RESUMEN
SIRT1 is a NAD(+)-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.
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Ansiedad/genética , Encéfalo/metabolismo , Conducta Exploratoria , Monoaminooxidasa/genética , Sirtuina 1/genética , Sirtuina 1/metabolismo , Secuencia de Aminoácidos , Animales , Conducta Animal , Impulso (Psicología) , Regulación de la Expresión Génica , Humanos , Ratones , Datos de Secuencia Molecular , Monoaminooxidasa/química , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Factores de Transcripción/genéticaRESUMEN
Background and Objective There is convincing evidence that small CGG expansion (41-54 repeats): FMR1 "gray zone" alleles (GZ) contribute to the risk of parkinsonism in males, but there is insufficient corresponding data in females. This study intends to fill this gap. Methods We screened whole-blood-derived DNA from a cohort of 601 females diagnosed with idiopathic PD, and from dry Guthrie blood spots from a local sample of 1,005 female newborns (population controls), for the size of the FMR1 CGG repeat using a PCR technique. Results We found a significant excess (8.2%) of GZ carriers compared with 5.2% in the control sample, with a P value of 0.009 for the difference in proportions. Conclusion FMR1 gray zone alleles are a significant risk factor for parkinsonism in females. These population data and occasional reports of FXTAS-like or parkinsonian manifestations in carriers suggest possible mechanisms whereby the effects of these alleles synergize with the existing pathologies underpinning parkinsonism. © 2018 International Parkinson and Movement Disorder Society.
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Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Predisposición Genética a la Enfermedad/genética , Trastornos Parkinsonianos/genética , Expansión de Repetición de Trinucleótido/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Trastornos Parkinsonianos/epidemiología , Factores de Riesgo , Factores SexualesRESUMEN
UNLABELLED: Prevention of relapse of Plasmodium vivax infection is a key treatment goal in malaria. Use of P. vivax genotyping in a multicenter, double-blind, randomized, placebo-controlled phase 2b study in Peru, India, Thailand, and Brazil allowed determination of genetically heterologous or homologous P. vivax infection recurrence following receipt of chloroquine plus one of 4 doses of tafenoquine (50, 100, 300, or 600 mg) or chloroquine plus primaquine, compared with receipt of chloroquine alone. The antihypnozoite efficacy of tafenoquine was evident as a reduction in homologous recurrences of P. vivax infection as drug doses were increased. No clear dose-response pattern was evident for heterologous recurrences of P. vivax infection. Rates of homologous recurrence of P. vivax infection appear to be clinically useful for comparing drug efficacy for the prevention of P. vivax infection relapse. CLINICAL TRIALS REGISTRATION: NCT01376167.
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Aminoquinolinas/uso terapéutico , Antimaláricos/uso terapéutico , Malaria Vivax/tratamiento farmacológico , Plasmodium vivax/genética , Prevención Secundaria , Aminoquinolinas/administración & dosificación , Antimaláricos/administración & dosificación , Cloroquina/administración & dosificación , Cloroquina/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Genotipo , Humanos , Primaquina/administración & dosificación , Primaquina/uso terapéuticoRESUMEN
BACKGROUND: Tafenoquine (TQ) and primaquine (PQ) are 8-aminoquinolines (8-AQ) with anti-hypnozoite activity against vivax malaria. PQ is the only FDA-approved medicine for preventing relapsing Plasmodium vivax infection and TQ is currently in phase 3 clinical trials for the same indication. Recent studies have provided evidence that cytochrome P450 (CYP) metabolism via CYP2D6 plays a role in PQ efficacy against P. vivax and have suggested that this effect may extend to other 8-AQs, including TQ. Here, a retrospective pharmacogenetic (PGx) investigation was performed to assess the impact of CYP2D6 metabolism on TQ and PQ efficacy in the treatment of P. vivax in the DETECTIVE study (TAF112582), a recently completed, randomized, phase 2b dose-ranging clinical trial. The impact of CYP2D6 on TQ pharmacokinetics (PK) was also investigated in TAF112582 TQ-treated subjects and in vitro CYP metabolism of TQ was explored. A limitation of the current study is that TAF112582 was not designed to be well powered for PGx, thus our findings are based on TQ or PQ efficacy in CYP2D6 intermediate metabolizers (IM), as there were insufficient poor metabolizers (PM) to draw any conclusion on the impact of the PM phenotype on efficacy. METHODS: The impact of genetically-predicted CYP2D6 reduced metabolism on relapse-free efficacy six months post-dosing of TQ or PQ, both administered in conjunction with chloroquine (CQ), was assessed using exact statistical methods in 198 P. vivax-infected study participants comparing IM to extensive metabolizers (EM). The influence of CYP2D6 metabolizer phenotypes on TQ PK was assessed comparing median TQ area under the curve (AUC). In vitro metabolism of TQ was investigated using recombinant, over-expressed human CYP enzymes and human hepatocytes. Metabolite identification experiments were performed using liquid chromatography-mass spectrometry. RESULTS: Reduction of CYP2D6 activity was not associated with an increase in relapse-rate in TQ-treated subjects (p = 0.57). In contrast, and in accordance with recent literature, CYP2D6 IMs were more common (p = 0.05) in PQ-treated subjects who relapsed (50 %) than in subjects who remained relapse-free (17 %). Further, CYP2D6 metabolizer phenotypes had no significant effect on TQ AUC, and only minimal metabolism of TQ could be detected in hepatic in vitro systems. CONCLUSION: Together, these data provide preliminary evidence that in CYP2D6 IMs, TQ efficacy in P. vivax-infected individuals is not diminished to the same extent as PQ. As there were no PMs in either the TQ or PQ treatment arms of TAF112582, no conclusions could be drawn on potential differences in PMs. These findings suggest that differential effects of CYP2D6 metabolism on TQ and PQ efficacy could be a differentiation factor between these 8-AQs, but results remain to be confirmed prospectively in the ongoing phase 3 studies.
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Aminoquinolinas/uso terapéutico , Antimaláricos/uso terapéutico , Citocromo P-450 CYP2D6/metabolismo , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/metabolismo , Cloroquina/uso terapéutico , Femenino , Humanos , Primaquina/uso terapéutico , Resultado del TratamientoRESUMEN
The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions.
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Leptina/inmunología , Leptina/metabolismo , Receptores de Leptina/metabolismo , Análisis de Varianza , Animales , Artritis Experimental/patología , Secuencia de Bases , Western Blotting , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cartilla de ADN/genética , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/patología , Citometría de Flujo , Células HEK293 , Humanos , Células MCF-7 , Masculino , Ratones , Ratones Mutantes , Datos de Secuencia Molecular , Glicoproteína Mielina-Oligodendrócito/toxicidad , Estructura Terciaria de Proteína/genética , Estructura Terciaria de Proteína/fisiología , Receptores de Leptina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Eliminación de Secuencia/genéticaRESUMEN
PURPOSE: Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. METHODS: The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated. RESULTS: The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-τ), Cmax and Cτ, respectively. CONCLUSIONS: Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.
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Benzoxazinas/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piridinas/farmacología , Pironas/farmacología , Ritonavir/farmacología , Adulto , Anciano , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Área Bajo la Curva , Benzoxazinas/efectos adversos , Estudios Cruzados , Ciclopropanos , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Oxazinas , Piperazinas , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridonas , Pironas/administración & dosificación , Pironas/efectos adversos , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , Sulfonamidas , Adulto JovenRESUMEN
Background: Opioid switching is common, however, conversion tables have limitations. Guidelines suggest postswitch dose reduction, yet, observations show opioid doses may increase postswitch. Objectives: To document the opioid conversion factor postswitch in cancer, and whether pain and adverse effect outcomes differ between switched opioid groups. Design/Setting: This multicenter prospective longitudinal study included people with advanced cancer in Australia. Clinical data (demographics, opioids) and validated instruments (pain, adverse effects) were collected twice, seven days apart. Results: Opioid switch resulted in dose increase (median oral morphine equivalent daily dose 90 mg [interquartile range {IQR} 45-184] to 150 mg [IQR 79-270]), reduced average pain (5.1 [standard deviation {SD} 1.7] to 3.8 [SD 1.6]), and reduced adverse effects. Hydromorphone dose increased 2.5 times (IQR 1.0-3.6) above the original conversion factor used. Conclusions: Opioid switching resulted in overall dose increase, particularly when switching to hydromorphone. Higher preswitch dosing may require higher dose conversion ratios. Dose reduction postswitch risks undertreatment and may not be always appropriate.
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Dolor en Cáncer , Dolor Crónico , Neoplasias , Humanos , Analgésicos Opioides , Hidromorfona/efectos adversos , Dolor en Cáncer/tratamiento farmacológico , Estudios Prospectivos , Estudios Longitudinales , Dolor Crónico/tratamiento farmacológico , Neoplasias/tratamiento farmacológicoRESUMEN
Aim: Associations between gene variants and opioid net effect are unclear. We conducted an exploratory pharmacogenetic analysis of 35 gene variants and opioid response in advanced cancer. Patients & methods: This multi-center prospective cohort study included clinical data, questionnaires (pain and adverse effects) and DNA (blood). Negative binomial regression and logistic regression were used. Results: Within 54 participants, eight statistically significant associations (p = 0.002-0.038) were observed between gene variants and opioid dose, pain scores or adverse effects, the majority being within the neuroimmune TLR4 pathway (IL1B [rs1143634], IL2 [rs2069762], IL6 [rs1800795], BDNF [rs6265]) and ARRB2 pathway (ARRB2 [rs3786047], DRD2 [rs6275]). Conclusion: Neuroimmune pathway genes may contribute to differences in opioid response in cancer and may be included in future similar studies.
RESUMEN
Genetic variation in LRRK2 predisposes to Parkinson disease (PD), which underpins its development as a therapeutic target. Here, we aimed to identify novel genotype-phenotype associations that might support developing LRRK2 therapies for other conditions. We sequenced the 51 exons of LRRK2 in cases comprising 12 common diseases (n = 9,582), and in 4,420 population controls. We identified 739 single-nucleotide variants, 62% of which were observed in only one person, including 316 novel exonic variants. We found evidence of purifying selection for the LRRK2 gene and a trend suggesting that this is more pronounced in the central (ROC-COR-kinase) core protein domains of LRRK2 than the flanking domains. Population genetic analyses revealed that LRRK2 is not especially polymorphic or differentiated in comparison to 201 other drug target genes. Among Europeans, we identified 17 carriers (0.13%) of pathogenic LRRK2 mutations that were not significantly enriched within any disease or in those reporting a family history of PD. Analysis of pathogenic mutations within Europe reveals that the p.Arg1628Pro (c4883G>C) mutation arose independently in Europe and Asia. Taken together, these findings demonstrate how targeted deep sequencing can help to reveal fundamental characteristics of clinically important loci.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Proteínas Serina-Treonina Quinasas/genética , Europa (Continente) , Predisposición Genética a la Enfermedad , Genética de Población , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Mutación , Enfermedad de Parkinson/genética , Población Blanca/genéticaRESUMEN
BACKGROUND: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established. OBJECTIVE: We aimed to identify genetic variants associated with progressive MS (PrMS). METHODS: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10(-4)) in two independent sets of primary progressive MS cases and controls. RESULTS: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934(T), p (combined)=6.7×10(-16), OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343(G), p (combined)=2.4×10(-5), OR=0.70, 95% CI=0.59-0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a 'cis' effect on RNA expression in lymphoblastic cell lines, but pathway analyses of 'trans' effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02). CONCLUSIONS: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.
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Cromosomas Humanos Par 7/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Esclerosis Múltiple Crónica Progresiva/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.
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Linfocitos T CD4-Positivos/inmunología , Hipersensibilidad/genética , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Activación de Linfocitos/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genética , Proliferación Celular , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Enfermedades Inflamatorias del Intestino/patología , Receptores CXCR3/metabolismoRESUMEN
Splicing is a post-transcriptional modification of RNA during which introns are removed and exons are joined. Most of the mammalian genes undergo constitutive and alternative splicing events. In addition to the strong signals of the splice sites, splicing is influenced at a distance by a range of trans factors that interact with cis regulatory elements and influence the spliceosome. The intention of the present mini-review is to give some insights into the complexity of this interaction and to introduce the consequences of some kinds of detrimental genetic variation on alternative splicing and disease.
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Empalme Alternativo , Enfermedad/genética , Variación Genética , Animales , Secuencia de Bases , Exones , Humanos , Intrones , Mutación , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
BACKGROUND: Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo. METHODS: A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS. RESULTS: Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration-dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists of H3R but not neutral antagonists promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis. CONCLUSIONS: From phenotypic screening to human genetics, we provide evidence for H3R as a novel therapeutic target to promote remyelination in patients with multiple sclerosis.
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Esclerosis Múltiple/genética , Vaina de Mielina/metabolismo , Oligodendroglía/citología , Receptores Histamínicos H3/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/patología , Diferenciación Celular , Proliferación Celular , Glutatión Transferasa/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Oligodendroglía/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple , Prosencéfalo/patología , Ratas , Receptores Histamínicos H3/genética , Transducción de SeñalRESUMEN
The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an intermediary between single nucleotide polymorphism (SNP) arrays and sequencing for genetic association studies. Multiplex families with multiple affected individuals may be enriched for disease-associated variants of this class compared to unrelated populations. We present an exome array study of schizophrenia in 99 multiplex families (n=341, including 118 cases) from the Western Australian Family Study of Schizophrenia (WAFSS). Compared to 55,726 individuals from the DIAGRAM sample not selected for schizophrenia, overall allele frequency of exome variants was higher in the WAFSS (P<2.2E-16). This was pronounced in variants nominally associated (P<0.05) with schizophrenia. Genes harbouring variants present only in WAFSS cases were enriched (FDR-corrected P=0.05) for membership of the 'extracellular matrix (ECM) - receptor interaction' biological pathway, adding to evidence that processes affecting the composition or turnover of ECM may contribute to neuropsychiatric disease. We did not find individual variants significantly associated with schizophrenia, although like previous studies, power to detect associations of small effect size was low. Cases did not exhibit a higher burden of variants compared to their unaffected relatives and the finding of previous exome chip studies of unrelated samples that 'schizophrenia gene-sets' were enriched for case-only variants was not replicated in the WAFSS. The higher frequency of moderately rare, exonic variants in these multiplex families compared to a population-based sample may account for some of their genetic liability to schizophrenia, and adds to evidence for a role of exome array variants from previous studies of unrelated samples.
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Exoma/genética , Salud de la Familia , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética , Matriz Extracelular/genética , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Transducción de Señal/genéticaRESUMEN
Results are presented from a genomewide haplotype association study on multiple sclerosis (MS) cases from Tasmania, an island state of Australia. Cases were ascertained on strict clinical and radiological grounds and on the fact that they had at least one grandparent born in the state. This enriched for early settler chromosomes among present day Tasmanians with MS and increased the chances of finding common haplotype sharing at disease predisposition loci in distant relatives sharing common ancestral haplotypes. Four-to-five close relatives were also collected for each of 170 cases and 105 population-based controls. All were genotyped at a 5cM resolution, haplotypes reconstructed and sharing estimated using an empirical approach based on sorting haplotypes to find the most common at each locus and then generating a test statistic for excess sharing in the cases based on permutation testing. Five initial loci were found where there was an excess sharing in the cases. These were fine-mapped with 10-12 additional markers. Only loci on chromosomes 6 and 10 remained after fine mapping. These loci demonstrate an increase in sharing of multi-marker haplotypes in MS cases compared to both population control transmitted haplotypes and case non-transmitted haplotypes.
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Haplotipos , Esclerosis Múltiple/genética , Humanos , Esclerosis Múltiple/epidemiología , Tasmania/epidemiologíaRESUMEN
AIM: To evaluate potential pharmacogenetic effects of UGT1A1 polymorphisms on the pharmacokinetics (PK) of dolutegravir (Tivicay®; ViiV Healthcare, NC, USA), an HIV-1 integrase inhibitor. PATIENTS & METHODS: Analysis of pooled data from nine Phase I and II clinical studies was undertaken for 89 subjects receiving repeat dolutegravir 50 mg once daily (tablet formulation) who were genotyped for known UGT1A1 functional variants. RESULTS: Geometric mean ratio (92% CI) for subjects carrying low (*28/*28 and *28/*37) and reduced activity (*1/*6, *1/*28, *1/*37, *28/*36 and *36/*37) polymorphisms compared with subjects with normal activity (*1/*1 and *1/*36) showed decreased oral clearance (CL/F; 0.765 [92% CI: 0.659-0.889]), increased area under the concentration-time curve (AUC(0-τ); 1.307 [1.125-1.518]) and C(max) (1.221 [1.063-1.402]), respectively. CONCLUSION: Increased dolutegravir exposure in carriers of UGT1A1 reduced function polymorphisms is not clinically significant based on accumulated safety data so dose adjustment in these individuals is not required.
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Glucuronosiltransferasa/genética , Infecciones por VIH/tratamiento farmacológico , Integrasa de VIH , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Genotipo , Infecciones por VIH/genética , VIH-1/efectos de los fármacos , VIH-1/enzimología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Oxazinas , Piperazinas , PiridonasRESUMEN
OBJECTIVES: Genomewide association studies (GWAS) have identified clear evidence of genetic markers for nicotine dependence. Other smoking phenotypes have been tested, but the results are less consistent. The tendency to relapse versus the ability to maintain long-term abstinence has received little attention in genetic studies; thus, our aim was to provide a better biological understanding of this phenotype through the identification of genetic loci associated with smoking relapse. METHODS: We carried out a GWAS on data from two European population-based collections, including a total of 835 cases (relapsers) and 990 controls (abstainers). Top-ranked findings from the discovery phase were tested for replication in two additional independent European population-based cohorts. RESULTS: Of the seven top markers from the discovery phase, none were consistently associated with smoking relapse across all samples and none reached genomewide significance. A single-nucleotide polymorphism rs1008509, within the Xylosyltransferase II (XYLT2) gene, was suggestively associated with smoking relapse in the discovery phase (ß=-0.504; P=5.6E-06) and in the first replication sample (ALSPAC) (ß=-0.27; P=0.004; n=1932), but not in the second sample (KORA) (ß=0.19; P=0.138; n=912). We failed to identify an association between loci implicated previously in other smoking phenotypes and smoking relapse. CONCLUSION: Although no genomewide significant findings emerged from this study, we found that loci implicated in other smoking phenotypes were not associated with smoking relapse, which suggests that the neurobiology of smoking relapse and long-term abstinence may be distinct from biological mechanisms implicated in the development of nicotine dependence.
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Estudio de Asociación del Genoma Completo , Fumar/genética , Población Blanca/genética , Estudios de Casos y Controles , Demografía , Femenino , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , RecurrenciaRESUMEN
[(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 × 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
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Acetamidas/metabolismo , Polimorfismo de Nucleótido Simple , Piridinas/metabolismo , Radiofármacos/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Adulto , Sustitución de Aminoácidos/genética , Unión Competitiva/genética , Plaquetas/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Femenino , Estudios de Asociación Genética , Humanos , Isoquinolinas/metabolismo , Masculino , Tomografía de Emisión de Positrones , Unión Proteica , Ensayo de Unión Radioligante , TritioRESUMEN
Multiple sclerosis (MS) is a complex autoimmune disease characterised by demyelinating lesions in the central nervous system (CNS) and myelin oligodendrocyte glycoprotein (MOG), a CNS-restricted protein expressed on the outer cell membrane of oligodendrocytes, has been linked with disease pathogenesis. We have investigated whether expression of MOG in post-mortem human brain tissue is associated with genetic variations in the MOG gene that have previously been associated with genetic susceptibility to MS (520G>A, rs3130253, V145I and 511G>C, rs2857766, V142L). Using quantitative reverse transcriptase PCR (qPCR), we found that the haplotype containing the 520A (rs3130253A, I145) allele is associated with a 1.7-fold increase in splicing of exon 2 to exon 3, which encodes the extracellular and transmembrane domains of MOG. Using predictive algorithms, we found that the 520G>A variant also alters a putative exonic splicing enhancer (ESE) involving the SC35 and SRp55 RNA-binding proteins, supporting the notion that this variation has a regulatory effect. No consistent differences in allele-specific expression were observed for any of the SNPs using the SNaPshot® method. In this exploratory study we have observed that changes in splicing, but not expression levels, are associated with common genetic variation in the MOG gene. Further work is now required to confirm these data and determine whether this altered MOG expression profile, which is predicted to be over-represented in Northern Europeans with MS, is relevant to the pathophysiology of this debilitating disease.