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

Jill A. Hollenbach(University of California, San Francisco), Paul J. Norman(University of Colorado Denver), Lisa E. Creary(Palo Alto University), Vincent Damotte(University of California, San Francisco), Gonzalo Montero-Martín(Palo Alto University), Stacy J. Caillier(University of California, San Francisco), Kirsten M. Anderson(University of California, San Francisco), Maneesh Kumar Misra(University of California, San Francisco), Neda Nemat‐Gorgani(Stanford University), Kazutoyo Osoegawa(Stanford Blood Center), Adam Santaniello(University of California, San Francisco), Adam Renschen(University of California, San Francisco), Wesley M. Marin(University of California, San Francisco), Ravi Dandekar(University of California, San Francisco), Peter Parham(Stanford University), Caroline M. Tanner(University of California, San Francisco), Stephen L. Hauser(University of California, San Francisco), Marcelo Fernández-Viña(Palo Alto University), Jorge R. Oksenberg(University of California, San Francisco)
Proceedings of the National Academy of Sciences
March 25, 2019
10.1073/pnas.1821778116
Cited by 80Open Access
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Abstract

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.

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