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 <i>KIR</i>-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced <i>KIR</i> genes from 1314 PD patients and 1978 controls using next-generation methods and identified <i>KIR</i> genotypes using custom bioinformatics. We examined associations of <i>KIR</i> with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two <i>KIR3DL1</i> alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: <i>KIR3DL1*015</i>/HLA-Bw4 from rigidity (<i>p</i> _c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and <i>KIR3DL1*002/</i>HLA-Bw4i from gait difficulties (p <i>_c</i> = 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 (<i>p_c</i> = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed <i>KIR3DL1</i> variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.