Thays Andrade Apolinário1, Dionatan Costa Rodrigues1, Mayra Braga Lemos2, Carmen Lúcia Antão Paiva3,2,4, Luciana Andrade Agostinho1,5. 1. Graduate Program in Neurology, Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ, Brazil. 2. Department of Genetics and Molecular Biology, Instituto Bimédico, UNIRIO, RJ, Brazil. 3. Graduate Program in Neurology, Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ, Brazil clapaiva1@gmail.com. 4. Graduate Program in Molecular and Cell Biology, UNIRIO, RJ, Brazil. 5. University Center UNIFAMINAS - UNIFAMINAS, Muriaé, MG, Brazil.
Abstract
BACKGROUND: Huntington's disease (HD)(MIM:143100) is an severe autosomal dominant neurodegenerative disease caused by the dynamic expansion of CAG trinucleotides (> 35) in the HTT gene [Genomic Coordinates- (GRCh38):4:3,074,680-3,243,959]. OBJECTIVES: The aim of this systematic review was to investigate the reported associations between the frequencies of the A1 and A2 haplotypes in HD-affected and non-affected populations from different countries on different continents, in order to demonstrate the overall profile of these haplotypes worldwide, pointing towards the most frequent haplotypes that could be useful for HTT mutant-specific allele silencing in different populations. METHODS: Publications in MEDLINE (PubMed) and Embase from the last 10 years (PROSPERO CRD42018115282) were assessed. RESULTS: A total of 20 articles from 113 were selected for evaluation in their entirety, and eight were eligible for this study. CONCLUSION: Regardless of the size of the CAG tract, the articles included in this review demonstrate that populations with high HD prevalence present higher frequencies of the A1 or A2 haplotypes than populations exhibiting low HD prevalence, even when similar average CAG numbers are noted. Based on the presented articles, we suggest that the haplotypic profile is more closely related to the ancestral origin than to the size of the CAG tract. The identification of populations presenting a higher frequency of high-risk genotypes can contribute to more accurate genetic counseling, in addition to providing knowledge on HD epidemiology. According to the continued progress in the development of specific genetic silencing therapies by different research groups and pharmaceutical companies, such as haplotype targeting strategies for allele-specific HTT suppression, we conclude that the definition of haplotypes in phase with CAG expansions will contribute to the design of gene-silencing drugs specific for different populations worldwide.
BACKGROUND: Huntington's disease (HD)(MIM:143100) is an severe autosomal dominant neurodegenerative disease caused by the dynamic expansion of CAG trinucleotides (> 35) in the HTT gene [Genomic Coordinates- (GRCh38):4:3,074,680-3,243,959]. OBJECTIVES: The aim of this systematic review was to investigate the reported associations between the frequencies of the A1 and A2 haplotypes in HD-affected and non-affected populations from different countries on different continents, in order to demonstrate the overall profile of these haplotypes worldwide, pointing towards the most frequent haplotypes that could be useful for HTT mutant-specific allele silencing in different populations. METHODS: Publications in MEDLINE (PubMed) and Embase from the last 10 years (PROSPERO CRD42018115282) were assessed. RESULTS: A total of 20 articles from 113 were selected for evaluation in their entirety, and eight were eligible for this study. CONCLUSION: Regardless of the size of the CAG tract, the articles included in this review demonstrate that populations with high HD prevalence present higher frequencies of the A1 or A2 haplotypes than populations exhibiting low HD prevalence, even when similar average CAG numbers are noted. Based on the presented articles, we suggest that the haplotypic profile is more closely related to the ancestral origin than to the size of the CAG tract. The identification of populations presenting a higher frequency of high-risk genotypes can contribute to more accurate genetic counseling, in addition to providing knowledge on HD epidemiology. According to the continued progress in the development of specific genetic silencing therapies by different research groups and pharmaceutical companies, such as haplotype targeting strategies for allele-specific HTT suppression, we conclude that the definition of haplotypes in phase with CAG expansions will contribute to the design of gene-silencing drugs specific for different populations worldwide.
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