Authors:
J. Hollenbach (San Francisco, US)
P. Norman (Stanford, US)
G. Montero-Martin (Stanford, US)
N. Nemat-Gorgani (Stanford, US)
L. Creary (Stanford, US)
M. Misra (San Francisco, US)
V. DAMOTTE (San Francisco, US)
K. Mallempati (Stanford, US)
S. Gangavarapu (Stanford, US)
I. Consortium (San Francisco, US)
J. Oksenberg (San Francisco, US)
M. Fernandez-Viña (Palo Alto, CA, US)
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease characterized by the classical motor signs of parkinsonism and a constellation of associated features including autonomic, sensory, cognitive and psychiatric changes. Both underlying immunoregulatory dysfunction and inflammatory processes have been proposed for PD. Under the auspices of the INDIGO (Immunogenetics of Neurological DIseases working GrOup) consortium, we analyzed HLA and KIR variation at high resolution via next-generation sequencing (NGS) methods in 1941 PD cases and 1612 controls. We find that the HLA class II haplotype DRB1*01:01~DQA1*01:01~DQB1*05:01 is predisposing to PD (p<0.005; OR=1.32). While the HLA class II region has been implicated in PD via GWAS and HLA imputation, this is the first large-scale PD study to directly examine HLA sequence-level variation. When KIR3DL1 alleles are examined in combination with HLA in a subset of individuals (1149 cases, 892 controls), we find a strong protective effect (p<0.005; OR=0.20) for individuals homozygous for KIR3DL1*004 in the presence of the Bw4 epitope with Isoleucine at position 80 (Bw4i). Low/null expression alleles defined as a group in combination with Bw4i are also protective in PD (p<0.01; OR=0.73) and protective with respect to age at onset (p=0.001). Our findings point to a role for KIR3DL1 expression level variation, in the presence of the strong HLA ligand Bw4i, with susceptibility to PD. While KIR3DL1*004 may be mis-folded and retained intracellularly, with very low levels of surface expression, in the presence of Bw4i it has been previously demonstrated to be the KIR allele offering the most protection from AIDS progression following infection with HIV. That PD protection is further mediated by low expression alleles implies a common mechanism related to expression of the inhibitory receptor and interaction with the ligand, perhaps due to NK cell licensing. In summary, we find a clear role for HLA class II in predisposition to PD, while protection is afforded by KIR in combination with HLA class I. Taken together, these results strongly support a role for immunogenetic variation in the immunopathology of PD.