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Taylor KM, Hanscombe KB, Prescott NJ, Iniesta R, Traylor M, Taylor NS, Fong S, Powell N, Irving PM, Anderson SH, Mathew CG, Lewis CM, Sanderson JD. Genetic and Inflammatory Biomarkers Classify Small Intestine Inflammation in Asymptomatic First-degree Relatives of Patients With Crohn's Disease. Clin Gastroenterol Hepatol 2020; 18:908-916.e13. [PMID: 31202982 DOI: 10.1016/j.cgh.2019.05.061] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 05/22/2019] [Accepted: 05/29/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Relatives of individuals with Crohn's disease (CD) carry CD-associated genetic variants and are often exposed to environmental factors that increase their risk for this disease. We aimed to estimate the utility of genotype, smoking status, family history, and biomarkers can calculate risk in asymptomatic first-degree relatives of patients with CD. METHODS We recruited 480 healthy first-degree relatives (full siblings, offspring or parents) of patients with CD through the Guy's and St Thomas' NHS Foundation Trust and from members of Crohn's and Colitis, United Kingdom. DNA samples were genotyped using the Immunochip. We calculated a risk score for 454 participants, based on 72 genetic variants associated with CD, family history, and smoking history. Participants were assigned to highest and lowest risk score quartiles. We assessed pre-symptomatic inflammation by capsule endoscopy and measured 22 markers of inflammation in stool and serum samples (reference standard). Two machine-learning classifiers (elastic net and random forest) were used to assess the ability of the risk factors and biomarkers to identify participants with small intestinal inflammation in the same dataset. RESULTS The machine-learning classifiers identified participants with pre-symptomatic intestinal inflammation: elastic net (area under the curve, 0.80; 95% CI, 0.62-0.98) and random forest (area under the curve, 0.87; 95% CI, 0.75-1.00). The elastic net method identified 3 variables that can be used to calculate odds for intestinal inflammation: combined family history of CD (odds ratio, 1.31), genetic risk score (odds ratio, 1.14), and fecal calprotectin (odds ratio, 1.04). These same 3 variables were among the 5 factors associated with intestinal inflammation in the random forest model. CONCLUSION Using machine learning classifiers, we found that genetic variants associated with CD, family history, and fecal calprotectin together identify individuals with pre-symptomatic intestinal inflammation who are therefore at risk for CD. A tool for detecting people at risk for CD before they develop symptoms would help identify the individuals most likely to benefit from early intervention.
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Affiliation(s)
- Kirstin M Taylor
- Department of Medical and Molecular Genetics, King's College London, London, United Kingdom; Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
| | - Ken B Hanscombe
- Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
| | - Natalie J Prescott
- Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
| | - Raquel Iniesta
- Department of Medical and Molecular Genetics, King's College London, London, United Kingdom; Department of Biostatistics and Health Informatics, King's College London, London, United Kingdom
| | - Matthew Traylor
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Nicola S Taylor
- Department of Gastroenterology, Southampton General Hospital, Southampton, United Kingdom
| | - Steven Fong
- Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
| | - Nicholas Powell
- Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
| | - Peter M Irving
- Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
| | - Simon H Anderson
- Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
| | - Christopher G Mathew
- Department of Medical and Molecular Genetics, King's College London, London, United Kingdom; Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Cathryn M Lewis
- Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
| | - Jeremy D Sanderson
- Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, United Kingdom
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Moller FT, Knudsen L, Harbord M, Satsangi J, Gordon H, Christiansen L, Christensen K, Jess T, Andersen V. Danish cohort of monozygotic inflammatory bowel disease twins: Clinical characteristics and inflammatory activity. World J Gastroenterol 2016; 22:5050-5059. [PMID: 27275097 PMCID: PMC4886380 DOI: 10.3748/wjg.v22.i21.5050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 03/21/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To describe the establishment of a Danish inflammatory bowel diseases (IBD) twin cohort with focus on concordance of treatment and inflammatory markers.
METHODS: We identified MZ twins, likely to be discordant or concordant for IBD, by merging information from the Danish Twin Register and the National Patient Register. The twins were asked to provide biological samples, questionnaires, and data access to patient files and public registries. Biological samples were collected via a mobile laboratory, which allowed for immediate centrifugation, fractionation, and storage of samples. The mean time from collection of samples to storage in the -80 °C mobile freezer was less than one hour. The diagnoses where validated using the Copenhagen diagnostic criteria.
RESULTS: We identified 159 MZ IBD twin pairs, in a total of 62 (39%) pairs both twins agreed to participate. Of the supposed 62 IBD pairs, the IBD diagnosis could be confirmed in 54 pairs. The cohort included 10 concordant pairs, whereof some were discordant for either treatment or surgery. The 10 concordant pairs, where both pairs suffered from IBD, included eight CD/CD pairs, one UC/UC pair and one UC/IBDU pair. The discordant pairs comprised 31 UC, 5 IBDU (IBD unclassified), and 8 CD discordant pairs. In the co-twins not affected by IBD, calprotectin was above 100 μg/g in 2 participants, and above 50 μg/g in a further 5 participants.
CONCLUSION: The presented IBD twin cohorts are an excellent resource for bioinformatics studies with proper adjustment for disease-associated exposures including medication and inflammatory activity in the co-twins.
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Michielan A, D’Incà R. Host-microbiome interaction in Crohn’s disease: A familiar or familial issue? World J Gastrointest Pathophysiol 2015; 6:159-168. [PMID: 26600974 PMCID: PMC4644880 DOI: 10.4291/wjgp.v6.i4.159] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 09/13/2015] [Accepted: 10/27/2015] [Indexed: 02/07/2023] Open
Abstract
An impaired interaction between the gut and the intestinal microbiome is likely to be the key element in the pathogenesis of Crohn’s disease (CD). Family studies have provided invaluable information on CD pathogenesis and on its etiology. Relatives share the same genetic risk of developing the disease as affected subjects. Relatives also exhibit similar features relating to their host-microbiome interaction, namely genetic variants in loci involved in detecting bacteria, a greater sero-reactivity to microbial components, and an impaired intestinal permeability. The burden of environmental factors such as cigarette smoking and dysbiosis also seems to be particularly relevant in these genetically predisposed subjects. Diet is emerging as an important factor and could account for the changing epidemiology of CD in recent years. Despite the pivotal role of genetics in the disease’s pathogenesis (especially in familial CD), screening tests in healthy relatives cannot be recommended.
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