Identification of Risk Loci for Crohn’s Disease Phenotypes Using a Genome-Wide Association Study

Alonso, Arnald; Domènech, Eugeni; Juliá, Antonio; Panés, Julián; García–Sánchez, Valle; Mateu, Pilar Nos; Gutiérrez, Ana; Gomollón, Fernando; Mendoza, Juan L.; García‐Planella, Esther; Acosta, Manuel Barreiro‐de; Muñoz, Fernándo; Vera, Maribel; Saro, Cristina; Esteve, María; Andreu, Montserrat; Chaparro, María; Manyé, Josep; Cabré, Eduard; López-Lasanta, María; Tortosa, Raül; Gelpí, Josep Lluís; García‐Montero, Andrés C.; Bertranpetit, Jaume; Absher, Devin; Myers, R; Marsal, Sara; Gisbert, Javier P.

doi:10.1053/j.gastro.2014.12.030

Cited by 47 publications

(42 citation statements)

References 62 publications

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“…Patients and controls included in the analysis were recruited by the Immune-Mediated Disease Consortium [29–32]. Informed consent was obtained from all participants, and protocols were reviewed and approved by local institutional review boards.…”

Section: Methodsmentioning

confidence: 99%

Urine metabolome profiling of immune-mediated inflammatory diseases

Alonso¹,

Juliá²,

Vinaixa

et al. 2016

BMC Med

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112

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BackgroundImmune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn’s disease, and ulcerative colitis.MethodsUsing nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls.ResultsIn the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (PFDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (PFDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an over-representation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways.ConclusionsThis study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0681-8) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Urine metabolome profiling of immune-mediated inflammatory diseases

Alonso¹,

Juliá²,

Vinaixa

et al. 2016

BMC Med

Self Cite

112

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“…Stenosing phenotype was found to be associated with NOD2 , JAK2 , and ATG16L1 (116). A separate recent study examining >10,000 European CD patients through GWAS of clinical phenotypes found that MAGI1 variant (which encodes a protein involved in intestinal epithelial tight junction) was associated with a complicated structuring phenotype, whereas variants in CLCA2 , 2q24.1 , and LY75 loci were associated with ileal involvement, mild disease course, and the presence of erythema nodosum, respectively (117). In UC, a SNP-based risk scoring system including 46 SNPs was able to differentiate medically refractory UC from non-medically refractory patients, thus predicting the need for surgery (118).…”

Section: Genotype-phenotype Correlation and Clinical Applicationsmentioning

confidence: 99%

Genetics and Pathogenesis of Inflammatory Bowel Disease

Liu

Stappenbeck

2016

Annu. Rev. Pathol. Mech. Dis.

231

156

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We are currently in an exciting time where our understanding of genetic underpinnings of inflammatory bowel disease (IBD) has undergone a revolution, based in large part by novel genotyping and sequencing technologies. With >160 susceptible loci identified for IBD, the goals now are to understand at a fundamental level, the function of these susceptibility alleles. Clinical relevance of how these susceptible genes shape the development of IBD is also a high priority. The main challenge is to understand how the environment and microbiome play a role in triggering disease in genetically susceptible individual, as the interactions may be complex. To advance the field, novel in vitro and mouse models that are designed to interrogate complex genetics and be able to functionally test hypotheses are needed. Ultimately, the goal of genetics studies will be to translate genetics to the patients with IBD and improve their care.

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“…Genome wide association studies have identified over 160 risk loci associated with IBD [1] with distinct genetic profiles associated with specific IBD phenotypes [2, 3]. In addition, a number of disease characteristics including location and behavior, age of onset, and disease duration are associated with different outcomes and response to therapy [4–6].…”

Section: Introductionmentioning

confidence: 99%

Clinical Activity and Quality of Life Indices Are Valid Across Ulcerative Colitis But Not Crohn’s Disease Phenotypes

Taleban

Stewart

et al. 2016

Dig Dis Sci

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Background Clinical activity and quality of life (QOL) indices assess disease activity in Crohn’s disease (CD) and ulcerative colitis (UC). However, a paucity of data exists on the validity of these indices according to disease characteristics. Aims To examine the correlation between QOL and clinical activity indices and endoscopic disease activity according to disease characteristics. Methods We used a prospective registry to identify CD and UC patients ≥18 years old with available information on Short Inflammatory Bowel Disease Questionnaire scores (SIBDQ), Harvey–Bradshaw Index (HBI) and simple endoscopic scores for CD (SES-CD), and Simple Clinical Colitis Activity Index (SCCAI) and Mayo endoscopic score for UC. We used Spearman rank correlations to calculate correlations between indices and Fisher transformation to compare correlations across disease characteristics. Results Among 282 CD patients, we observed poor correlation between clinical activity and QOL indices to SES-CD with no differences in correlation according to disease characteristics. Conversely, among 226 UC patients, clinical activity and QOL had good correlation to Mayo endoscopic score (r = 0.55 and −0.56, respectively) with better correlations observed with left-sided versus extensive colitis (r = 0.73 vs. 0.45, p = 0.005) and shorter duration of disease (r = 0.61 vs. 0.37, p = 0.04). Conclusions Our data suggest good correlation between SCCAI and endoscopic disease activity in UC, particularly in left-sided disease. Poor correlations between HBI or SIBDQ and SES-CD appear to be consistent across different disease phenotypes.

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Identification of Risk Loci for Crohn’s Disease Phenotypes Using a Genome-Wide Association Study

Cited by 47 publications

References 62 publications

Urine metabolome profiling of immune-mediated inflammatory diseases

Urine metabolome profiling of immune-mediated inflammatory diseases

Genetics and Pathogenesis of Inflammatory Bowel Disease

Clinical Activity and Quality of Life Indices Are Valid Across Ulcerative Colitis But Not Crohn’s Disease Phenotypes

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