Mitochondrial NADH Dehydrogenase Subunit 3 Polymorphism Associated with an Earlier Age at Onset in Male Machado-Joseph disease Patients

Abstract

Aims: To investigate the potential effect of six previously reported candidate single nucleotide polymorphisms on age at onset (AAO) among Chinese patients with Machado-Joseph disease (MJD).

Methods: Three hundred and twenty-four unrelated molecular-confirmed MJD patients were recruited between January 2006 and December 2014. The screening of candidate polymorphisms was first performed in 173 subjects using the SNaPshot(®) Multiplex System. The mitochondrial NADH dehydrogenase subunit 3 (MT-ND3) polymorphism 10398A>G (rs2853826) was further verified with Sanger sequencing in additional 151 patients.

Results: An inverse correlation was found between expanded CAG repeat length and AAO. The expanded CAG repeat length can explain 63% of AAO variance. The 10398A polymorphism was significantly associated with a 3-year earlier AAO in male patients with MJD (P = 0.001). Stepwise multiple regressions revealed that the 10398A polymorphism could account for nearly 2% of AAO variance in male patients.

Conclusion: Six candidate SNPs have been screened in Chinese patients with MJD. A remarkable earlier AAO was noted in male Chinese MJD patients with MT-ND3 gene 10398A polymorphism.

Keywords: ATXN3; Age at onset; CAG repeat; MJD; MT-ND3.