RESUMO
NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, inducing gene transcription and synthesis of proteins required to initiate a balanced immune response. Mutations in NOD2 have been associated with an increased risk of Crohn's Disease (CD), a disabling inflammatory bowel disease (IBD). Because NOD2 signaling plays a key role in CD, it is important to further characterize the network of protein interacting with NOD2. Using yeast two hybrid (Y2H) screens, we identified new NOD2 interacting proteins (NIP). The primary interaction was confirmed by coimmunoprecipitation and/or bioluminescence resonance energy transfer (BRET) experiments for 11 of these proteins (ANKHD1, CHMP5, SDCCAG3, TRIM41, LDOC1, PPP1R12C, DOCK7, VIM, KRT15, PPP2R3B, and C10Orf67). These proteins are involved in diverse functions, including endosomal sorting complexes required for transport (ESCRT), cytoskeletal architecture and signaling regulation. Additionally, we show that the interaction of 8 NIPs is compromised with the 3 main CD associated NOD2 mutants (R702W, G908R and 1007fs). Furthermore, to determine whether these NOD2 protein partners could be encoded by IBD susceptibility genes, a transmission disequilibrium test (TDT) was performed on 101 single nucleotide polymorphisms (SNPs) and the main corresponding haplotypes in genes coding for 15 NIPs using a set of 343 IBD families with 556 patients. Overall this work did not increase the number of IBD susceptibility genes but extends the NOD2 protein interaction network and suggests that NOD2 interactome and signaling depend upon the NOD2 mutation profile in CD.
Assuntos
Doença de Crohn/genética , Doença de Crohn/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Mapeamento de Interação de Proteínas , Linhagem Celular , Humanos , Macrófagos/metabolismo , Mutação , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Numerous genetic and environmental risk factors play a role in human complex genetic disorders (CGD). However, their complex interplay remains to be modelled and explained in terms of disease mechanisms. METHODS AND FINDINGS: Crohn's Disease (CD) was modeled as a modular network of patho-physiological functions, each summarizing multiple gene-gene and gene-environment interactions. The disease resulted from one or few specific combinations of module functional states. Network aging dynamics was able to reproduce age-specific CD incidence curves as well as their variations over the past century in Western countries. Within the model, we translated the odds ratios (OR) associated to at-risk alleles in terms of disease propensities of the functional modules. Finally, the model was successfully applied to other CGD including ulcerative colitis, ankylosing spondylitis, multiple sclerosis and schizophrenia. CONCLUSION: Modeling disease incidence may help to understand disease causative chains, to delineate the potential of personalized medicine, and to monitor epidemiological changes in CGD.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Redes Reguladoras de Genes , Modelos Genéticos , Esclerose Múltipla/genética , Esquizofrenia/genética , Espondilite Anquilosante/genética , Adulto , Alelos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/patologia , Simulação por Computador , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Epistasia Genética , Feminino , Interação Gene-Ambiente , Humanos , Incidência , Masculino , Cadeias de Markov , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/patologia , Razão de Chances , Fatores de Risco , Esquizofrenia/diagnóstico , Esquizofrenia/patologia , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/patologiaRESUMO
Complex diseases involve both a genetic component and a response to environmental factors or lifestyle changes. Recently, genome-wide association studies (GWAS) have succeeded in identifying hundreds of polymorphisms that are statistically associated with complex diseases. However, the association is usually weak and none of the associated allelic forms is either necessary or sufficient for the disease occurrence. We argue that this promotes a network view, centred on functional redundancy. We adapted reliability theory to the concerned sub-network, modelled as a parallel array of functional modules. In our model, as long as one module remains active, the function correlated with the respective disease is ensured and disease does not occur. Genetic factors reduce the initial number of available modules while environment, contingent surroundings, personal history, epigenetics, and some intrinsic stochasticity influence their persistence time. This model reproduces age-specific incidence curves and explains the influence of environmental changes. It offers a new paradigm, according to which disease occurs due to a lack of functional elements, depending on many idiosyncratic factors. Genetic risk assessed from GWAS is only a statistical notion with no direct interpretation at the individual level. However, genomic profiling could be useful at population level in devising models to guide decisions in health care policy.
Assuntos
Predisposição Genética para Doença , Modelos Biológicos , Fatores Etários , Epidemiologia , Estudo de Associação Genômica Ampla , Humanos , Incidência , Filosofia Médica , Polimorfismo GenéticoRESUMO
Estimation of genotype-specific risks at a disease susceptibility locus is an important question that is best carried out in a prospective study. Nevertheless it is usually desirable to make use of data from the families that have already been collected to identify the susceptibility locus. Assuming that the families have been collected without regard to genotype at the locus in question, most of the information can be extracted by writing the likelihood in terms of the risk for a genotype relative to the standard genotype and conditional on the parental mating type. Parameters may then be estimated by explicit solution of likelihood equations. This method permits estimation of risks for heterozygotes and homozygotes for different alleles, testing of different modes of inheritance and heterogeneity of risk between alleles. It is applicable to risk alleles for any disease locus or incompletely penetrant phenotype. We have used the method to estimate risks of Crohn disease for different CARD/NOD2 15 mutations, using the families originally collected to identify this susceptibility locus. The odds ratio of Crohn disease were, respectively, 1.97+/-0.85, 3.05+/-* and 4.55+/-1.34 for the R702W, G9068R and 1007fs heterozygotes and 3.29+/-0.64, 12.13+/-* and 34.66+/-12.87 for the corresponding homozygotes. (* Signifies insufficient data to estimate these values.) These results confirm the dosage effect for CARD15/NOD2 mutations and demonstrate that the disease risks are very different in homozygotes. This last observation illustrates the power of this approach, especially for alleles with low or moderate frequency in the general population.
Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença , Proteína Adaptadora de Sinalização NOD2/genética , Linhagem , Substituição de Aminoácidos , Interpretação Estatística de Dados , Humanos , Funções Verossimilhança , Razão de ChancesRESUMO
The beneficial effects of spironolactone, eplerenone, amiloride and potassium in preventing cardiovascular damage in various experimental models of salt-induced hypertension can be dissociated from blood pressure effects, and have drawn attention to the direct genomic and non-genomic actions of aldosterone at the level of the vessels, the heart and the kidneys. Exposure to endogenous aldosterone could be decreased by direct and specific aldosterone-synthase inhibition. FAD 286A, the dextroenantiomer of the aromatase inhibitor fadrozole, might be a first candidate to investigate in humans, the physiological impact and therapeutic properties of aldosterone-synthase inhibition, especially in various forms of primary aldosteronism.
Assuntos
Inibidores da Aromatase/farmacologia , Citocromo P-450 CYP11B2/efeitos dos fármacos , Fadrozol/farmacologia , Animais , Citocromo P-450 CYP11B2/antagonistas & inibidores , Fadrozol/química , HumanosRESUMO
Previous studies have indicated that average telomere length is partly inherited (Slagboom et al., 1994; Rufer et al., 1999) and that there is an inherited telomere pattern in each cell (Graakjaer et al., 2003); (Londoño-Vallejo et al., 2001). In this study, we quantify the importance of the initially inherited telomere lengths within cells, in relation to other factors that influence telomere length during life. We have estimated the inheritance by measuring telomere length in monozygotic (MZ) twins using Q-FISH with a telomere specific peptide nucleic acid (PNA)-probe. Homologous chromosomes were identified using subtelomeric polymorphic markers. We found that identical homologous telomeres from two aged MZ twins show significantly less differences in relative telomere length than when comparing the two homologues within one individual. This result means that towards the end of life, individual telomeres retain the characteristic relative length they had at the outset of life and that any length alteration during the lifespan impacts equally on genetically identical homologues. As the result applies across independent individuals, we conclude that, at least in lymphocytes, epigenetic/environmental effects on relative telomere length are relatively minor during life.