(CAG)n loci as genetic modifiers of age-at-onset in patients with Machado-Joseph disease from mainland China.

Sir,We read with great interest the article published in Brain by Tezenas du Montcel et al. (2014) reporting modifying factors of age-at-onset in 1255 individuals affected with spinocerebellar ataxia (SCA) types 1, 2, 3, 6 and 7, recruited through the European Consortium on Spinocerebellar Ataxias (EUROSCA). We would like to report our findings on genetic modifiers and age-at-onset in 802 Chinese Han patients (429 males, 373 females) with Machado-Joseph disease (MJD/SCA3), on behalf of the Chinese Clinical Research Cooperative Group for Spinocerebellar Ataxias (CCRCG-SCA). Our study was approved by the ethics committee of Xiangya Hospital, Central South University. Blood samples were collected after written informed consent from all subjects. All MJD patients were genotyped for ATXN3 and nine other polyQ-related genes ( ATXN1 , ATXN2 , CACNA1A , ATXN7 , TBP , ATN1 , KCNN3 , RAI1 and HTT ). None of the MJD patients was a ‘homozygote’ (i.e. bearing two expanded alleles).We used a similar statistical strategy as described by the EUROSCA consortium (Tezenas du Montcel et al. , 2014). For some polyQ-related genes ( ATXN1 , TBP , ATN1 and HTT ), the sizes of the shorter and the longer alleles were considered (separately) as continuous variables; given the skewed distribution of allele size in the other genes ( ATXN2 , ATXN3 , ATXN7 , CACNA1A and RAI1 ) these were classified as short, short-medium, medium or long (Table 1). The interaction between both alleles, their mean length and the size difference between alleles at each locus were also considered as dependent variables. View this table:Table 1 Classification of polyQ-related normal alleles according to the number of CAG repeatsThe logarithmically transformed age-at-onset was treated as a dependent variable with homoscedasticity. Linear regression analysis (linear and quadratic effects) was performed to estimate the effect on age-at-onset of the expanded allele at ATXN3. Different models were then …