RESUMEN
INTRODUCTION: Methamphetamine (MAMP) use is highly associated with psychiatric disorders with 12-13% of MAMP-dependent patients experiencing psychotic symptoms. Substance abuse and dependence may primarily involve the mesolimbic pathway and dopaminergic brain structures. It follows that dopaminergic genes, particularly COMT (encoding catechol-O-methyltransferase) and its val158met polymorphism (rs4680), are natural candidates for susceptibility loci to addiction. We have previously found an association with rs4680 and MAMP addiction. METHODS: We present additional genotyping of rs165599 in 423 cases and 502 controls of a Taiwanese MAMP user sample. We carried out an in-silico evaluation of rs165599 for a possible impact on microRNA binding or UTR stability. We also carried out a review of transcript sequences across the COMT 3'UTR. RESULTS: Genotype counts were (cases/controls): AA 94/110, AG 198/210 and GG 93/109. There were no significant allele or genotype differences between cases and controls for rs165599. However, a haplotype main effect was detected using both rs4680 and rs165599 using the χ²-test in UNPHASED. The global P-value was P=0.0044 with the effect appearing to derive from one haplotype that is underrepresented in cases: A/G for rs4680/rs165599 (haplotype P=0.001). rs165599 is a single nucleotide polymorphism located in the COMT 3' untranslated region (UTR), a noncoding transcript region subject to posttranscriptional down-regulation by mechanisms such as microRNA binding. A review of transcript sequences across the COMT 3'UTR found evidence to suggest antisense interference of COMT from the 3'UTR of the neighbouring 'Armadillo repeat gene deleted in velocardiofacial syndrome' gene.
Asunto(s)
Catecol O-Metiltransferasa/genética , Predisposición Genética a la Enfermedad , Haplotipos/genética , Metanfetamina/efectos adversos , Trastornos Relacionados con Sustancias/enzimología , Trastornos Relacionados con Sustancias/genética , Adolescente , Adulto , Proteínas del Dominio Armadillo/genética , Niño , Biología Computacional , Síndrome de DiGeorge/enzimología , Síndrome de DiGeorge/genética , Pruebas de Enzimas , Femenino , Regulación Enzimológica de la Expresión Génica , Humanos , Luciferasas/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Pruebas Genéticas , Humanos , Calicreínas/genética , Masculino , Proteínas de la Membrana/genética , Proteínas de Secreción Prostática/genética , Proteínas Serina-Treonina Quinasas/genética , Factores de RiesgoRESUMEN
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at