Study Of Age At Onset Related Modifying Genes For Machado-joseph Disease Patients In Eastern China

Objective: To investigate the potential effect of ten previously reported candidate single nucleotide polymorphisms(SNPs) on age at onset(AAO) in Chinese Machado-Joseph disease(MJD) patients.Design: Three hundred and twenty-four unrelated molecular confirmed MJD patients were recruited between January, 2006 and December, 2014. The screening of 10 candidate polymorphisms were first performed in 173 subjects using the SNa Pshot® Multiplex System. The mitochondrial A10398 G polymorphism(rs2853826) was further verified with Sanger sequencing in additional 151 patients. In addition, 183 patients with disease duration less than 5 years were selected to further consolidate the association between the MT-ND3 polymorphism and AAO variance in MJD.Results:1. In the first stage, the average AAO in 173 Chinese MJD patients was 36.60 ± 10.66(15-60). Mean ATXN3 normal allele CAG repeats number was 20.41±6.87(14-36). Mean ATXN3 expended allele CAG repeats number was 75.60±3.60(60-84). The ATXN3 expended allele CAG repeats can explain approximately 62.7% AAO variance.2. In the second stage, the average AAO in 324 Chinese MJD patients was 36.07±10.94(10-72). Mean normal ATXN3 allele CAG repeats number was 19.95±6.99(14-38). Mean expended ATXN3 allele CAG repeats number was 75.88±3.76(53-87). The expended ATXN3 allele CAG repeats can explain approximately 63.2% AAO variance. Neither the CAG repeats number in expended ATXN3 allele nor the AAO variance was significantly associated with the normal allele CAG repeats number(p=0.478 & p=0.403).3. In the first stage, after screening the candidate genes, we found MT-ND3 polymorphism 10398 A was significantly associated with an earlier AAO in male MJD patients when adjusting for the effect of expanded ATXN3 allele(p=0.002). In the screening of other 9 SNPs, no significant differences in AAO were found even when adjusting for the effect of expanded ATXN3 allele.4. We increased the number of patients up to 324. It still revealed that male MJD patients with 10398 A polymorphism appeared to experience a 3 years earlier AAO when adjusting for the effect of expanded ATXN3 allele(p=0.001). Stepwise multiple regressions revealed that the 10398 A polymorphism could account for nearly 2% of AAO variance in male patients. In the further confirmation group of 184 patients with disease duration less 5 years, the 10398 A polymorphism was still significantly associated with an earlier AAO in male MJD patients when adjusting for the effect of expanded ATXN3 allele(p=0.011).Conclusion:1. An inverse correlation was found between expanded CAG repeats length and AAO. The expanded CAG repeats length can explain 63% AAO variance.2. Neither the CAG repeats number in expended ATXN3 allele nor the AAO variance was significantly associated with the normal allele CAG repeats number. Additionally, the family inheritance pattern were associated neither the CAG repeats number in expended ATXN3 allele nor the AAO variance.3. The MT-ND3 polymorphism 10398 A was significantly associated with a 3 years earlier AAO in male MJD patients when adjusting for the effect of expanded ATXN3 allele. This polymorphism could account for nearly 2% of AAO variance in male patients.4. In the screening of other 9 SNPs, no significant differences in AAO were found even when adjusting for the effect of expanded ATXN3 allele.