ATXN2 polymorphism modulates age at onset in Machado-Joseph disease.

Abstract

Sir, It is well known that age at onset of Machado-Joseph disease (MJD/SCA3) is negatively related with the length of expanded CAG repeats in ATXN3 , but it could only explain 50–70% of age at onset variability, emphasizing other potential factors may contribute to the variability (Stevanin et al. , 2000; Chen et al. , 2016 a ). Recently, an increasing number of studies have explored the effects of repeat alleles on age at onset within MJD in other, non-causal genes (Pulst et al. , 2005; de Castilhos et al. , 2014). Previously, Tezenas et al. (2014) demonstrated that the age at onset of MJD was influenced by CAG repeats in ATXN2 , ATN1 and HTT in European ancestry. Interestingly, our research team has also confirmed that MJD patients with long normal CAG repeats in ATXN2 (but not ATN1 or HTT ) were associated with an earlier age at onset in Chinese population (Chen et al. , 2016 b ). These results may indicate specific genetics architecture of age at onset existing in different populations. Here we would like to report a new substantial association, other than CAG repeats in ATXN2 and ATXN3 , between age at onset and a functional SNP, rs7969300 within ATXN2 in a Chinese population. A 517-patient subset from the previous cohort was enrolled in the present study. Data of age at onset, written informed consent and methods of examining CAG repeats in ATXN3 and ATXN2 were extracted from the previous study (Chen et al. , 2016 b ). In this study, we paid attention to the potential component, single nucleotide polymorphisms (SNPs), which may contribute to the missing age at onset variability of MJD. Genotypes of a set of SNPs (unpublished data) were examined by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry via MassARRAY® system (Sequenom). To confirm the …