RESUMO
A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Melanoma/genética , Doença de Parkinson/genética , Neoplasias Cutâneas/genética , Estudos de Coortes , Receptor DCC , Dopamina/biossíntese , Genótipo , Humanos , Melaninas/biossíntese , Glicoproteínas de Membrana/genética , Monofenol Mono-Oxigenase , Oxirredutases/genética , Pigmentação/genética , Receptor ErbB-4/genética , Receptores de Superfície Celular/genética , Risco , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
Suboptimal care at the end-of-life can be due to lack of access or knowledge of patient wishes. Ambiguity is often the result of non-standardized formats. Borrowing digital technology from other industries and using existing health information infrastructure can greatly improve the completion, storage, and distribution of advance directives. We believe several simple, low-cost adaptations to regional and federal programs can raise the standard of end-of-life care.