The &lt;emph type="ital"&gt;APOE&lt;/emph&gt; ε2 Allele Increases the Risk of Earlier Age at Onset in Machado-Joseph Disease

Bettencourt, Conceição; Raposo, Mafalda; Kazachkova, Nadiya; Cymbron, Teresa; Santos, Cristina; Kay, Teresa; Vasconcelos, João; Maciel, Patrı́cia; Donis, Karina Carvalho; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Sequeiros, Jorge; Lima, Manuela

doi:10.1001/archneurol.2011.636

Cited by 36 publications

(25 citation statements)

References 42 publications

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“…The characteristics of this patient cohort are presented in Table 1 . There was no significant difference in the genotypic or allelic distributions of APOE between the present cohort and the cohorts reported by Bettencourt et al [20] (genotype: p = 0.789; allele: p = 0.501) and Peng et al [21] (genotype: p = 0.44; allele: p = 0.872). Patients carrying different APOE genotypes showed no differences in the AAO adjusted for the expanded ATXN3 allele (ANCOVA, F = 0.18, p = 0.9474).…”

Section: Resultscontrasting

confidence: 54%

“…The variability in the AAO attributable to the expanded CAG repeat was calculated using linear regression. Either Fisher's exact test or a chi-square test was used to compare the distribution frequency of APOE genotypes or alleles between our cohort and the cohorts reported by Bettencourt et al [20] and Peng et al [21]. Differences in the AAO according to the APOE genotype and gender of the patient were examined using a two-tailed t-test or an ANCOVA, adjusted for the expanded ATXN3 allele.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, two independent groups reported an association of the APOE ε2 allele with an earlier AAO for MJD in small samples (fewer than 200 patients) [20], [21]. To further investigate this issue, we collected a large cohort of MJD patients (more than 400 individuals) from eastern and southeastern China and then analyzed the association of APOE polymorphisms with the AAO.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Apolipoprotein E as a Risk Factor for an Earlier Age at Onset for Machado-Joseph Disease Is Doubtful

et al. 2014

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Machado-Joseph disease (MJD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene. Although the principal genetic determinant of the age at onset (AAO) is the length of the expanded CAG repeat, the additional genetic contribution of MJD toward the AAO has mostly not yet been clarified. It was recently suggested in two independent studies that apolipoprotein E (APOE) might be associated with AAO variability in MJD patients. To identify the potential modifier effect of APOE polymorphisms on the AAO of MJD patients, 403 patients with MJD (confirmed by molecular tests) from eastern and southeastern China were enrolled in the present study. CAG repeats in the ATXN3 and APOE polymorphisms were genotyped. Data were analyzed using a statistical package. No contribution of APOE polymorphisms to the variance in disease onset was observed using ANCOVA (F = 0.183, P = 0.947). However, significant effects on the AAO of MJD were found for the normal ATXN3 allele and for the interaction of mutant and normal ATXN3 alleles in a multiple linear regression model (P = 0.043 and P = 0.035, respectively). Our study does not support a role for APOE as a genetic modifier of the AAO of MJD. Additionally, our study presents evidence that the normal ATXN3 allele and its interaction with mutant alleles contribute toward AAO variance in MJD patients.

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Section: Resultscontrasting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Role of Apolipoprotein E as a Risk Factor for an Earlier Age at Onset for Machado-Joseph Disease Is Doubtful

et al. 2014

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“…Similar to several other neurodegenerative disorders, the TTR gene point mutation alone does not fully determine the AO variation or the course of the disease. Therefore, we have applied, for the first time, a family-centered approach also used in studies of other The role of RBP4 and AR genes in FAP ATTRV30M D Santos et al diseases 19,23 and focused on modifier genes related with (1) TTR functional pathways involved in pathophysiological processes related to FAP ATTRV30M pathogenesis and also (2) sex-linked genes because of observed differences between genders and parent-oforigin effects associated with AO variation. In a previous study, Soares et al 9 analyzed five SNPs (also studied by us) in a Portuguese sample of 92 patients and 85 controls using a classic case-control approach.…”

Section: Discussionmentioning

confidence: 99%

Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M)

et al. 2015

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Familial amyloid polyneuropathy (FAP) ATTRV30M is a neurodegenerative disorder due to point mutations in the transthyretin gene, with V30M being the commonest. FAP ATTRV30M shows a wide variation in age at onset (AO) between clusters, families and generations. Portuguese patients also show remarkable AO differences between genders. Genes found to be associated with FAP ATTRV30M pathways may act as AO modifiers. Our aim was to further explore the role of APCS and RBP4 genes and to study for the first time the involvement of sex-linked genetic modifiers -AR and HSD17B1 genes -in AO variation in Portuguese families. We collected DNA from a sample of 318 patients, currently under follow-up. A total of 18 tagging SNPs from APCS, RBP4, AR and HSD17B1 and 5 additional SNPs from APCS and RBP4 previously studied were genotyped. To account for nonindependency of AO between members of the same family, we used generalized estimating equations (GEEs). We found that APCS and RBP4 were associated with late AO. In addition, rs11187545 of the RBP4 was associated with an early AO. For the AR, in the male group three SNPs were associated with an early AO, whereas in the female group four were associated with both an early and later AO. These results strengthened the role of APCS and RBP4 genes and revealed for the first time the contribution of AR genes as an AO modifier in both males and females. These findings may have important implications in genetic counseling and for new therapeutic strategies.

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“…The Genetic Modifiers of Huntington's Disease (GeM‐HD) genome‐wide association study (GWAS)6 found two genome‐wide loci associated with age at motor onset in HD on chromosomes 15 and 8, with two independent signals at the same locus on chromosome 15. A few SCA genetic modifiers have been proposed3, 5, 7, 8, 9 and no GWAS have been reported.…”

mentioning

confidence: 99%

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

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199

186

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ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990

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The <emph type="ital">APOE</emph> ε2 Allele Increases the Risk of Earlier Age at Onset in Machado-Joseph Disease

Cited by 36 publications

References 42 publications

The Role of Apolipoprotein E as a Risk Factor for an Earlier Age at Onset for Machado-Joseph Disease Is Doubtful

The Role of Apolipoprotein E as a Risk Factor for an Earlier Age at Onset for Machado-Joseph Disease Is Doubtful

Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M)

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

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