RESUMO
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.
Assuntos
Desenvolvimento Infantil/fisiologia , Estado Nutricional/fisiologia , Puberdade/fisiologia , Receptor Tipo 3 de Melanocortina/metabolismo , Maturidade Sexual/fisiologia , Adolescente , Idoso de 80 Anos ou mais , Animais , Criança , Ciclo Estral/genética , Ciclo Estral/fisiologia , Feminino , Homozigoto , Humanos , Hipotálamo/citologia , Hipotálamo/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Melanocortinas/metabolismo , Menarca/genética , Menarca/fisiologia , Camundongos , Fenótipo , Puberdade/genética , Receptor Tipo 3 de Melanocortina/deficiência , Receptor Tipo 3 de Melanocortina/genética , Maturidade Sexual/genética , Fatores de Tempo , Aumento de PesoRESUMO
Celiac disease is a common disease with a prevalence of approximately 1%. A recent genome-wide association study (GWAS) and follow-up study identified eight loci significantly associated with celiac disease risk. We genotyped the top 1020 non-HLA single nucleotide polymorphisms (SNPs) from the GWAS study that were genotyped in the previous follow-up study. After quality control assessments, 975 SNPs were analyzed for association with 906 celiac disease cases and 3819 controls, using logistic regression. Additional genotype data were generated by imputation and analyzed across the regions showing the strongest statistical evidence for association. Twenty SNPs were associated with celiac disease with P < 0.01 in the current study as well as in the previous follow-up study, of which 16 had P < 0.001 and 11 had P < 1 x 10(-11). Five of eight regions identified in the follow-up study were strongly associated with celiac disease, including regions on 1q31, 3q25, 3q28, 4q27 and 12q24. The strongest associations were at 4q27, the region most strongly associated in the GWAS and follow-up study and containing IL2 and IL21, and at 3q28 harboring LPP. In addition, we provide new evidence for an association, not previously reported, on 2q31 harboring a strong candidate gene, ITGA4. In conclusion, in this first follow-up study of celiac cases from the USA, we provide additional evidence that five of eight previously identified regions harbor risk alleles for celiac disease, and new evidence for an association on 2q31. The underlying functional mutations responsible for these replicated associations need to be identified.
Assuntos
Doença Celíaca/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 4/genética , Seguimentos , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Humanos , Modelos Logísticos , Reino Unido , Estados UnidosRESUMO
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 alfaRESUMO
BACKGROUND: Coeliac disease (gluten-sensitive enteropathy; GSE) and inflammatory bowel disease (IBD) are common gastrointestinal disorders. Both display enhanced intestinal permeability, initiated by gluten exposure (GSE) or bacterial interactions (IBD). Previous studies showed the association of both diseases with variants in MYO9B, presumably involved in epithelial permeability. AIM: It was hypothesised that genetic variants in tight junction genes might affect epithelial barrier function, thus contributing to a shared pathogenesis of GSE and IBD. METHODS: This hypothesis was tested with a comprehensive genetic association analysis of 41 genes from the tight junction pathway, represented by 197 tag single nucleotide polymorphism (SNP) markers. RESULTS: Two genes, PARD3 (two SNPs) and MAGI2 (two SNPs), showed weak association with GSE in a Dutch cohort. Replication in a British GSE cohort yielded significance for one SNP in PARD3 and suggestive associations for two additional SNPs, one each in PARD3 and MAGI2. Joint analysis of the British and Dutch data further substantiated the association for both PARD3 (rs10763976, p = 6.4 x 10(-5); OR 1.23, 95% CI 1.11 to 1.37) and MAGI2 (rs6962966, p = 7.6 x 10(-4); OR 1.19, 95% CI 1.08 to 1.32). Association was also observed in Dutch ulcerative colitis patients with MAGI2 (rs6962966, p = 0.0036; OR 1.26, 95% CI 1.08 to 1.47), and suggestive association with PARD3 (rs4379776, p = 0.068). CONCLUSIONS: These results suggest that coeliac disease and ulcerative colitis may share a common aetiology through tight junction-mediated barrier defects, although the observations need further replication.
Assuntos
Doença Celíaca/genética , Proteínas de Ciclo Celular/genética , Colite Ulcerativa/genética , Proteínas de Membrana/genética , Proteínas/genética , Junções Íntimas/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte , Doença Celíaca/fisiopatologia , Estudos de Coortes , Colite Ulcerativa/fisiopatologia , Predisposição Genética para Doença , Testes Genéticos/métodos , Genótipo , Guanilato Quinases , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The first genome-wide association study performed in a UK coeliac disease (CD) case-control cohort revealed association with a linkage disequilibrium block containing the KIAA1109/Tenr/IL2/IL21 genes. Also recently, an association with a non-synonymous polymorphism in FcgammaRIIa (CD32a) was reported in CD with an unusually strong P-value. We aimed to replicate the reported associations with the single nucleotide polymorphisms rs13119723 A>G and rs6822844 G>T in the KIAA1109/Tenr/IL2/IL21 region and rs1801274 G>A in the FcgammaRIIa gene in a family sample consisting of 325 Swedish/Norwegian families using the robust transmission disequilibrium test. The family sample used in this study included 100 families with two or more children affected by CD and 225 families with one affected child. We could confirm significant association between the polymorphisms rs13119723 A>G and rs6822844 G>T located in the KIAA1109/Tenr/IL2/IL21 region and CD (P-value 0.001 and 0.002, respectively). However, we found no association with the FcgammaRIIa rs1801274 G>A polymorphism (P-value=0.3). In conclusion, our results support the KIAA1109/Tenr/IL2/IL21 region as a true CD susceptibility region.
Assuntos
Doença Celíaca/genética , Predisposição Genética para Doença , Interleucina-2/genética , Interleucinas/genética , Receptores de IgG/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 4 , Família , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Noruega , Linhagem , Polimorfismo de Nucleotídeo Único , SuéciaRESUMO
Recent advances in immunological and genetic research in coeliac disease provide new and complementary insights into the immune response driving this chronic intestinal inflammatory disorder. Both approaches confirm the central importance of T cell-mediated immune responses to disease pathogenesis and have further begun to highlight other relevant components of the mucosal immune system, including innate immunity and the control of lymphocyte trafficking to the mucosa. In the last year, the first genome wide association study in celiac disease led to the identification of multiple new risk variants. These risk regions implicate genes involved in the immune system. Overlap with autoimmune diseases is striking with several of these regions being shown to confer susceptibility to other chronic immune-mediated diseases, particularly type 1 diabetes.
Assuntos
Doença Celíaca/genética , Imunogenética , Antígenos/imunologia , Autoimunidade , Doença Celíaca/imunologia , Previsões , Trato Gastrointestinal/imunologia , Predisposição Genética para Doença , Glutens/imunologia , Humanos , Imunidade InataRESUMO
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine, commonly diagnosed as either ulcerative colitis (UC) or Crohn's disease (CD). Epidemiological studies have consistently shown that both genetic and environmental factors influence the pathogenesis of IBD. A number of genome scans have been conducted in cohorts of IBD families with affected sibling pairs (ASPs) to identify chromosomal regions that harbour IBD susceptibility genes. Several putative linked loci have been identified, including two loci on chromosomes 16 and 12, IBD1 and IBD2, which have subsequently been replicated by independent region-specific studies. We have conducted both a replication study on another linkage region, chromosome 6p (IBD3), and extension studies on two other regions, chromosomes 3p and 7q. Microsatellite markers across each region were genotyped in 284 IBD ASPs from 234 families. A nonparametric peak multipoint LOD score of 3.0 was observed near D6S291, replicating the previous linkage to chromosome 6p (IBD3). Nominal evidence of linkage was observed at both the 3p and 7q regions.
Assuntos
Cromossomos Humanos Par 6/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Doenças Inflamatórias Intestinais/genética , Mapeamento Cromossômico/estatística & dados numéricos , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Marcadores Genéticos/genética , Genótipo , Humanos , Escore Lod , Núcleo FamiliarRESUMO
The pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD) is still unknown, but the importance of genetic susceptibility has been clearly shown by epidemiological data from family and twin studies. Linkage studies have identified two susceptibility loci for inflammatory bowel disease (IBD) on chromosomes 12 and 16. Importantly, these linkages have been replicated by independent investigators, and studies of positional candidates within these regions continue, together with fine mapping strategies. Regions of 'suggestive' linkage on chromosomes 1, 3, 4, 6, 7, 10, 22 and X have also been reported in individual studies. Other important candidate genes investigated include the interleukin-1 receptor antagonist, MUC3 and genes of the human leukocyte antigen (HLA) system. The apparently conflicting data in different studies from around the world may be explained by ethnic differences, case mix and genetic heterogeneity. Replicated class II HLA associations include HLA DRB1*0103 and DR2 (DRB1*1502), involved in UC susceptibility, and HLA DRB1*03 and DR4 as resistance alleles for CD and UC respectively. Animal studies have provided insights from targeted mutations and quantitative trait locus analysis. The goals of continuing research include narrowing the regions of linkages and analysis of candidate genes, and possibly the application of newly developed methods using single nucleotide polymorphisms. Advances in IBD genetics hold the potential to provide knowledge about the disease pathogenesis at the molecular level, with ensuing benefits for clinical practice.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Animais , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 16 , Análise por Conglomerados , Etnicidade/genética , Ligação Genética , Predisposição Genética para Doença , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Polimorfismo Genético , Estudos em Gêmeos como AssuntoRESUMO
BACKGROUND: Coeliac disease (CD) is due to an inappropriate T cell mediated response to specific gluten peptides. Measured by interferon gamma (IFN-gamma) ELISPOT, about half of the gliadin specific T cells induced with in vivo wheat gluten exposure in HLA-DQ2+ CD are specific for an alpha/beta-gliadin peptide (p57-73 QE65; QLQPFPQPELPYPQPQS) that includes two overlapping T cell epitopes (PFPQPELPY and PQPELPYPQ). AIM: To define minimally substituted variants of p57-73 QE65 universally devoid of IFN-gamma stimulatory capacity but capable of antagonising IFN-gamma secretion from polyclonal T cells specific for p57-73 QE65. METHODS: Peripheral blood mononuclear cells collected from 75 HLA-DQ2+ CD patients after in vivo gluten challenge were used in overnight ELISPOT assays to screen 218 single or double substituted variants of p57-73 QE65 for cytokine stimulatory and antagonist activity. RESULTS: The region p60-71 (PFPQPELPYPQP) and especially p64-67 (PELP) was sensitive to substitution. Twelve substitutions in p64-67 stimulated no IFN-gamma ELISPOT response. Among 131 partial agonists identified, 45 produced statistically significant inhibition of IFN-gamma ELISPOT responses when cocultured in fivefold excess with p57-73 QE65 (n = 10). Four substituted variants of p57-73 QE65 were inactive by IFN-gamma ELISPOT but consistently antagonised IFN-gamma ELISPOT responses to p57-73 QE65, and also retained interleukin 10 stimulatory capacity similar to p57-73 QE65. CONCLUSIONS: Altered peptide ligands of p57-73 QE65, identified using polyclonal T cells from multiple HLA-DQ2+ CD donors, have properties in vitro that suggest that a single substitution to certain alpha/beta-gliadins could abolish their capacity to stimulate IFN-gamma from CD4 T cells and also have anti-inflammatory or protective effects in HLA-DQ2+ CD.
Assuntos
Doença Celíaca/imunologia , Epitopos de Linfócito T/imunologia , Gliadina/imunologia , Interferon gama/metabolismo , Fragmentos de Peptídeos/imunologia , Triticum/imunologia , Adulto , Idoso , Aminoácidos/imunologia , Células Cultivadas , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Gliadina/antagonistas & inibidores , Humanos , Interferon gama/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
BACKGROUND AND AIMS: Development of coeliac disease involves an interaction between environmental factors (especially dietary wheat, rye, and barley antigens) and genetic factors (there is strong inherited disease susceptibility). The known human leucocyte antigen (HLA)-DQ2 and -DQ8 association explains only a minority of disease heritability. A recent study in the Dutch population suggested that genetic variation in the 3' region of myosin IXB (MYO9B) predisposes to coeliac disease. MYO9B is a Rho family GTPase activating protein involved in epithelial cell cytoskeletal organisation. MYO9B is hypothesised to influence intestinal permeability and hence intestinal antigen presentation. METHODS: Four single nucleotide polymorphisms were chosen to tag all common haplotypes of the MYO9B 3' haplotype block (exons 15-27). We genotyped 375 coeliac disease cases and 1366 controls (371 healthy and 995 population based). All individuals were of White UK Caucasian ethnicity. RESULTS: UK healthy control and population control allele frequencies were similar for all MYO9B variants. Case control analysis showed no significant association of any variant or haplotype with coeliac disease. CONCLUSIONS: Genetic variation in MYO9B does not have a major effect on coeliac disease susceptibility in the UK population. Differences between populations, a weaker effect size than originally described, or possibly a type I error in the Dutch study might explain these findings.
Assuntos
Doença Celíaca/genética , Miosinas/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Reino UnidoRESUMO
BACKGROUND: Nucleotide binding oligomerisation domain 2 (NOD2; also known as CARD15) mutations are associated with Crohn's disease but how mutations cause disease is poorly understood. Innate immune responses are reportedly enhanced by combined NOD2 ligand (muramyl dipeptide, MDP) and Toll-like receptor 4 ligand (TLR4, lipopolysaccharide) stimulation. Intestinal TLR signalling has a dual role-maintaining intestinal homeostasis and protection from injury as well as initiating inflammatory responses. TLR9 is functional in the intestinal epithelium where it is most strongly expressed in Paneth cells. AIMS: To study possible interactions between CpG DNA (TLR9 ligand) and MDP using primary human cells of differing NOD2 genotypes. SUBJECTS: NOD2 wild-type healthy controls (n = 7) and NOD2 homozygous Crohn's disease patients (n = 19), age and sex matched. METHODS: Peripheral blood mononuclear cells were stimulated with CpG DNA and MDP. Cytokines were measured by enzyme linked immunosorbent assay. RESULTS: Tumour necrosis factor alpha (TNF-alpha) and interleukin 8 (IL-8) responses to CpG DNA were similar in NOD2 wild-type and homozygous mutant cells. Concomitant NOD2 stimulation had a marked synergistic effect on CpG DNA induced TNF-alpha responses at 10-100 ng/ml MDP. A mean 2.1-fold increase in CpG DNA induced TNF-alpha responses and a mean 3.7-fold increase in IL-8 responses were observed in NOD2 wild-type cells with 10 ng/ml MDP. This effect was abolished in NOD2 homozygous cells. CONCLUSIONS: NOD2 stimulation normally enhances innate immune responses to CpG DNA. This marked synergistic effect is lost in Crohn's disease patients homozygous for NOD2 mutations, with implications for TLR mediated intestinal homeostasis and inflammation.
Assuntos
Doença de Crohn/genética , Doença de Crohn/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Glicoproteínas de Membrana/imunologia , Receptores de Superfície Celular/imunologia , Acetilmuramil-Alanil-Isoglutamina/imunologia , Adulto , Western Blotting , Células Cultivadas , Ilhas de CpG/imunologia , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Imunidade nas Mucosas , Interleucina-8/biossíntese , Mucosa Intestinal/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ligantes , Masculino , Pessoa de Meia-Idade , Mutação , Proteína Adaptadora de Sinalização NOD2 , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Receptor 4 Toll-Like , Receptor Toll-Like 9 , Receptores Toll-Like , Fator de Necrose Tumoral alfa/biossínteseRESUMO
BACKGROUND: Current understanding of T cell epitopes in coeliac disease (CD) largely derives from intestinal T cell clones in vitro. T cell clones allow identification of gluten peptides that stimulate T cells but do not quantify their contribution to the overall gluten specific T cell response in individuals with CD when exposed to gluten in vivo. AIMS: To determine the contribution of a putative dominant T cell epitope to the overall gliadin T cell response in HLA-DQ2 CD in vivo. PATIENTS: HLA-DQ2+ individuals with CD and healthy controls. METHODS: Subjects consumed 20 g of gluten daily for three days. Interferon gamma (IFN-gamma) ELISPOT was performed using peripheral blood mononuclear cells (PBMC) to enumerate and characterise peptide and gliadin specific T cells before and after gluten challenge. RESULTS: In 50/59 CD subjects, irrespective of homo- or heterozygosity for HLA-DQ2, IFN-gamma ELISPOT responses for an optimal concentration of A-gliadin 57-73 Q-E65 were between 10 and 1500 per million PBMC, equivalent to a median 51% of the response for a "near optimal" concentration of deamidated gliadin. Whole deamidated gliadin and gliadin epitope specific T cells induced in peripheral blood expressed an intestinal homing integrin (alpha4beta7) and were HLA-DQ2 restricted. Peripheral blood T cells specific for A-gliadin 57-73 Q-E65 are rare in untreated CD but can be predictably induced two weeks after gluten exclusion. CONCLUSION: In vivo gluten challenge is a simple safe method that allows relevant T cells to be analysed and quantified in peripheral blood by ELISPOT, and should permit comprehensive high throughput mapping of gluten T cell epitopes in large numbers of individuals with CD.
Assuntos
Antígenos , Doença Celíaca/imunologia , Glutens , Linfócitos T/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/métodos , Epitopos de Linfócito T , Feminino , Gliadina/imunologia , Antígenos HLA-DQ/análise , Humanos , Imunidade Celular , Imunofenotipagem , Integrinas/análise , Interferon gama/imunologia , Mucosa Intestinal/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
BACKGROUND: It is now well established that susceptibility to inflammatory bowel disease is in part genetic, with one localization on chromosome 6 (IBD3) having been replicated in a number of populations. A candidate in that region, TNF-alpha, contains polymorphisms in the promoter region that appear to be associated with disease. METHODS: More than 600 individuals from 170 multiplex IBD families were genotyped for four polymorphisms in the TNF-alpha gene and analysed for association. RESULTS AND CONCLUSION: A strong association was observed between transmission of the -857 C allele and disease. This effect was strongest in those families in which the NOD2 risk alleles are also segregating, supporting the existence of an interaction between IBD3 and IBD1 on chromosome 16.
Assuntos
Proteínas de Transporte/genética , Doenças Inflamatórias Intestinais/genética , Peptídeos e Proteínas de Sinalização Intracelular , Fator de Necrose Tumoral alfa/genética , Austrália/epidemiologia , Cromossomos Humanos Par 6 , Predisposição Genética para Doença , Genótipo , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/imunologia , Proteína Adaptadora de Sinalização NOD2 , Polimorfismo Genético , Regiões Promotoras GenéticasRESUMO
We report the complication of knotted percutaneous endoscopic jejunostomy (PEJ) feeding tubes in three patients with intestinal dysmotility. The management of PEJ tube dysfunction and strategies to prevent this complication are discussed.
Assuntos
Nutrição Enteral/instrumentação , Enteropatias/terapia , Jejunostomia/métodos , Idoso , Endoscopia , Falha de Equipamento , Feminino , Motilidade Gastrointestinal/fisiologia , Humanos , Enteropatias/etiologia , Enteropatias/fisiopatologia , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Linkage studies from five groups worldwide have confirmed the presence of an inflammatory bowel disease susceptibility locus on chromosome 12q. Beta 7 integrin is a strong candidate gene within this region, and is involved in lymphocyte homing to the gut and retention of intra-epithelial lymphocytes. Monoclonal antibodies to beta7 integrin ameliorate colitis in animal models. We obtained genomic sequence for beta7 integrin, and screened all 16 exons and 1.7 kb of 5' promoter region for polymorphisms in 24 individuals. Fourteen single nucleotide polymorphisms were identified in total and, of these, two common (frequency > or =10%) intronic and two amino acid changing polymorphisms were assessed for potential disease associations. Data were available from 102 multiply affected inflammatory bowel disease families (affected sibling pairs) and 362 simplex (one affected proband) families containing 254 ulcerative colitis, 13 indeterminate colitis and 300 Crohn's disease trios (parents + affected child). No significant associations with any disease phenotype were found with the transmission disequilibrium test. Beta 7 integrin is unlikely to be involved in the genetic susceptibility to inflammatory bowel disease, and therefore future studies on chromosome 12 should focus on other positional candidate genes.
Assuntos
Doenças Inflamatórias Intestinais/genética , Cadeias beta de Integrinas , Integrinas/genética , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Genética Populacional , Genótipo , Humanos , Masculino , MutaçãoRESUMO
The advent of advanced molecular biological techniques in the last two decades has allowed the study of genetic factors in inflammatory bowel disease (IBD). A variety of techniques have been employed to elucidate the effects of genes, starting with the clinical observations that IBD is more common in the relatives of patients than the general population, and the consistency of clinical features within families. The situation is likely to be much more complicated than single gene disorders, and it is estimated that between 10 and 20 genes may be involved. Genome scanning techniques using microsatellite markers have been employed to highlight areas of chromosomes linked to disease such as those on chromosomes 12 and 16. In addition association studies of specific genes such as HLA and cytokine genes have been carried out on functional or positional grounds. It is likely that a combination of these techniques will be required to elucidate the role of individual genes. Recently much work has been focused on genes that may determine clinical phenotype such as disease extent or severity or the response to treatment. Identification of these genes may lead to better targeting of therapy and prognostication, and they are likely to be easier to identify than disease susceptibility genes.
Assuntos
Doenças Inflamatórias Intestinais/genética , Cromossomos Humanos/genética , Ligação Genética , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/imunologia , Complexo Principal de Histocompatibilidade , Modelos Genéticos , Epidemiologia Molecular , FenótipoRESUMO
We report on a patient with acute painful diabetic neuropathy in whom abdominal pain and severe weight loss mimicked neoplastic disease. Positive recognition of the diabetic neuropathic cachexia syndrome might have avoided extensive invasive investigation. Intensive enteral nutritional support was associated with prompt resolution.
Assuntos
Caquexia/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/diagnóstico , Nutrição Enteral , Redução de Peso , Adulto , Caquexia/terapia , Feminino , HumanosRESUMO
BACKGROUND AND AIMS: Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in both ulcerative colitis (UC) and Crohn's disease (CD). A locus on chromosome 5q has been implicated in susceptibility to CD, and recently refined by linkage disequilibrium mapping to a conserved 250 kb haplotype (5q31). No data regarding the contribution of this locus to clinical phenotype exist. In this case control study, we investigated the contribution of this haplotype to both susceptibility and phenotype of CD and UC. PATIENTS AND METHODS: We studied 330 Caucasian CD and 457 UC patients recruited from a single UK centre. Association with disease susceptibility and phenotype was analysed with haplotypes reconstructed from three single nucleotide polymorphisms chosen to span this susceptibility region. Evidence for possible genetic epistasis between IBD5 and NOD2/CARD15 was sought. RESULTS: Linkage disequilibrium across this region was confirmed, with two haplotypes comprising 88% of all chromosomes. Susceptibility to CD, but not to UC, was associated with homozygosity for a common haplotype, H2 (p(c)=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (p(c)=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (p(c)=0.0005; RR 3.0). Importantly, no association with H2 was found in 186 patients without perianal disease. No evidence of epistasis between IBD5 and NOD2/CARD15 was demonstrated. CONCLUSIONS: The IBD5 risk haplotype is associated with CD only. Genotype-phenotype analysis reveals that the strongest association is observed in patients with perianal CD. While the precise gene involved is unclear, these data provide further molecular evidence for a genetic basis of the clinical heterogeneity of CD.
Assuntos
Cromossomos Humanos Par 5/genética , Doença de Crohn/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de RiscoRESUMO
The highly polymorphic nonclassical MHC class I chain-related (MIC) genes MICA and MICB encode stress inducible glycoproteins expressed on a variety of epithelial cells including intestinal cells. Interaction with the receptor NKG2D is likely to provide an important costimulatory signal for activation and proliferation of NK cells, activated macrophages and CD8 alphabeta and gammadelta T cells. Fifty-four MICA and 17 MICB alleles have been described to date. Although the functional significance of this polymorphism is not known, the high degree of nonconservative substitution, concentration to the putative ligand-binding site and recent observation that different MICA alleles bind to NKG2D with varying affinity has generated much interest. The MIC genes are attractive functional and positional candidate genes for inflammatory bowel disease susceptibility as a consequence of their position in the HLA region and expression on the gastrointestinal epithelium. We developed a robust, high-resolution PCR-SSP genotyping method that can be incorporated into the standard 'Phototyping' system and which effectively identifies 46 of 54 MICA alleles, and all 17 MICB alleles. We applied this system in combination with microsatellite genotyping of the exon 5 variable number of tandem repeats (VNTR) to the investigation of genetic susceptibility to the inflammatory bowel diseases, ulcerative colitis and Crohn's disease. We studied 248 patients with Crohn's disease, 329 with ulcerative colitis and 354 ethnically matched controls. Linkage disequilibrium patterns between HLA-B, MICA and MICB are presented. Analysis by individual allele or by multilocus haplotype failed to identify any significant disease associations.
Assuntos
Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Doenças Inflamatórias Intestinais/genética , Reação em Cadeia da Polimerase/métodos , Alelos , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/análise , Humanos , Doenças Inflamatórias Intestinais/etnologia , Desequilíbrio de Ligação , Polimorfismo Genético , Sensibilidade e Especificidade , População Branca/genéticaRESUMO
BACKGROUND AND AIMS: Genetic variation in the chromosome 5q31 cytokine cluster (IBD5 risk haplotype) has been associated with Crohn's disease (CD) in a Canadian population. We studied the IBD5 risk haplotype in both British and Japanese cohorts. Disease associations have also been reported for CARD15/NOD2 and TNF variants. Complex interactions between susceptibility loci have been shown in animal models, and we tested for potential gene-gene interactions between the three CD associated loci. METHODS: Family based association analyses were performed in 457 British families (252 ulcerative colitis, 282 CD trios) genotyped for the IBD5 haplotype, common CARD15, and TNF-857 variants. To test for possible epistatic interactions between variants, transmission disequilibrium test analyses were further stratified by genotype at other loci, and novel log linear analyses were performed using the haplotype relative risk model. Case control association analyses were performed in 178 Japanese CD patients and 156 healthy controls genotyped for the IBD5 haplotype. RESULTS: The IBD5 haplotype was associated with CD (p=0.007), but not with UC, in the British Caucasian population. The CARD15 variants and IBD5 haplotype showed additive main effects, and in particular no evidence for epistatic interactions was found. Variants from the IBD5 haplotype were extremely rare in the Japanese. CONCLUSIONS: The IBD5 risk haplotype is associated with British CD. Genetic variants predisposing to CD show heterogeneity and population specific differences.