RESUMEN
We have studied the association of a null mutation of Glutathione Transferase M1 (GST M1*0/0) with Parkinson's disease (MIM 168600) in a Chilean population with a strong Amerindian genetic component. We determined the genotype in 349 patients with idiopathic Parkinson's disease (174 female and 175 male; 66.84+/-10.7 years of age), and compared that to 611 controls (457 female and 254 male; 62+/-13.4 years of age). A significant association of the null mutation in GST M1 with Parkinson's disease was found (p=0.021), and the association was strongest in the earlier age range. An association of GSTM1*0/0 with Parkinson's disease supports the hypothesis that Glutathione Transferase M1 plays a role in protecting astrocytes against toxic dopamine oxidative metabolism, and most likely by preventing toxic one-electron reduction of aminochrome.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Glutatión Transferasa/genética , Estrés Oxidativo/genética , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/metabolismo , Astrocitos/enzimología , Encéfalo/enzimología , Encéfalo/fisiopatología , Chile/etnología , Citoprotección/genética , Análisis Mutacional de ADN , Dopamina/metabolismo , Femenino , Pruebas Genéticas , Genotipo , Humanos , Indígenas Sudamericanos/etnología , Indígenas Sudamericanos/genética , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/etnologíaRESUMEN
Pathogenic substitutions in the leucine-rich repeat kinase 2 protein (Lrrk2), R1441G and G2019S, are a prevalent cause of autosomal dominant and sporadic Parkinson's disease in the Northern Spanish population. In this study we examined the frequency of these two substitutions in 166 Parkinson's disease patients and 153 controls from Chile, a population with Spanish/European-Amerindian admixture. Lrrk2 R1441G was not observed, however Lrrk2 G2019S was detected in one familial and four sporadic Parkinson's disease patients. These findings suggest Lrrk2 G2019S may play an important role in Parkinson's disease on the South American Continent and further studies are now warranted.
Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Edad de Inicio , Chile/epidemiología , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la PolimerasaRESUMEN
Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease, with frequencies displaying a high degree of population-specificity. Although more than 100 coding substitutions have been identified, only seven have been proven to be highly penetrant pathogenic mutations. Studies however are lacking in non-white populations. Recently, Lrrk2 p.Q1111H (rs78365431) was identified in two affected Hispanic brothers and absent in 386 non-Hispanic white healthy controls. We therefore screened this variant in 1460 individuals (1150 PD patients and 310 healthy controls) from 4 Latin American countries (Peru, Chile, Uruguay and Argentina). In our case-control series from Peru and Chile we observed an increased frequency of Lrrk2 p.Q1111H in patients (7.9%) compared to controls (5.4%) although the difference did not reach significance (OR 1.38; p = 0.10). In addition, the frequency of Lrrk2 p.Q1111H varied greatly between populations and further screening in a set of pure Amerindian and pure Spanish controls suggested that this variant likely originated in an Amerindian population. Further studies in other Latin American populations are warranted to assess its role as a risk factor for Parkinson's disease. Screening in Parkinson's disease patients from under-represented populations will increase our understanding of the role of LRRK2 variants in disease risk worldwide.