Association of Long ATXN2 CAG Repeat Sizes With Increased Risk of Amyotrophic Lateral Sclerosis

Centre for Excellence in Neuromics, CHUM Research Center, Université de Montréal, 2099 Alexandre De-Seve St, Montreal, QC H2L 2W5, Canada.
Archives of neurology (Impact Factor: 7.42). 06/2011; 68(6):739-42. DOI: 10.1001/archneurol.2011.111
Source: PubMed


To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS.
Case-control study.
France and Quebec, Canada.
A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin.
We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases.
Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.

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Available from: Veronique V Belzil, Nov 11, 2014
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    • "Other follow-up reports generally confirmed this initial finding, but there is no consensus with regards to which repeat length is associated with ALS. One study using ROC (receiver operating characteristic) curves showed that more than 29 CAG repeats in the ATXN2 gene was associated with an increased risk of ALS [54]; however, other studies have linked ALS with greater than 30 CAG repeats in Italy [52], 30–35 CAG repeats in Germany [65], and ≥28 CAG repeats in Italy [48]. Here, we used 30–33 repeats as the cut-off for association with ALS because the difference between ALS cases and corresponding controls was not apparent when the CAG repeat in ATXN2 is less than 29 or greater than 34. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30-33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91-6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58-8.17) and sporadic ALS cases (OR = 3.16, 1.88-5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.
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    • "Single-nucleotide polymorphisms (SNPs) have an important function in the development of neurodegenerative disorders (Ramanan and Saykin, 2013). For example, polymorphisms in the promoter Rep1 of alpha-synuclein (SNCA), polyglutamine repeats in ATXN2, and Val343Ala in coenzyme Q2 4-hydroxybenzoate polyprenyltransferase increase the risk for PD (Mata et al., 2010), ALS (Daoud et al., 2011), and MSA (Collaboration, 2013), respectively. SNCA, which is encoded by the SNCA gene, is the major component of Lewy bodies and neurites, which are the pathologic hallmarks of PD (Mollenhauer et al., 2011). "
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    • "Further, an increase in ataxin-2 polyglutamine length is a risk factor for ALS demonstrating the clinical relevance of these findings [Elden et al., 2010; Daoud et al., 2011]. "
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