Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease.

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated -allelic polymorphism to interrogate the role of NK cells in PD. We sequenced genes from 1314 PD patients and 1978 controls using next-generation methods and identified genotypes using custom bioinformatics. We examined associations of with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: /HLA-Bw4 from rigidity ( = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and HLA-Bw4i from gait difficulties (p = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity ( = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.