A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson’s disease

Significance Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease with both familial and sporadic forms and a clear genetic component. In addition, underlying immunoregulatory dysfunction and inflammatory processes have been implicated in PD pathogenesis. In this study, deep sequencing of HLA genes, which encode highly variable cell surface immune receptors, reveals specific variants conferring either risk or protection in PD. Because a history of cigarette smoking is known to be protective in PD, we analyzed the interaction of these genetic variants with smoking history in PD patients and healthy controls and found that the genetic effects are modified by history of cigarette smoking. These results provide a molecular model that explains the unique epidemiology of smoking in PD.