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

Domenighetti, C., Douillard, V., Sugier, P‐E, Sreelatha, A.A.K., Schulte, C., Grover, S., May, P., Bobbili, D.R., Radivojkov‐Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Gourraud, P‐A, Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J‐C, Chartier‐Harlin, M‐C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Nakayama, A., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Kolber, P., van de Warrenburg, B.P.C., Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Correia Guedes, L., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez‐Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Ygland Rödström, E., Clarke, C.E., Morrison, K.E., Tan, M., KraincMD, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., Vince, N. and Elbaz, A. (2022) The Interaction between HLA‐DRB1 and Smoking in Parkinson's Disease Revisited. Movement Disorders . Early View.

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Abstract

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 × 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, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-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.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics
Publisher: Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Copyright: © 2022 The Authors.
URI: http://researchrepository.murdoch.edu.au/id/eprint/65476
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