RESUMO
BACKGROUND AND AIMS: Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD. METHODS: A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn's disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci [pQTL] analysis). Intestinal mucosal RNA sequencing and faecal metagenomic data were used for complementary analyses. RESULTS: Thirty-two proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins were independent of active inflammation; 69 proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 [FUT2] gene [rs602662] and two independent cis-pQTLs of C-C motif chemokine 25 [CCL25] affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression [e]QTL-variant [rs3745387] of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of faecal butyrate-producing bacteria. CONCLUSIONS: This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD, and identifies disease-associated pathways that may help to improve disease management in the future.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Estudos de Casos e Controles , Colite Ulcerativa/diagnóstico , Genótipo , Humanos , Doenças Inflamatórias Intestinais/genética , Fenótipo , Proteoma/genéticaRESUMO
BACKGROUND: Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn's disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity. MATERIALS AND METHODS: Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. RESULTS: Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. CONCLUSIONS: We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD.
Assuntos
Adalimumab/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Infliximab/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/patologia , Feminino , Expressão Gênica , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis-expression quantitative trait loci (cis-eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis-eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis-eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis-eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD.
Assuntos
Regulação da Expressão Gênica , Variação Genética , Inflamação/genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Adulto , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
BACKGROUND AND AIMS: The human gastrointestinal tract harbours distinct microbial communities essential for health. Little is known about small intestinal communities, despite the small intestine playing a fundamental role in nutrient absorption and host-microbe immune homeostasis. We aimed to explore the small intestine microbial composition and metabolic potential, in the context of inflammatory bowel disease [IBD]. METHODS: Metagenomes derived from faecal samples and extensive phenotypes were collected from 57 individuals with an ileostomy or ileoanal pouch, and compared with 1178 general population and 478 IBD faecal metagenomes. Microbiome features were identified using MetaPhAn2 and HUMAnN2, and association analyses were performed using multivariate linear regression. RESULTS: Small intestinal samples had a significantly lower bacterial diversity, compared with the general population and, to a lesser extent, IBD samples. Comparing bacterial composition, small intestinal samples clustered furthest from general population samples and closest to IBD samples with intestinal resections. Veillonella atypica, Streptococcus salivarius, and Actinomyces graevenitzii were among the species significantly enriched in the small intestine. Predicted metabolic pathways in the small intestine are predominantly involved in simple carbohydrate and energy metabolism, but also suggest a higher pro-inflammatory potential. CONCLUSIONS: We described the bacterial composition and metabolic potential of the small intestinal microbiota. The colonic microbiome of IBD patients, particularly with intestinal resections, showed resemblance to that of the small intestine. Moreover, several features characterising the small intestinal microbiome have been previously associated with IBD. These results highlight the importance of studying the small intestinal microbiota to gain new insight into disease pathogenesis.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Intestino Delgado/microbiologia , Estudos de Coortes , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10-05 ) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10-05 ) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.
Assuntos
Transplante de Fígado , Trombose , Adulto , Criança , Estudo de Associação Genômica Ampla , Sobrevivência de Enxerto , Humanos , Transplante de Fígado/efeitos adversos , Doadores Vivos , Estudos Retrospectivos , Fatores de Risco , Trombose/genética , Doadores de TecidosRESUMO
BACKGROUND AND AIM: While major efforts were made studying the complex etiology of inflammatory bowel disease (IBD) including environmental factors, less is known about underlying causes leading to the heterogeneous and highly variable course of disease. As cigarette smoking cessation is the best-known environmental factor with beneficial effect in Crohn's disease (CD), more exposome factors are likely involved. Further insights into the role of the exposome in heterogeneity of disease might not only further knowledge of underlying pathways, but also allow for better risk stratification. METHODS: Seven hundred twenty-eight IBD patients completed the validated Groningen IBD Environmental Questionnaire, collecting exposome data for 93 exposome factors. Associations with disease course, that is, for need for surgery or biological therapy, were evaluated using univariate and multivariate-adjusted logistic regression modeling. RESULTS: No significant associations were seen after Bonferroni correction. However, 11 novel exposome factors were identified with P < 0.05. Two factors were associated with course of CD and ulcerative colitis (UC): beer (CD OR0.3/UC OR0.3) and cannabis (0.5/2.2). While in CD, carpet flooring (0.5) was associated with biological use, and four factors were associated with surgery: working shifts (1.8), appendectomy (2.4), frequent tooth brushing (2.8), and large household size (0.1). For UC, migrants more often required biologicals (10.2). Childhood underweight (3.4), amphetamine use (6.2), and cocaine use (4.8) were associated with surgery. Five factors were replicated. CONCLUSIONS: We identified 16 environmental factors nominally associated with biological use and surgery in established IBD. These new insights form an important stepping stone to guide research on biological pathways involved, risk stratification, tailor-made interventions, and preventive strategies in IBD.
Assuntos
Fatores Biológicos/uso terapêutico , Colite Ulcerativa/cirurgia , Doença de Crohn/cirurgia , Expossoma , Adulto , Apendicectomia , Cerveja/efeitos adversos , Cannabis/efeitos adversos , Fumar Cigarros/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/etiologia , Colite Ulcerativa/prevenção & controle , Doença de Crohn/tratamento farmacológico , Doença de Crohn/etiologia , Doença de Crohn/prevenção & controle , Feminino , Pisos e Cobertura de Pisos , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Jornada de Trabalho em Turnos/efeitos adversos , Abandono do Hábito de Fumar , Inquéritos e Questionários , Escovação DentáriaRESUMO
BACKGROUND: The role of Mycobacterium avium paratuberculosis [MAP] in inflammatory bowel disease [IBD], especially Crohn's disease [CD] is controversial due conflicting results and lack of reproducibility and standardised tests. The current study focuses on the role of MAP in disease progression and genetic susceptibility, as MAP is likely one of many factors involved in the complex pathogenesis of IBD, potentially affecting a subgroup depending on genetic susceptibility. METHODS: Serum from 812 patients was evaluated with seven immunoglobulin [Ig] isotype-specific serology tests assessing humoral response to three different MAP antigens. For each of these in total 21 tests, the intra-assay and inter-assay coefficients were used to evaluate test accuracy. Reliable assays were subsequently analysed in relation to disease characteristics and need for biologic therapy/surgery. Genome-wide genotyping was available for all participants. Genetic determinants of humoral response to MAP antigens were evaluated using genome-wide association analysis and polygenic risk scores [PRS]. RESULTS: High IgA or IgM response to MAP2609 was associated with increased use of biologic therapy in CD and ulcerative colitis [UC] [odds ratios 2.69; 95% confidence interval 1.44-5.01; and 2.60, 1.46-4.64, respectively]. No associations were seen for risk of surgery [p-valuesâ >â 0.29]. We could not identify genetic determinants nor polygenic risk scores for MAP response with genome-wide significance. CONCLUSIONS: Extensive assays for serological response to MAP were evaluated using stringent criteria for reliability. Increased IgA and IgM response to MAP antigens was seen in patients exposed to biologic therapy, but no genetic determinants underlying this humoral response were found.
Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Terapia Biológica , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mycobacterium avium subsp. paratuberculosis/imunologia , Estudos de Coortes , Estudos Transversais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunoglobulina A/sangue , Imunoglobulina M/sangue , Doenças Inflamatórias Intestinais/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium avium subsp. paratuberculosis/genética , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Thrombosis after liver transplantation is a leading cause of graft loss, morbidity, and mortality. Several known recipient- and surgery-related characteristics have been associated with increased risk of thrombosis after transplantation. Potential donor-related risk factors, however, remain largely undefined. OBJECTIVES: We aimed to identify risk factors for early post-transplantation thrombosis (<90 days) and to determine the impact of early postoperative thrombosis on long-term graft and patient survival. PATIENTS/METHODS: A post hoc analysis was performed of an observational cohort study including all primary, adult liver transplantations performed between 1993 and 2018. Donor-, recipient-, and surgery-related characteristics were collected. Competing risk model analyses and multivariable regression analyses were performed to identify risk factors for developing early post-transplant thrombosis and graft failure. RESULTS: From a total of 748 adult liver transplantations, 58 recipients (7.8%) developed a thrombosis after a median of 7 days. Post-transplantation thrombotic events included 25 hepatic artery thromboses, 13 portal vein thromboses, and 22 other thrombotic complications. Donor history of smoking was independently associated with early postoperative thrombosis (odds ratio [OR] 2.42; 95% confidence interval [CI], 1.29-4.52). Development of early post-transplant thrombosis was independently associated with patient mortality (hazard ratio [HR] 3.61; 95% CI 1.54-8.46) and graft failure (HR 5.80, 95% CI 3.26-10.33), respectively. CONCLUSION: Donor history of smoking conveys a more than two-fold increased risk of thrombosis after liver transplantation, independent of other factors. Post-transplant thrombosis was independently associated with decreased patient and graft survival.
Assuntos
Transplante de Fígado , Trombose , Adulto , Artéria Hepática , Humanos , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Trombose/epidemiologia , Trombose/etiologia , Fumar TabacoRESUMO
OBJECTIVES: Cytomegalovirus (CMV) infection is common in the general population. CMV infection negatively affects disease course in transplant recipients and HIV patients. Whereas primary CMV infections may occur sporadically in seronegative patients, all seropositive patients with inflammatory bowel syndrome (IBD) are at risk for CMV reactivation due to the inflammatory mucosal and use of immunosuppressive medication. It is unclear whether latent CMV infection, and risk of reactivations, influences long-term disease outcomes. In this study, we aim to explore whether CMV infection affects disease outcomes in IBD patients. METHODS: We performed a cross-sectional cohort study with 1404 patients with IBD from a single center. Clinical characteristics and disease outcomes were prospectively collected. We scrutinized CMV serology test results and performed additional CMV serology testing if serum was available. RESULTS: Out of 699 IBD patients with CMV serology, 303 (43.3%) were seropositive, comparable to the general Dutch population. CMV seropositivity was associated with older age, longer IBD disease duration, non-Western origin, birth outside the Netherlands and a lower educational level (p-values ≤ .004). CMV seropositivity was not associated with more complicated long-term disease outcomes of IBD (p-values > .05). Seropositive patients presented with symptoms and were diagnosed at an older age compared to seronegative patients (p-values < .01). CONCLUSIONS: CMV seropositivity does not influence disease outcomes of IBD patients and seems to be associated with a delay in IBD onset. Guidelines regarding CMV screening in patients with IBD are currently based on a low level of evidence. These data support the recommendation that routine CMV serology measurement is not necessary in the clinical care of IBD.
Assuntos
Infecções por Citomegalovirus , Infecções por HIV , Doenças Inflamatórias Intestinais , Idoso , Estudos Transversais , Citomegalovirus , Infecções por Citomegalovirus/complicações , Humanos , Doenças Inflamatórias Intestinais/complicações , Países BaixosRESUMO
BACKGROUND: High inter-individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre-treatment pharmacogenetic testing into clinical guidelines has been slow. AIM: To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response. METHODS: Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole-exome sequencing and the Illumina Global Screening Array. An in-house-developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic-guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD. RESULTS: Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses. CONCLUSIONS: This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses.
Assuntos
Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Variantes Farmacogenômicos/genética , Transcriptoma , Adolescente , Adulto , Idoso , Biomarcadores Farmacológicos/análise , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Transcriptoma/efeitos dos fármacos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low. AIM: To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment. METHODS: Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed. RESULTS: In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring. CONCLUSION: Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval.
Assuntos
Técnicas de Laboratório Clínico , Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Quimioterapia de Manutenção , Purinas/uso terapêutico , Adulto , Alopurinol/uso terapêutico , Azatioprina/uso terapêutico , Técnicas de Laboratório Clínico/métodos , Monitoramento de Medicamentos/métodos , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/diagnóstico , Quimioterapia de Manutenção/métodos , Masculino , Mercaptopurina/uso terapêutico , Pessoa de Meia-Idade , Países Baixos , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Metiltransferases/metabolismo , Pirofosfatases/genética , Adolescente , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Exoma , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Contagem de Leucócitos , Masculino , Metiltransferases/genética , Metiltransferases/uso terapêutico , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , População Branca , Adulto JovemRESUMO
BACKGROUND: Gene-microbiome interactions are important in aetiology and pathogenesis of inflammatory bowel disease, a chronic inflammatory disorder of the gastrointestinal tract consisting of Crohn's disease and ulcerative colitis. Scarce studies on gene-microbiome interactions show very little overlap in their results. Therefore, it is of utmost importance that gene-microbiome studies are repeated. We aimed to replicate the association between the SLC39A8 [Thr]391 risk allele and gut microbiome composition in patients with inflammatory bowel disease and healthy controls. METHODS: We collected faecal samples, peripheral blood and extensive phenotype data from 291 patients with inflammatory bowel disease and 476 healthy controls. Carrier status information was obtained from whole exome sequencing data, generated using the Illumina HiSeq. The gut microbiome composition was determined by tag-sequencing the 16S rRNA gene. Associations between carrier status and disease were tested using the Wilcoxon-Mann-Whitney test. Associations between carriers and gut microbiome composition were determined using principal coordinate analyses, variance explained, alpha diversity and additive general linear models in inflammatory bowel disease, healthy controls and all groups combined. RESULTS: Crohn's disease patients were more often carriers of the missense variant (21/171, 12.3%) than controls (30/476, 6.3%) (OR = 2.1, P = 0.01). We could not identify associations between carrier status and overall gut microbiome composition and microbial richness in all tested groups after correcting for potential confounding factors. We did identify 37 different operational taxonomical units to be associated with carrier status among the tested groups. Two of these 37 were identified before in the discovery study. CONCLUSIONS: We could confirm the genetic association of the SLC39A8 [Thr]391 risk allele with Crohn's disease but we could only limited replicate the association in gut microbiome composition. Independent replication of gene-microbiome studies is warranted to identify true biological mechanisms.
Assuntos
Bactérias/classificação , Proteínas de Transporte de Cátions/genética , Doença de Crohn/genética , Mutação de Sentido Incorreto , RNA Ribossômico 16S/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Bactérias/genética , Bactérias/isolamento & purificação , Estudos de Casos e Controles , DNA Bacteriano/genética , DNA Ribossômico/genética , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Análise de Componente PrincipalAssuntos
Doença de Crohn/genética , Estudo de Associação Genômica Ampla , Íleo/patologia , Terapia de Alvo Molecular , Linfócitos T/citologia , Adulto , Células Cultivadas , Estudos de Coortes , Colagenases/uso terapêutico , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Ácido Edético/uso terapêutico , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA , Linfócitos T/efeitos dos fármacos , Resultado do TratamentoRESUMO
Changes in the gut microbiota have been associated with two of the most common gastrointestinal diseases, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Here, we performed a case-control analysis using shotgun metagenomic sequencing of stool samples from 1792 individuals with IBD and IBS compared with control individuals in the general population. Despite substantial overlap between the gut microbiome of patients with IBD and IBS compared with control individuals, we were able to use gut microbiota composition differences to distinguish patients with IBD from those with IBS. By combining species-level profiles and strain-level profiles with bacterial growth rates, metabolic functions, antibiotic resistance, and virulence factor analyses, we identified key bacterial species that may be involved in two common gastrointestinal diseases.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Síndrome do Intestino Irritável/microbiologia , Bactérias/crescimento & desenvolvimento , Bactérias/patogenicidade , Biodiversidade , Estudos de Casos e Controles , Resistência Microbiana a Medicamentos , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Metagenoma , Modelos Biológicos , Fenótipo , Análise de Componente Principal , Curva ROC , Especificidade da Espécie , VirulênciaRESUMO
Recent studies have greatly improved our insight into the genetic background of inflammatory bowel disease (IBD). New high-throughput technologies and large-scale international collaborations have contributed to the identification of 200 independent genetic risk loci for IBD. However, in most of these loci, it is unclear which gene conveys the risk for IBD. More importantly, it is unclear which variant within or near the gene is causal to the disease. Using targeted GWAS, imputation, resequencing of risk loci, and in silico fine-mapping of densely typed loci, several causal variants have been identified in IBD risk genes, and various pathological pathways have been uncovered. Current research in the field of IBD focuses on the effect of these causal variants on gene expression and protein function. However, more elements than only the genome must be taken into account to disentangle the multifactorial pathology of IBD. The genetic risk loci identified to date only explain a small part of genetic variance in disease risk. Currently, large multi-omics studies are incorporating factors ranging from the gut microbiome to the environment. In this review, we present the progress that has been made in IBD genetic research and stress the importance of studying causality to increase our understanding of the pathogenesis of IBD. We highlight important causal genetic variants in the candidate genes NOD2, ATG16L1, IRGM, IL23R, CARD9, RNF186, and PRDM1. We describe their downstream effects on protein function and their direct effects on the gut immune system. Furthermore, we discuss the future role of genetics in unravelling disease mechanisms in IBD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Doença de Crohn/genética , Patrimônio Genético , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Animais , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , HumanosRESUMO
Graft survival after pancreas transplantation alone (PTA) is significantly poorer than graft survival after simultaneous pancreas kidney (SPK) and is particularly affected by difficulty in monitoring rejection. Exocrine bladder drainage allows assessment of pancreas graft function as urinary amylase (UA). However, standards for UA collection and interpretation are not well defined. In this study, 21 bladder-drained PTA recipients were monitored with daily values for UA and urine creatinine (Creat) concentration from post-transplant 10-mL samples and 24-h collections. Clinical events were documented and correlated to UA measurements. UA values were found to increase post-transplant until day 15, and large interpatient variability was noted (median 12 676 IU/L, range 668-60 369 IU/L). A strong correlation was found total 24-h UA production and spot UA/Creat ratio (r = 0.80, p < 0.001). UA/Creat ratio showed less variation during episodes of impaired renal function; therefore, urinary amylase baseline was defined as the median UA/Creat ratio after day 15. A > 25% decrease of UA predicted 9/13 (69%) events. We conclude that individual baselines should be set once the values have stabilized after 15 d post-transplant and that spot UA/Creat measures are reliable, patient friendly and indicate potential events after PTA.