title: Promoter Variation and Expression Levels of Inflammatory Genes IL1A, IL1B, IL6 and TNF in Blood of Spinocerebellar Ataxia Type 3 (SCA3) Patients.
abstract: 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 (IL1A, IL1B, IL6 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.
authors.affiliation: Department of Biology, University of the Azores, Rua Mãe de Deus, Apartado 1422, 9501-801, Ponta Delgada, Azores, Portugal. mafalda.sb.raposo@uac.pt.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. mafalda.sb.raposo@uac.pt.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal. mafalda.sb.raposo@uac.pt.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Raposo
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.|Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Conceição
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Department of Biology, University of the Azores, Rua Mãe de Deus, Apartado 1422, 9501-801, Ponta Delgada, Azores, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
authors.forename: Amanda
authors.initials: A
authors.lastname: Ramos
authors.affiliation: Department of Biology, University of the Azores, Rua Mãe de Deus, Apartado 1422, 9501-801, Ponta Delgada, Azores, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
authors.forename: Nadiya
authors.initials: N
authors.lastname: Kazachkova
authors.affiliation: Department of Neurology, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Vasconcelos
authors.affiliation: Department of Clinical Genetics, Hospital of D. Estefania, Lisbon, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Kay
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.|SEEBMO, Hospital do Santo Espírito da Ilha Terceira, Angra do Heroísmo, Portugal.
authors.forename: Jácome
authors.initials: J
authors.lastname: Bruges-Armas
authors.affiliation: Department of Biology, University of the Azores, Rua Mãe de Deus, Apartado 1422, 9501-801, Ponta Delgada, Azores, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Lima
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D053329:Apolipoprotein E2 / Q000097:blood / Q000502:physiology; D001057:Apolipoproteins E / Q000097:blood / Q000502:physiology*; D000067699:Ataxin-3 / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007249:Inflammation; D053582:Interleukin-1alpha / Q000097:blood / Q000235:genetics* / Q000502:physiology; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics* / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics* / Q000502:physiology; D017827:Machado-Joseph Disease / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D018911:Trinucleotide Repeats; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D053329:Apolipoprotein E2; D001057:Apolipoproteins E; C508584:IL1A protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: Cytokines; MJD; Polyglutamine disease; mRNA levels