RESUMO
The multifunctional cytokine interleukin-6 (IL-6) is involved in inflammatory processes in the central nervous system and increased levels of IL-6 have been found in patients with Parkinson's disease (PD). It is known that estrogen inhibits the production of IL-6, via action on estrogen receptors, thereby pointing to an important influence of estrogen on IL-6. In a previous study, we reported an association between a G/A single nucleotide polymorphism (SNP) at position 1730 in the gene coding for estrogen receptor beta (ERbeta) and age of onset of PD. To investigate the influence of a G/C SNP at position 174 in the promoter of the IL-6 gene, and the possible interaction of this SNP and the ERbeta G-1730A SNP on the risk for PD, the G-174C SNP was genotyped, by pyrosequencing, in 258 patients with PD and 308 controls. A significantly elevated frequency of the GG genotype of the IL-6 SNP was found in the patient group and this was most obvious among patients with an early age of onset (
Assuntos
Receptor beta de Estrogênio/genética , Predisposição Genética para Doença/genética , Interleucina-6/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Idade de Início , Alelos , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de LigaçãoRESUMO
Several findings obtained recently indicate that inflammation may contribute to the pathogenesis in Parkinson's disease (PD). Genetic variants of genes coding for components involved in immune reactions in the brain might therefore influence the risk of developing PD or the age of disease onset. Five single nucleotide polymorphisms (SNPs) in the genes coding for interferon-gamma (IFN-gamma; T874A in intron 1), interferon-gamma receptor 2 (IFN-gamma R2; Gln64Arg), interleukin-10 (IL-10; G1082A in the promoter region), platelet-activating factor acetylhydrolase (PAF-AH; Val379Ala), and intercellular adhesion molecule 1 (ICAM-1; Lys469Glu) were genotyped, using pyrosequencing, in 265 patients with PD and 308 controls. None of the investigated SNPs was found to be associated with PD; however, the G1082A polymorphism in the IL-10 gene promoter was found to be related to the age of disease onset. Linear regression showed a significantly earlier onset with more A-alleles (P = 0.0095; after Bonferroni correction, P = 0.048), resulting in a 5-year delayed age of onset of the disease for individuals having two G-alleles compared with individuals having two A-alleles. The results indicate that the IL-10 G1082A SNP could possibly be related to the age of onset of PD.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Inflamação/genética , Molécula 1 de Adesão Intercelular/genética , Interferon gama/genética , Interleucina-10/genética , Doença de Parkinson/genética , Receptores de Interferon/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Fatores Etários , Alelos , Encéfalo/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Primers do DNA/genética , Genótipo , Humanos , Inflamação/complicações , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Receptores de Interferon/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Receptor de Interferon gamaRESUMO
BACKGROUND: Recently, linkage disequilibrium mapping of the major histocompatibility complex region on the short arm of human chromosome 6 suggested that the NOTCH4 locus is highly associated with schizophrenia. OBJECTIVES AND METHODS: We analysed two polymorphisms in this gene in Swedish schizophrenic patients ( =74) and control subjects ( =135). The NOTCH4 variants were also analysed in schizophrenic patients with regard to subdiagnosis, age at first hospitalization, abuse/dependence of alcohol, solvents, or drugs, previous suicide attempts, extrapyramidal symptoms, treatment with anticholinergic drugs, and response to anti-psychotic drug treatment. Control subjects were scrutinized with regard to personality, another partially heritable trait suggested being of importance in schizophrenia. In addition, two intermediate endophenotypes suggested being of importance in schizophrenia, dopamine D(2) receptor density in striatum and monoamine metabolites in cerebrospinal fluid, respectively, were investigated with regard to the two NOTCH4 variants. RESULTS: There was no significant association between the patients and the controls for the two investigated polymorphisms neither for the parameters analysed in the schizophrenia material. The NOTCH4 SNP2 variant, an A-->G substitution, was associated with the Karolinska Scales of Personality Irritability scale. The NOTCH4 (CTG)(n) variant was associated with the revised NEO personality inventory Extraversion and Activity (E4) scales. However, after correction for multiple testing, no difference remained significant. The results for the endophenotypes and the polymorphisms were non-significant. CONCLUSIONS: The present study does not support that the investigated NOTCH4 variants have a major influence on susceptibility to schizophrenia or related neurobiological traits.