The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited

Background Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. Objective To perform a large-scale independent replication of the HLA-DRB1 x smoking interaction. Methods We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. Results At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P-Interaction = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of alpha-synuclein on binding affinity showed findings consistent with this interaction pattern. Conclusions Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Automated summary

This study conducted a large-scale independent replication of the interaction between HLA-DRB1 and smoking in Parkinson's disease. The valine at position 11 (V11) in HLA-DRB1 showed the strongest association with PD at the amino acid level. The results suggest an inverse association between genetically predicted smoking initiation and PD, particularly in individuals without the V11 variant. In silico predictions support this interaction pattern by showing the influence of V11 and smoking-induced modifications on binding affinity of alpha-synuclein.