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.

Common polymorphisms of chemokine (C‐X3‐C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population‐based study

“…More recently, a large international meta‐analysis of GWAS found 2 loci (at 10q23, SNP rs139550538 and at 1p36, rs2412208) in which the presence of the minor alleles in the homozygous state were significantly associated with a reduction of survival of 7 and 4 months, respectively . Also, the presence of at least 1 minor allele of the rs3011225 SNP located on chromosome 1p34.1 was associated with earlier age of onset in a meta‐analysis of 13 GWAS cohorts . Finally, the presence of an intermediate CAG repeat expansion in the ATXN2 gene not only is a risk factor for ALS but also is associated with a spinal phenotype and reduces survival by 1 year …”

“…28 Also, the presence of at least 1 minor allele of the rs3011225 SNP located on chromosome 1p34.1 was associated with earlier age of onset in a meta-analysis of 13 GWAS cohorts. 29 Finally, the presence of an intermediate CAG repeat expansion in the ATXN2 gene not only is a risk factor for ALS 24 but also is associated with a spinal phenotype and reduces survival by 1 year. 30,31 In summary, we used a large population-based cohort of ALS patients to show that functional variants of the CX3CR1 gene potentially influence ALS survival.…”

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

“…The authors went on to describe that the degree of ATXN2 polyglutamine expansion was correlated with the extent of TDP-43 toxicity in both Drosophila and yeast models. Furthermore, ATXN2 intermediate repeat expansion was confirmed as a risk factor in ALS patients [20,106,[144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159], and more recently as a possible modifier of C9orf72 repeat expansion toxicity in ALS/FTD [107,108].…”

Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate‐length CAG repeat expansions in Ataxin‐2 does not have 1C2‐positive polyglutamine inclusions

“…[25] then demonstrated that intermediate (27–33) CAG repeat expansions were present in many ALS patients (henceforth ATXN2 ‐ALS). Two subsequent meta‐analyses of data from a variety of geographical and ethnic backgrounds found increased risk of ALS for CAG repeat lengths of 29–33 [26] and 30–33 [27], respectively.…”

“…Overexpression of TDP-43 is associated with significant cytotoxicity, and thus, levels of this protein are strictly regulated by a number of mechanisms, including an autoregulatory negative feedback loop [24]. On finding that this toxicity was exacerbated by homologues of Ataxin-2 in yeast and flies, Elden et al [25] then demonstrated that intermediate (27)(28)(29)(30)(31)(32)(33) CAG repeat expansions were present in many ALS patients (henceforth ATXN2-ALS). Two subsequent meta-analyses of data from a variety of geographical and ethnic backgrounds found increased risk of ALS for CAG repeat lengths of 29-33 [26] and 30-33 [27], respectively.…”