RESUMO
BACKGROUND: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. METHODS: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. RESULTS: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. CONCLUSIONS: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.
Assuntos
Expressão Gênica/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Doença de Parkinson/genética , Proteínas tau/genética , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Cromossomos Humanos Par 17/genética , Estudos de Coortes , Análise Mutacional de DNA , Expansão das Repetições de DNA/genética , Feminino , Testes Genéticos , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
OBJECTIVE: The NHLBI Family Heart Study (FHS) genome-wide linkage scan identified a region of chromosome 7q with a logarithm of odds score of 4.9 for body mass index (BMI). DESIGN: We report the results of fine mapping the linkage peak using 1020 single nucleotide polymorphisms (SNPs) to test for association to obesity in families exhibiting linkage to chromosome 7. Association observed in linked families (284 obese cases/381 controls) was examined in an independent set of unrelated FHS participants (172 obese cases/308 controls) to validate the observed association. Two dichotomous obesity phenotypes were studied based on clinical BMI cutoffs and the sex-specific distribution of both BMI and leptin levels. RESULTS: Using a P-value of 0.01 as criteria for association in the linked families, a P-value of 0.05 as criteria for association in the unrelated sample, and requiring consistency in the direction of the effect of the minor allele between the two samples, we identified two coding SNPs in the NYD-SP18 gene with minor alleles increasing the risk of obesity. Adjustment for exercise, smoking and FTO genotype did not influence the result in linked families, but improved the result in the unrelated sample. Carrying a minor allele of the nonsynonymous SNP rs6971091 conferred an odds ratio of at least 2 for obesity defined by both BMI and leptin levels. CONCLUSION: The effect of the NYD-SP18 SNP on obesity was larger than the effect of FTO in FHS families. Publicly available results from genome-wide association studies support the association between NYD-SP18 and BMI. The NYD-SP18 gene is described as testes development related, but little is known about the gene's function or the mechanism by which it may influence risk for obesity.
Assuntos
Ligação Genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Índice de Massa Corporal , Mapeamento Cromossômico , Cromossomos Humanos Par 7/genética , Métodos Epidemiológicos , Feminino , Expressão Gênica/genética , Genótipo , Humanos , Leptina/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.
Assuntos
Glutationa S-Transferase pi/genética , Herbicidas/efeitos adversos , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Doença de Parkinson Secundária/genética , Medição de Risco/métodos , Suscetibilidade a Doenças/induzido quimicamente , Feminino , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson Secundária/induzido quimicamente , Fatores de RiscoRESUMO
Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Transtornos Parkinsonianos/genética , Polimorfismo Genético/genética , Idade de Início , Análise Mutacional de DNA , Saúde da Família , Frequência do Gene , Testes Genéticos , Haplótipos/genética , Homozigoto , Modelos Estatísticos , Transtornos Parkinsonianos/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Oncogênicas/genética , Doença de Parkinson/genética , Fatores de Transcrição/genética , alfa-Sinucleína/genética , Idoso , Deleção de Genes , Predisposição Genética para Doença , Variação Genética/genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Pessoa de Meia-Idade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Mutação Puntual/genética , Reação em Cadeia da Polimerase , Proteína Desglicase DJ-1 , Fatores de RiscoRESUMO
We have developed a computational approach that allows for one-to-one mapping of the airway anatomy when predicting the overall lung mechanical properties and their response to explicit constriction patterns imposed on the airway tree. Specifically, we have exploited the database from Raabe et al. (LF-53 Albuquerque, NM: Lovelace foundation for radical Education and Research), to build the first anatomically based computational model of the rat. The model was then used to predict the response to homogeneous and heterogeneous peripheral airway constriction. Unlike in humans, the inherent asymmetry in the airway tree of rats is predicted to be a dominant contributor to the frequency dependence of lung resistance and elastance even if the constriction is imposed homogeneously. A similar approach would, in principal, be applicable for humans, but the Raabe data is not sufficiently complete to permit this.