RESUMEN
A point mutation in PDGFRB causes autosomal-dominant Penttinen syndrome Johnston JJ et al. (2015) American Journal of Human Genetics 97(3): 465-474.
Asunto(s)
Acroosteólisis/genética , Acroosteólisis/patología , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Mutación Puntual/genética , Progeria/genética , Progeria/patología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal/genética , Femenino , Humanos , MasculinoAsunto(s)
Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Péptidos y Proteínas de Señalización Intercelular/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Mutación/genética , Dermatosis del Cuero Cabelludo/congénito , Transducción de Señal/genética , HumanosRESUMEN
Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of â¼ 4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Variación Genética/genética , Biotransformación , Europa (Continente) , Humanos , SingapurRESUMEN
The vast range of genetic diversity contributes to a wonderful array of human traits and characteristics. Unfortunately, a consequence of this genetic diversity is large variability in drug response between people, meaning that no single medication is safe and effective in everyone. The debilitating and sometimes deadly consequences of adverse drug reactions (ADRs) are a major and unmet problem of modern medicine. Pharmacogenomics can uncover associations between genetic variation and drug safety and has the potential to predict ADRs in individual patients. Here we review pharmacogenomic successes leading to changes in clinical practice, as well as clinical areas probably to be impacted by pharmacogenomics in the near future. We also discuss some of the challenges, and potential solutions, that remain for the implementation of pharmacogenomic testing into clinical practice for the significant improvement of drug safety.
Asunto(s)
Biomarcadores Farmacológicos , Pruebas Genéticas/métodos , Variación Genética , Farmacogenética/métodos , Farmacogenética/tendencias , Medicina de Precisión/métodos , Antraciclinas/farmacología , Carbamazepina/farmacología , Cisplatino/farmacología , Codeína/farmacología , Humanos , Medicina de Precisión/tendencias , Warfarina/farmacologíaRESUMEN
There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Neoplasias/genética , Tuberculosis/genética , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/patología , Población Negra/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Tuberculosis/tratamiento farmacológico , Tuberculosis/patología , Población Blanca/genéticaRESUMEN
Killer cell immunoglobulin-like receptors (KIRs) on chromosome 19q13.4 regulate the function of not only human natural killer (NK) cells but also T cells. An increase in activating KIR- human leucocyte antigen ligand pairs has been associated with an additional risk to develop type 1 diabetes (T1D). T1D families [n = 184 (552 individuals); n = 176 (528 subjects)], unrelated T1D patients (n = 380; n = 394) and healthy controls (n = 315; n = 401) from Germany and Belgium, respectively, were genotyped for the rs2756923 polymorphism within the KIR gene cluster haplotype B in exon 8 of the KIR2DL2 gene. We observed in both Germans and Belgians an overtransmission of the allele 'G' of the KIR2DL2-rs2756923 polymorphism (64.2% vs 35.8%, P = 3 x 10(-4) and 60.0% vs 40.0%, P = 0.02, respectively). In addition, this allele was more frequent in German patients than in healthy controls (78.4% vs 21.6%, P = 1 x 10(-3)). Preliminary results from a cytotoxicity assay suggest that inhibition of NK-cell cytotoxicity may be impaired in individuals carrying the rs2756923 G allele. These data suggest a potential role of the KIR2DL2-rs2756923 polymorphism in T1D in Germans and Belgians.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Frecuencia de los Genes/genética , Antígenos HLA-C/genética , Células Asesinas Naturales/metabolismo , Receptores KIR2DL2/genética , Alelos , Bélgica , Línea Celular Tumoral , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Alemania , Antígenos HLA-C/metabolismo , Haplotipos/genética , Humanos , Células Asesinas Naturales/inmunología , Masculino , Polimorfismo de Nucleótido Simple/genética , Receptores KIR2DL2/inmunologíaRESUMEN
Type 1 diabetes is an autoimmune heterogeneous disease that is determined by environmental and genetic factors. A possible retroviral etiology has been inferred from the observation that human endogenous retrovirus (HERV)-K18 encoding a superantigen (SAg) has a polymorphism associated with this disease. Type 1 diabetes families from Germany and Belgium were genotyped for the novel HERV-8914 (303 families) and for the known HERV-8594 (284 families) polymorphisms within the SAg-coding region on the HERV-K18. Case-control analysis was performed for the HERV-8914 polymorphism (506 patients) and for the HERV-8594 polymorphism (370 patients) and compared with 350 German controls. Haplotypes were constructed. Additionally, a microsatellite within the CD48 gene was analyzed in German type 1 diabetes families (n=125) as well as in patients (n=375) and in healthy controls (n=350). No association was found for HERV-K18 polymorphisms or the CA repeat within the CD48 gene with type 1 diabetes mellitus either in families or by comparing patients and controls. In conclusion, we cannot confirm a role of HERV-K18 polymorphisms -HERV-8914 and HERV-8594- or of the CD48 CA repeat for type 1 diabetes susceptibility.
