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1.
Nature ; 604(7907): 732-739, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35418674

RESUMO

The gut microbiome is associated with diverse diseases1-3, but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.


Assuntos
Microbioma Gastrointestinal , Bactérias/genética , Dieta , Meio Ambiente , Humanos , Estilo de Vida , Países Baixos , Fatores Socioeconômicos
2.
Anal Chem ; 95(22): 8461-8468, 2023 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-37220321

RESUMO

In recent years, feces has surfaced as the matrix of choice for investigating the gut microbiome-health axis because of its non-invasive sampling and the unique reflection it offers of an individual's lifestyle. In cohort studies where the number of samples required is large, but availability is scarce, a clear need exists for high-throughput analyses. Such analyses should combine a wide physicochemical range of molecules with a minimal amount of sample and resources and downstream data processing workflows that are as automated and time efficient as possible. We present a dual fecal extraction and ultra high performance liquid chromatography-high resolution-quadrupole-orbitrap-mass spectrometry (UHPLC-HR-Q-Orbitrap-MS)-based workflow that enables widely targeted and untargeted metabolome and lipidome analysis. A total of 836 in-house standards were analyzed, of which 360 metabolites and 132 lipids were consequently detected in feces. Their targeted profiling was validated successfully with respect to repeatability (78% CV < 20%), reproducibility (82% CV < 20%), and linearity (81% R2 > 0.9), while also enabling holistic untargeted fingerprinting (15,319 features, CV < 30%). To automate targeted processing, we optimized an R-based targeted peak extraction (TaPEx) algorithm relying on a database comprising retention time and mass-to-charge ratio (360 metabolites and 132 lipids), with batch-specific quality control curation. The latter was benchmarked toward vendor-specific targeted and untargeted software and our isotopologue parameter optimization/XCMS-based untargeted pipeline in LifeLines Deep cohort samples (n = 97). TaPEx clearly outperformed the untargeted approaches (81.3 vs 56.7-66.0% compounds detected). Finally, our novel dual fecal metabolomics-lipidomics-TaPEx method was successfully applied to Flemish Gut Flora Project cohort (n = 292) samples, leading to a sample-to-result time reduction of 60%.


Assuntos
Lipidômica , Metabolômica , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Fluxo de Trabalho , Reprodutibilidade dos Testes , Metabolômica/métodos , Lipídeos/análise
3.
Genes Immun ; 16(4): 247-52, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25611558

RESUMO

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.


Assuntos
Cadeias HLA-DRB1/genética , Hepatite Autoimune/genética , Adulto , Idade de Início , Idoso , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Cadeias HLA-DRB1/imunologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/etiologia , Hepatite Autoimune/terapia , Humanos , Imunoglobulina G/sangue , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Resultado do Tratamento
4.
Biochim Biophys Acta ; 1842(10): 1981-1992, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24882755

RESUMO

The human gut is colonized by a wide diversity of micro-organisms, which are now known to play a key role in the human host by regulating metabolic functions and immune homeostasis. Many studies have indicated that the genomes of our gut microbiota, known as the gut microbiome or our "other genome" could play an important role in immune-related, complex diseases, and growing evidence supports a causal role for gut microbiota in regulating predisposition to diseases. A comprehensive analysis of the human gut microbiome is thus important to unravel the exact mechanisms by which the gut microbiota are involved in health and disease. Recent advances in next-generation sequencing technology, along with the development of metagenomics and bioinformatics tools, have provided opportunities to characterize the microbial communities. Furthermore, studies using germ-free animals have shed light on how the gut microbiota are involved in autoimmunity. In this review we describe the different approaches used to characterize the human microbiome, review current knowledge about the gut microbiome, and discuss the role of gut microbiota in immune homeostasis and autoimmunity. Finally, we indicate how this knowledge could be used to improve human health by manipulating the gut microbiota. This article is part of a Special Issue entitled: From Genome to Function.

5.
Ann Rheum Dis ; 73(6): 1163-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23696630

RESUMO

OBJECTIVES: The severity of joint destruction is highly variable between rheumatoid arthritis (RA) patients. The majority of its heritability is still unexplained. Several autoimmune diseases share genetic risk variants that may also influence disease progression. We aimed to identify genetic risk factors for the severity of joint damage in RA by studying genetic susceptibility loci of several autoimmune diseases. METHODS: In phase 1, 3143 sets of x-rays of 646 Dutch RA patients taken over 7 years (Sharp van der Heijde (SHS) scored) were studied. Genotyping was done by Immunochip. Associations of single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) >0.01 and joint destruction were analysed. In phase 2, 686 North American RA patients with 926 SHS-scored x-rays over 15 years of follow-up were evaluated. In both phases multiple testing corrections were done for the number of uncorrelated SNPs; the thresholds for significance were p<1.1×10(-6) and p<0.0036. Matrix metalloproteinase 9 (MMP-9) levels were measured with ELISA in baseline serum samples. RESULTS: In phase 1, 109 SNPs associated significantly with joint destruction (p<1.1×10(-6)). Of these, 76 were located in the HLA region; the 33 non-HLA variants were studied in phase 2. Here two variants were associated with the severity of joint destruction: rs451066 on chromosome 14 (p=0.002, MAF=0.20) and rs11908352 on chromosome 20 (p=0.002, MAF=0.21). Rs11908352 is located near the gene encoding MMP-9. Serum levels of MMP-9 were significantly associated with the rs11908352 genotypes (p=0.007). CONCLUSIONS: These data indicate that two loci that confer risk to other autoimmune diseases also affect the severity of joint destruction in RA. Rs11908352 may influence joint destruction via MMP-9 production.


Assuntos
Artrite Reumatoide/genética , Metaloproteinase 9 da Matriz/genética , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Progressão da Doença , Feminino , Articulações do Pé/diagnóstico por imagem , Predisposição Genética para Doença , Genótipo , Articulação da Mão/diagnóstico por imagem , Humanos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Radiografia , Índice de Gravidade de Doença
6.
Arthritis Rheum ; 65(7): 1684-93, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23529819

RESUMO

OBJECTIVE: Heritability studies have suggested an important role of genetic predisposition in the progression of joint destruction in rheumatoid arthritis (RA); the heritability is estimated at 45-58%. Several single-nucleotide polymorphisms (SNPs) have been identified as being associated with RA susceptibility. Our objective was to study the association of several of these loci with progression of joint destruction. METHODS: We studied 1,750 RA patients in 4 independent data sets with 4,732 radiographs scored using the modified Sharp/van der Heijde method. Thirteen susceptibility SNPs that were not previously associated with joint destruction were tested in 596 Dutch RA patients. Subsequently, significant SNPs were studied in data sets of RA patients from North America and Iceland. Data were summarized in inverse-weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped. RESULTS: In stage 1, 3 loci (AFF3, IL2RA, and BLK) were significantly associated with the rate of joint destruction and were further analyzed in the additional data sets. In the combined meta-analyses, the minor (C) allele of IL2RA (rs2104286) was associated with less progression of joint destruction (P = 7.2 × 10(-4) ). Furthermore, the IL2RA (rs2104286) protective genotype was associated with lower (0.85-fold [95% confidence interval 0.77-0.93], P = 1.4 × 10(-3) ) circulating levels of soluble interleukin-2 receptor α (sIL-2Rα). Additionally, lower sIL-2Rα levels were associated with a lower rate of joint destruction (P = 3.4 × 10(-3) ). The association of IL2RA with the rate of joint destruction was further localized to a 40-kb region encompassing the IL2RA intron 1 and the 5' region of IL2RA and RBM17. CONCLUSION: The present genetic and serologic data suggest that inherited altered genetic constitution at the IL2RA locus may predispose to a less destructive course of RA.


Assuntos
Artrite Reumatoide/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Estudos de Coortes , Progressão da Doença , Feminino , Articulações do Pé/diagnóstico por imagem , Predisposição Genética para Doença , Articulação da Mão/diagnóstico por imagem , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Radiografia
7.
Arthritis Rheum ; 65(12): 3051-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23983153

RESUMO

OBJECTIVE: The progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL4 and IL4R genes have been associated with RA severity, but this finding has not been replicated. This study was undertaken to investigate the association between IL4- and IL4R-tagging single-nucleotide polymorphisms (SNPs) and the progression rate of joint damage in RA in a multicohort candidate gene study. METHODS: IL4- and IL4R-tagging SNPs (n = 8 and 39, respectively) were genotyped in 600 RA patients for whom 2,846 sets of radiographs of the hands and feet were obtained during 7 years of followup. Subsequently, SNPs significantly associated with the progression of joint damage were genotyped and studied in relation to 3,415 radiographs of 1,953 RA patients; these included data sets from Groningen (The Netherlands), Lund (Sweden), Sheffield (UK), the North American Rheumatoid Arthritis Consortium (US), Wichita (US), and the National Data Bank (US). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta-analysis was performed on the 6 data sets that together formed the replication phase. RESULTS: In the discovery phase, none of the IL4 SNPs and 7 of the IL4R SNPs were significantly associated with the joint damage progression rate. In the replication phase, 2 SNPs in the IL4R gene were significantly associated with the joint damage progression rate (rs1805011 [P = 0.02] and rs1119132 [P = 0.001]). CONCLUSION: Genetic variants in IL4R were identified, and their association with the progression rate of joint damage in RA was independently replicated.


Assuntos
Artrite Reumatoide/genética , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Interleucina-4/genética , Receptores de Interleucina-4/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico por imagem , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Índice de Gravidade de Doença
8.
Arthritis Rheum ; 65(3): 582-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23440692

RESUMO

OBJECTIVE: Genetic factors account for an estimated 45-58% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. METHODS: A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. RESULTS: SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 × 10(-4)). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 × 10(-5)). CONCLUSION: SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Variação Genética/genética , Granzimas/genética , Adulto , Idoso , Condrócitos/patologia , Condrócitos/fisiologia , Estudos de Coortes , Progressão da Doença , Feminino , Genótipo , Humanos , Articulações/patologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , Índice de Gravidade de Doença
9.
Clin Exp Immunol ; 173(1): 76-83, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23607884

RESUMO

Rodent models for arthritis implicate a role for complement in disease development and progression. In humans, complement deposition has been observed in inflamed synovia of rheumatoid arthritis (RA) patients. In this study we analysed whether genetic variants of complement component C1q predispose to RA. We genotyped single nucleotide polymorphisms (SNPs) in and around the C1q genes, C1qA, C1qB and C1qC, in a Dutch set of 845 RA cases and 1046 controls. Replication was sought in a sample set from North America (868 cases/1193 controls), and a meta-analysis was performed in a combined samples set of 8000 cases and 23 262 controls of European descent. We determined C1q serum levels in relation to C1q genotypes. In the discovery phase, five of the 13 SNPs tested in the C1q genes showed a significant association with RA. Additional analysis of the genomic area around the C1q genes revealed that the strongest associating SNPs were confined to the C1q locus. Within the C1q locus we observed no additional signal independent of the strongest associating SNP, rs292001 [odds ratio (OR) = 0·72 (0·58-0·88), P = 0·0006]. The variants of this SNP were associated with different C1q serum levels in healthy controls (P = 0·006). Interestingly, this SNP was also associated significantly in genome-wide association studies (GWAS) from the North American Rheumatoid Arthritis Consortium study, confirming the association with RA [OR = 0·83 (0·69-1·00), P = 0·043]. Combined analysis, including integrated data from six GWAS studies, provides support for the genetic association. Genetic variants in C1q are correlated with C1q levels and may be a risk for the development of RA.


Assuntos
Artrite Reumatoide/genética , Complemento C1q/genética , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/epidemiologia , Canadá/epidemiologia , Estudos de Coortes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Grécia/epidemiologia , Humanos , Países Baixos/epidemiologia , RNA Mensageiro/genética , Receptor EphA8/genética , Receptor EphB2/genética , Estados Unidos/epidemiologia
10.
Ann Rheum Dis ; 72(5): 769-75, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23041840

RESUMO

BACKGROUND: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/ß-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. OBJECTIVE: To study variants in the genes encoding these proteins in relation to progression of joint destruction. METHODS: 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. RESULTS: In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). CONCLUSIONS: Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Marcadores Genéticos/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteínas de Membrana/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Endonucleases/fisiologia , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Articulações/metabolismo , Articulações/patologia , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Osteoblastos/citologia , Osteoblastos/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Índice de Gravidade de Doença , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
11.
Gut Microbes ; 15(2): 2281360, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38017662

RESUMO

The gut microbiome is involved in the bi-directional relationship of the gut - brain axis. As most studies of this relationship are small and do not account for use of psychotropic drugs (PTDs), we explored the relations of the gut microbiome with several internalizing disorders, while adjusting for PTDs and other relevant medications, in 7,656 Lifelines participants from the Northern Netherlands (5,522 controls and 491 participants with at least one internalizing disorder). Disorders included dysthymia, major depressive disorder (MDD), any depressive disorder (AnyDep: dysthymia or MDD), generalized anxiety disorder (GAD) and any anxiety disorder (AnyAnx: GAD, social phobia and panic disorder). Compared to controls, 17 species were associated with depressive disorders and 3 were associated with anxiety disorders. Around 90% of these associations remained significant (FDR <0.05) after adjustment for PTD use, suggesting that the disorders, not PTD use, drove these associations. Negative associations were observed for the butyrate-producing bacteria Ruminococcus bromii in participants with AnyDep and for Bifidobacterium bifidum in AnyAnx participants, along with many others. Tryptophan and glutamate synthesis modules and the 3,4-Dihydroxyphenylacetic acid synthesis module (related to dopamine metabolism) were negatively associated with MDD and/or dysthymia. After additional adjustment for functional gastrointestinal disorders and irritable bowel syndrome, these relations remained either statistically (FDR <0.05) or nominally (P < 0.05) significant. Overall, multiple bacterial species and functional modules were associated with internalizing disorders, including gut - brain relevant components, while associations to PTD use were moderate. These findings suggest that internalizing disorders rather than PTDs are associated with gut microbiome differences relative to controls.


Assuntos
Transtorno Depressivo Maior , Microbioma Gastrointestinal , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Depressão , Transtornos de Ansiedade , Ansiedade , Psicotrópicos
13.
Gut Microbes ; 13(1): 1943288, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34313538

RESUMO

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies.We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing.Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing-based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC ≈ 0.7).HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data.


Assuntos
Fezes/química , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/fisiopatologia , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/fisiopatologia , Complexo Antígeno L1 Leucocitário/análise , beta-Defensinas/análise , Adulto , Biomarcadores/análise , Biópsia/normas , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Guias de Prática Clínica como Assunto
14.
J Med Genet ; 46(1): 60-3, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18805825

RESUMO

BACKGROUND AND AIMS: The first genome wide association study on coeliac disease (CD) and its follow-up have identified eight new loci that contribute significantly towards CD risk. Seven of these loci contain genes controlling adaptive immune responses, including IL2/IL21 (4q27), RGS1 (1q31), IL18RAP (2q11-2q12), CCR3 (3p21), IL12A (3q25-3q26), TAGAP (6q25) and SH2B3 (12q24). METHODS: We selected the nine most associated single nucleotide polymorphisms to tag the eight new loci in an Italian cohort comprising 538 CD patients and 593 healthy controls. RESULTS: Common variation in IL2/IL21, RGS1, IL12A/SCHIP and SH2B3 was associated with susceptibility to CD in our Italian cohort. The LPP and TAGAP regions also showed moderate association, whereas there was no association with CCR3 and IL18RAP. CONCLUSION: This is the first replication study of six of the eight new CD loci; it is also the first CD association study in a southern European cohort. Our results may imply there is a genuine population difference across Europe regarding the loci contributing to CD.


Assuntos
Doença Celíaca/genética , Adulto , Idoso , Estudos de Coortes , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética
15.
Gut ; 58(6): 799-804, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19201773

RESUMO

OBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs. METHODS: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed. RESULTS: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35 x 10(-10), rs13119723 p = 8.60 x 10(-8), rs6840978 p = 3.0 7x 10(-8), rs6822844 p = 2.77 x 10(-9)). A moderate association with CD was also found in the pooled analysis (p value range 0.0016-9.86 x 10(-5)). CONCLUSIONS: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease.


Assuntos
Colite Ulcerativa/genética , Interleucina-2/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Distribuição de Qui-Quadrado , Doença de Crohn/genética , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Itália , Países Baixos , Razão de Chances , Estados Unidos
16.
Gut ; 58(8): 1078-83, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19240061

RESUMO

OBJECTIVE: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. DESIGN: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). RESULTS: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. CONCLUSIONS: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.


Assuntos
Doença Celíaca/genética , Genes rel , Peptídeos e Proteínas de Sinalização Intracelular/genética , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Estudos de Casos e Controles , Doença Celíaca/metabolismo , Proteínas de Ligação a DNA , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Desequilíbrio de Ligação , Masculino , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
17.
Obes Rev ; 19(12): 1719-1734, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30144260

RESUMO

A hallmark of obesity is chronic low-grade inflammation, which plays a major role in the process of atherosclerotic cardiovascular disease (ACVD). Gut microbiota is one of the factors influencing systemic immune responses, and profound changes have been found in its composition and metabolic function in individuals with obesity. This systematic review assesses the association between the gut microbiota and markers of low-grade inflammation in humans. We identified 14 studies which were mostly observational and relatively small (n = 10 to 471). The way in which the microbiome is analysed differed extensively between these studies. Lower gut microbial diversity was associated with higher white blood cell counts and high sensitivity C-reactive protein (hsCRP) levels. The abundance of Bifidobacterium, Faecalibacterium, Ruminococcus and Prevotella were inversely related to different markers of low-grade inflammation such as hsCRP and interleukin (IL)-6. In addition, this review speculates on possible mechanisms through which the gut microbiota can affect low-grade inflammation and thereby ACVD. We discuss the associations between the microbiome and the inflammasome, the innate immune system, bile acids, gut permeability, the endocannabinoid system and TMAO. These data reinforce the importance of human research into the gut microbiota as potential diagnostic and therapeutic strategy to prevent ACVD.


Assuntos
Aterosclerose/microbiologia , Microbioma Gastrointestinal , Inflamação/microbiologia , Obesidade/microbiologia , Humanos
18.
Neurogastroenterol Motil ; 30(9): e13358, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29673008

RESUMO

BACKGROUND: Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. METHODS: Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. KEY RESULTS: Suggestive GWAS signals (P ≤ 5.0 × 10-6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10-10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. CONCLUSION & INFERENCES: Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Canais Iônicos/genética , Síndrome do Intestino Irritável/genética , Humanos
20.
J Breath Res ; 11(1): 016013, 2017 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-28140379

RESUMO

BACKGROUND: Thousands of endogenous and exogenous volatile organic compounds (VOCs) are excreted in each breath. Inflammatory and deviant metabolic processes affect the level of endogeneous VOCs, which can serve as specific biomarkers for clinical diagnosis and disease monitoring. Important issues that still need to be tackled are related to potential confounding factors like gender and age and endogenous and exogenous factors, like f.i. smoking. METHODS: The aim of this study was to systematically access the effect of endogenous and exogenous factors on VOC composition of exhaled breath. In the current study breath samples from 1417 adult participants from the LifeLines cohort, a general population cohort in the Netherlands, were collected and the total content of VOCs was measured using gas chromatography-time-of-flight-mass spectrometry. Breath samples were collected in Groningen and transferred to carbon tubes immediately. These samples were then shipped to Maastricht and measured in batches. VOCs profiles were correlated to 14 relevant characteristics of all participants including age, BMI, smoking and blood cell counts and metabolic parameters as well as to 16 classes of medications. RESULTS: VOCs profiles were shown to be significantly influenced by smoking behavior and to a lesser extent by age, BMI and gender. These factors need to be controlled for in breath analysis studies. We found no evidence whatsoever in this 1417 subjects' cohort that white blood cell counts, cholesterol or triglycerides levels have an influence on the VOC profile. Thus they may not have to be controlled for in exhaled breath studies. CONCLUSION: The large cohort of volunteers used here represents a unique opportunity to gauge the factors influencing VOCs profiles in a general population i.e. the most clinically relevant population. Classical clinical parameters and smoking habits clearly influence breath content and should therefore be accounted for in future clinical studies involving breath analysis.


Assuntos
Testes Respiratórios/métodos , Expiração , Compostos Orgânicos Voláteis/análise , Fatores Etários , Biomarcadores/análise , Índice de Massa Corporal , Estudos de Casos e Controles , Colesterol/sangue , Fatores de Confusão Epidemiológicos , Anticoncepção , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Países Baixos , Fumar
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