Intermediate CAG repeat expansion in the ATXN2 gene is a unique genetic risk factor for ALS--a systematic review and meta-analysis of observational studies

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.

Figure 1. Flow chart for ataxin-2 and ALS related article search, screen, evaluation, and data analysis.

Figure 2. Identification of the differences of the presence of intermediate CAG repeats and potential ethnic variances in the ATXN2 gene among ALS and control subjects.

The data about the number of CAG repeats in ALS and control subjects from 9 included studies in Caucacians and from 2 included studies from Chinese were summarized and plotted separately (left panel; right panel).

Figure 3. The presence of intermediate CAG 30–33 repeats in the ATXN2 gene is associated with ALS.

The data of intermediate CAG 30–33 repeats in ATXN2 were extracted from 13 included studies and the OR of intermediate CAG repeat among ALS and control subjects was synthesized with meta-analysis using random effects model. Similar results were also obtained when use fixed effects model (data not shown).

Figure 4. The heterogeneity among included studies was reduced dramatically after excluding two studies from China.

This meta-analysis was conducted using same protocol as in Figure 3 except excluding two studies with patients with Chinese background. Please refer to Figure 3.

Figure 5. The synthesized OR of the presence of intermediate CAG repeats with meta-analysis is not different from FALS and SALS cases in the ATXN2 gene.

The relative risks (OR) among fALS cases (top panel) or sALS cases (lower Panel) compared to controls were synthesized with meta-analysis using extracted data from 4 included case-control studies. The results from random effects model were presented. Similar results were also obtained when use fixed effects model (data not shown).