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

Abstract

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10^-4; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.

Keywords: HLA; Parkinson’s disease; shared epitope; smoking.

Fig. 1.

Association analysis results for all HLA class I and class II alleles. HLA alleles that were detected in the study population are shown around the perimeter. Decreasing P values are indicated by the distance of points from the center, with P = 0.01 indicated by the black dotted concentric line. The magnitude of ORs is indicated by the diameter of points, with filled points indicating OR >1 and open points indicating OR <1. The magnitude of global linkage disequilibrium between loci is indicated by the width of interior lines.

Fig. 2.

HLA-DRB1 amino acid positions mediating risk and protection in PD. Position 11 (pink) is located in the β-pleated sheet on the floor of the peptide-binding groove of the HLA-DR molecule. The SE at positions 70–74 (green) is located on the second α-helix, bordering the peptide-binding groove of HLA-DR.