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2019

ANUÁRIO DO HOSPITAL
DONA ESTEFÂNIA

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PROMOTER VARIATION AND EXPRESSION LEVELS OF INFLAMMATORY GENES IL1A, IL1B, IL6 AND TNF IN BLOOD OF SPINOCEREBELLAR ATAXIA TYPE 3 (SCA3) PATIENTS

Mafalda Raposo1,2,3; Conceição Bettencourt4,5; Amanda Ramos1,2,3; Nadiya Kazachkova1,2,3; João Vasconcelos6; Teresa Kay7; Jácome Bruges-Armas2,3,8; Manuela Lima1,2,3

1- Departamento de Biologia, Universidade dos Açores, Ponta Delgada, Açores, Portugal.
2- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal.
3- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
4- Department of Clinical Experimental Epilepsy, UCL Institute of Neurology, London, UK.
5- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
6- Departamento de Neurologia, Hospital do Divino Espírito Santo, Ponta Delgada, Açores, Portugal.
7- Serviço de Genética Médica, Hospital de Dona Estefânia, Lisboa, Portugal.
8- SEEBMO, Hospital do Santo Espírito da Ilha Terceira, Angra do Heroísmo, Açores, Portugal.

- Neuromolecular Medicine (2016). doi:10.1007/s12017-016-8416-8

Resumo: Age at onset in spinocerebellar ataxia type 3 (SCA3/MJD) is incompletely explained by the size of the CAG tract at the ATXN3 gene, implying the existence of genetic modifiers. A role of inflammation in SCA3 has been postulated, involving altered cytokines levels; promoter variants leading to alterations in cytokines expression could influence onset. Using blood from 86 SCA3 patients and 106 controls, this work aimed to analyse promoter variation of four cytokines (IL1AIL1BIL6 and TNF) and to investigate the association between variants detected and their transcript levels, evaluated by quantitative PCR. Moreover, the effect of APOE isoforms, known to modulate cytokines, was investigated. Correlations between cytokine variants and onset were tested; the cumulative modifier effects of cytokines and APOE were analysed. Patients carrying the IL6*C allele had a significant earlier onset (4 years in average) than patients carrying the G allele, in agreement with lower mRNA levels produced by IL6*C carriers. The presence of APOE*ɛ2 allele seems to anticipate onset in average 10 years in patients carrying the IL6*C allele; a larger number of patients will be needed to confirm this result. These results highlight the pertinence of conducting further research on the role of cytokines as SCA3 modulators, pointing to the presence of shared mechanisms involving IL6 and APOE.

Palavras Chave: MJD; Polyglutamine disease; mRNA levels; Cytokines