Objective: To investigate the interaction between smoking and Asian-specific LRRK2 variants (G2385R and R1628P) in Parkinson’s disease (PD) risk, examining whether smoking modifies the genetic susceptibility associated with these variants.

Background:

PD is a complex neurodegenerative disorder influenced by genetic and environmental factors. LRRK2 mutations are among the most common genetic contributors to PD, with G2385R and R1628P conferring a 1.5- to 2.0-fold increased risk in East Asian populations. Smoking is paradoxically associated with reduced PD risk, yet the gene-environment interaction remains underexplored. Given the potential influence of smoking on LRRK2-related pathways, understanding this interaction may provide insights into PD pathogenesis and potential protective mechanisms.​​​​​​​

Method: A case-control study was conducted involving 4,382 participants (1,706 PD patients and 2,674 controls) recruited from tertiary hospitals and community health screenings. Genotyping was performed using TaqMan SNP assays, and statistical analyses were conducted using logistic regression adjusted for age, sex, and family history of movement disorders. Gene-environment interactions were assessed using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) to evaluate biological interaction.

Results: Non-smoking G2385R carriers had a significantly higher PD risk (OR 2.20, 95% CI 1.47–3.31) compared to wild-type smokers. A similar but weaker association was observed for R1628P carriers (OR 1.48, 95% CI 0.973–2.23). Interaction analysis revealed a positive biological interaction for G2385R (RERI = 1, AP = 3.20, S = 0.538) and R1628P (RERI = 0.929, AP = 2.89, S = 0.422), suggesting smoking may mitigate the genetic risk of PD.

Conclusion: This study highlights a gene-environment interaction between smoking and LRRK2 variants in PD risk. Non-smoking carriers of G2385R exhibited a 2.2-fold increased PD risk, supporting the hypothesis that smoking confers a protective effect, potentially by modulating LRRK2-related neurodegenerative pathways. Further functional studies are needed to elucidate the biological mechanisms underlying this interaction, which could inform precision medicine approaches for PD prevention and treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/smoking-and-genetic-interactions-in-parkinsons-disease/