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1.
Gastroenterology ; 167(2): 315-332, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38490347

RESUMO

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.


Assuntos
Colangite Esclerosante , Colite Ulcerativa , Doença de Crohn , Humanos , Feminino , Masculino , Adulto , Colangite Esclerosante/imunologia , Colangite Esclerosante/genética , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/complicações , Pessoa de Meia-Idade , Colite Ulcerativa/imunologia , Colite Ulcerativa/genética , Colite Ulcerativa/diagnóstico , Doença de Crohn/imunologia , Doença de Crohn/genética , Doença de Crohn/diagnóstico , Adolescente , Fatores de Risco , Criança , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/complicações , Predisposição Genética para Doença , Adulto Jovem , Fatores Sexuais , Dermatopatias/etiologia , Dermatopatias/imunologia , Dermatopatias/genética , Oftalmopatias/etiologia , Oftalmopatias/imunologia , Oftalmopatias/diagnóstico , Oftalmopatias/genética , Oftalmopatias/epidemiologia , Fenótipo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/diagnóstico , Modelos Logísticos , Idoso
2.
Am J Hum Genet ; 108(9): 1765-1779, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450030

RESUMO

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.


Assuntos
Colectomia/estatística & dados numéricos , Colite Ulcerativa/cirurgia , Doença de Crohn/cirurgia , Locos de Características Quantitativas , Transcriptoma , Bancos de Espécimes Biológicos , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Colo/metabolismo , Colo/patologia , Colo/cirurgia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Conjuntos de Dados como Assunto , Progressão da Doença , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Prognóstico , Medição de Risco , Reino Unido
3.
Am J Hum Genet ; 108(3): 431-445, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33600772

RESUMO

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.


Assuntos
Calbindina 2/genética , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Negro ou Afro-Americano/genética , Idoso , Idoso de 80 Anos ou mais , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Doença de Crohn/genética , Doença de Crohn/patologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Sequenciamento Completo do Genoma
4.
Artigo em Inglês | MEDLINE | ID: mdl-39181428

RESUMO

BACKGROUND AND AIMS: The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds. METHODS: We performed a multicenter, retrospective cohort study comprising 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1∗05; their ancestral origin (European, African, or Amerindian); and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, in exposed patients. RESULTS: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15, which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15∗4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1∗05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1∗05 in the European allele subset. CONCLUSIONS: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian/Alaska Native ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1∗05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with inflammatory bowel disease.

5.
Dig Dis Sci ; 69(1): 235-245, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38015321

RESUMO

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.


Assuntos
Doença de Crohn , Humanos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/prevenção & controle , Doença de Crohn/cirurgia , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Estudos Retrospectivos , Estudos Prospectivos , Fator de Necrose Tumoral alfa , Necrose
6.
Gut ; 72(11): 2068-2080, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37080587

RESUMO

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.


Assuntos
Fator B do Complemento , Doença de Crohn , Humanos , Fator B do Complemento/genética , Doença de Crohn/complicações , Qualidade de Vida , Seguimentos , Fagocitose
7.
Hum Mol Genet ; 30(5): 356-369, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33555323

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.


Assuntos
Colite Ulcerativa/genética , Etnicidade/genética , Predisposição Genética para Doença , Antígenos HLA/genética , Antígenos HLA-DQ/genética , Cadeias HLA-DRB1/genética , Peptídeos/genética , Alelos , Estudos de Coortes , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Ligação Proteica
8.
Exp Physiol ; 108(4): 568-580, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36744850

RESUMO

NEW FINDINGS: What is the central question of this study? Non-responsive stunting is characterised by a progressive decline of circulating glucagon-like peptide 2: what are the possible causes of this decline? What is the main finding and its importance? In contrast with the established loss of Paneth and goblet cells in environmental enteropathy, there was no evidence of a parallel loss of enteroendocrine cells as seen by positive tissue staining for chromogranin A. Transcriptomic and genomic analyses showed evidence of genetic transcripts that could account for some of the variability seen in circulating glucagon-like peptide 2 values. ABSTRACT: Nutrient sensing determines digestive and hormonal responses following nutrient ingestion. We have previously reported decreased levels of glucagon-like peptide 2 (GLP-2) in children with stunting. Here we demonstrate the presence of enteroendocrine cells in stunted children and explore potential pathways that may be involved in reduced circulating levels of GLP-2. At the time of performing diagnostic endoscopies for non-responsive stunted children, intestinal biopsies were collected for immunofluorescence staining of enteroendocrine cells and transcriptomic analysis. Circulating levels of GLP-2 were also measured and correlated with transcriptomic data. An exploratory genome-wide association study (GWAS) was conducted on DNA samples (n = 158) to assess genetic contribution to GLP-2 variability. Intestinal tissue sections collected from non-responsive stunted children stained positive for chromogranin A (88/89), alongside G-protein-coupled receptors G-protein receptor 119 (75/87), free fatty acid receptor 3 (76/89) and taste 1 receptor 1 (39/45). Transcriptomic analysis found three pathways correlated with circulating GLP-2: sugar metabolism, epithelial transport, and barrier function, which likely reflect downstream events following receptor-ligand interaction. GWAS analysis revealed potential genetic contributions to GLP-2 half-life and receptor binding. Enteroendocrine cell loss was not identified in stunted Zambian children as has been observed for goblet and Paneth cells. Transcriptomic analysis suggests that GLP-2 has pleiotrophic actions on the intestinal mucosa in malnutrition, but further work is needed to dissect pathways leading to perturbations in nutrient sensing.


Assuntos
Estudo de Associação Genômica Ampla , Peptídeo 2 Semelhante ao Glucagon , Transtornos do Crescimento , Criança , Humanos , Cromogranina A , Transtornos do Crescimento/metabolismo , Zâmbia
9.
Nature ; 547(7662): 173-178, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28658209

RESUMO

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Doenças Inflamatórias Intestinais/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação , Cromatina/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Epigênese Genética/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Proteína Smad3/genética , Fatores de Transcrição/metabolismo , Adulto Jovem
10.
Gastroenterology ; 160(3): 771-780.e4, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33098885

RESUMO

BACKGROUND AND AIMS: The largest cause of mortality in patients with inflammatory bowel disease (IBD) remains thromboembolic disease (TED). Recent reports have demonstrated that both monogenic and polygenic factors contribute to TED and 10% of healthy subjects are genetically at high risk for TED. Our aim was to utilize whole-exome sequencing and genome-wide genotyping to determine the proportion of IBD patients genetically at risk for TED and investigate the effect of genetic risk of TED in IBD. METHODS: The TED polygenic risk score was calculated from genome-wide genotyping. Thrombophilia pathogenic variants were extracted from whole-exome sequencing. In total, 792 IBD patients had both whole-exome sequencing and genotyping data. We defined patients at genetically high risk for TED if they had a high TED polygenic risk score or carried at least 1 thrombophilia pathogenic variant. RESULTS: We identified 122 of 792 IBD patients (15.4%) as genetically high risk for TED. Among 715 of 792 subjects whose documented TED status were available, 63 of the 715 patients (8.8%) had TED events. Genetic TED risk was significantly associated with increased TED event (odds ratio, 2.5; P = .0036). In addition, we confirmed an additive effect of monogenic and polygenic risk on TED (P = .0048). Patients with high TED genetic risk more frequently had thrombosis at multiple sites (78% vs 42%, odds ratio, 3.96; P = .048). CONCLUSIONS: Genetic risk (both poly- and monogenic) was significantly associated with TED history. Our results suggest that genetic traits identify approximately 1 in 7 patients with IBD who will experience 2.5-fold or greater risk for TED.


Assuntos
Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/complicações , Tromboembolia/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Voluntários Saudáveis , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Prevalência , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Tromboembolia/genética , Sequenciamento do Exoma
11.
Gastroenterology ; 160(3): 809-822.e7, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33160965

RESUMO

BACKGROUND AND AIMS: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls. METHODS: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Intestinos/efeitos dos fármacos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/genética , Anti-Inflamatórios/efeitos adversos , COVID-19/enzimologia , COVID-19/imunologia , COVID-19/virologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Colite Ulcerativa/enzimologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Doença de Crohn/enzimologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Bases de Dados Genéticas , Feminino , Regulação Enzimológica da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Intestinos/enzimologia , Intestinos/imunologia , Masculino , Pessoa de Meia-Idade , América do Norte , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Virais/metabolismo , SARS-CoV-2/enzimologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
12.
Gastroenterology ; 160(5): 1709-1724, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33421512

RESUMO

BACKGROUND & AIMS: Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC. METHODS: Colon tissues were collected from patients with UC for bulk RNA sequencing and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing. Genetic association of all protein-altering G-protein coupled receptor single-nucleotide polymorphism was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into Chinese hamster ovary (CHO) and human mast cell (HMC) 1.1 cells to detect genotype-dependent effects on ß-arrestin recruitment, IP-1 accumulation, and phosphorylated extracellular signal-regulated kinase. RESULTS: Mast cell-specific mediators and adrenomedullin (proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are up-regulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated with and was bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances ß-arrestin recruitment, decreases IP-1, and increases phosphorylated extracellular signal-regulated kinase with MRGPRX2 agonists. Single-cell RNA sequencing defines that adrenomedullin is expressed by activated fibroblasts and epithelial cells and that interferon gamma is a key upstream regulator of mast cell gene expression. CONCLUSION: Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.


Assuntos
Degranulação Celular , Colite Ulcerativa/metabolismo , Colo/metabolismo , Mastócitos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Adrenomedulina/genética , Adrenomedulina/metabolismo , Animais , Células CHO , Estudos de Casos e Controles , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colo/imunologia , Cricetulus , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Variação Genética , Humanos , Fosfatos de Inositol/metabolismo , Ligantes , Mastócitos/imunologia , Proteínas do Tecido Nervoso/genética , Fosforilação , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos/genética , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismo
13.
J Pediatr Gastroenterol Nutr ; 74(4): 529-534, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724448

RESUMO

OBJECTIVES: Stunting, the most common form of childhood undernutrition, is associated with environmental enteropathy (EE). Enteric infections are believed to play a role in the pathophysiology of EE and stunting though the exact mechanism remains undetermined. The FUT2 (secretor) and FUT3 (Lewis) genes have been shown to be associated with some symptomatic enteric infections in both children and adults. These genes are responsible for the presence of histo-blood group antigens (HBGAs) in various secretions and epithelial surfaces.We evaluated whether the secretor and Lewis status influences asymptomatic enteric infections and thus EE severity on duodenal biopsies of stunted children. METHODS: In this case-control study, we used saliva samples to determine the secretor and Lewis status of stunted children (cases, n = 113) enrolled in a nutritional rehabilitation program and from their well-nourished counterparts (controls, n = 42). Where available, saliva was also collected from the mothers. Baseline stool samples were used to detect asymptomatic enteropathogen carriage. Duodenal biopsies were collected from a subgroup of stunted children (n = 77) who had an upper gastrointestinal endoscopy done as part of the evaluation process for their non-response to nutritional therapy. RESULTS: The proportion of secretors was similar between the cases and the controls (82% vs 81%, P = 0.81). The stunted children had significantly higher rates of carrying multiple enteropathogens, but this was not associated with their secretor status nor that of their mothers. The secretor status was also not associated with mucosal morphometry of duodenal biopsies. CONCLUSION: This case-control analysis in Zambian children does not support the hypothesis that fucosylation status determines asymptomatic enteropathogen carriage in stunting.


Assuntos
Antígenos de Grupos Sanguíneos , Enteropatias , Adulto , Estudos de Casos e Controles , Criança , Fezes , Feminino , Transtornos do Crescimento/etiologia , Humanos , Zâmbia/epidemiologia
15.
PLoS Genet ; 14(5): e1007329, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29795570

RESUMO

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10-16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.


Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença/genética , Judeus/genética , Doenças Raras/genética , Algoritmos , Doença de Crohn/epidemiologia , Genética Populacional , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Modelos Genéticos , Epidemiologia Molecular , Polimorfismo de Nucleotídeo Único , Doenças Raras/epidemiologia
16.
Hum Mol Genet ; 27(22): 3901-3910, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30084967

RESUMO

Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRß1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Doenças Inflamatórias Intestinais/genética , Alelos , Substituição de Aminoácidos/genética , Aminoácidos/química , Aminoácidos/genética , Povo Asiático/genética , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Feminino , Estudos de Associação Genética , Genótipo , Cadeias HLA-DRB1/química , Haplótipos/genética , Humanos , Doenças Inflamatórias Intestinais/patologia , Japão , Masculino , Conformação Proteica , República da Coreia
17.
Gastroenterology ; 152(1): 206-217.e2, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27693347

RESUMO

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.


Assuntos
Negro ou Afro-Americano/genética , Moléculas de Adesão Celular Neuronais/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Predisposição Genética para Doença/genética , Cadeias HLA-DRB1/genética , Proteínas Repressoras/genética , Ubiquitina Tiolesterase/genética , Adenilil Ciclases/genética , Estudos de Casos e Controles , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Cadeias alfa de HLA-DQ/genética , Humanos , Subunidade p40 da Interleucina-12/genética , Canal de Potássio KCNQ2/genética , Polimorfismo de Nucleotídeo Único , Receptores CXCR6 , Receptores de Quimiocinas/genética , Receptores de Interleucina/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores Virais/genética , Nexinas de Classificação/genética , Tenascina/genética , População Branca/genética
18.
Nature ; 491(7422): 119-24, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23128233

RESUMO

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , Mycobacterium/imunologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/fisiopatologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/microbiologia , Doença de Crohn/fisiopatologia , Genoma Humano/genética , Haplótipos/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mycobacterium/patogenicidade , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/microbiologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
19.
Gastroenterology ; 151(4): 724-32, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27492617

RESUMO

BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.


Assuntos
Proteínas de Transporte de Cátions/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Microbioma Gastrointestinal/genética , Mutação de Sentido Incorreto , Alelos , Estudos de Casos e Controles , Colite Ulcerativa/microbiologia , Doença de Crohn/microbiologia , Feminino , Pleiotropia Genética , Genótipo , Humanos , Masculino , Fatores de Risco
20.
Gastroenterology ; 151(4): 710-723.e2, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27377463

RESUMO

BACKGROUND & AIMS: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor ß common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared. RESULTS: In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. CONCLUSIONS: In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.


Assuntos
Doença de Crohn/genética , Subunidade beta Comum dos Receptores de Citocinas/genética , Mutação da Fase de Leitura , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Judeus/genética , Estudos de Casos e Controles , Doença de Crohn/etnologia , Doença de Crohn/patologia , Feminino , Humanos , Intestinos/citologia , Intestinos/patologia , Masculino , Monócitos/metabolismo , Fatores de Risco , Transdução de Sinais/genética
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