allele or genotype frequencies and ulcerative colitis or Crohn's disease. Stratification of TNF-alpha and DLG5 cases by CARD15 genotype made no significant difference in the strength of associations. CONCLUSIONS: We have confirmed an association between the TNF-857 promoter polymorphism and IBD in a large independent UK dataset but were unable to replicate an association at the previously reported loci within DLG5. This may reflect heterogeneity between the populations, a smaller effect size than originally predicted, or possibly a false-positive result in the original study. Further fine mapping studies of the TNF promoter region and studies assessing functional consequences of TNF promoter polymorphisms are now required in IBD.