Objective: Investigating the interaction between genetic susceptibility and caffeine intake in modulating Parkinson’s disease (PD) risk.

Background: PD arises from a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified the single nucleotide polymorphisms (SNPs) rs6826785 and rs356182 of the alpha-synuclein gene (SNCA) as strongly associated with PD. Yet, their interaction with caffeine–a modifiable lifestyle factor suggested to reduce PD risk–remains unclear.

Method: This case-control study (n=1812; 875 PD cases, 937 controls) [Table 1] evaluated the interaction between caffeine intake (lifetime coffee and tea consumption; Yes vs No intake) and the above SNP genotypes. Multivariate logistic regression adjusted for age, sex, family history of PD, and smoking status assessed the independent and combined effects of genetic risk and caffeine intake on PD odds. Gene-caffeine interactions were evaluated using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S).

Results: Both rs6826785 and rs356182 risk-variants were significantly associated with increased PD risk, with homozygous carriers having the highest risk [OR 2.28 (1.64–3.15) and OR 1.82 (1.23–2.69), respectively] [Table 2]. Caffeine intake was also inversely associated with PD risk across all genotypes [Table 3, 4]. Notably, the combined effect of genetic risk and caffeine abstinence exceeded the sum of their individual effects, suggesting a synergistic gene-environment interaction. rs6826785 risk-variant carriers with no caffeine intake exhibited a 13.14-fold increased PD risk [OR 13.14 (7.53–22.92)] compared to homozygous non-carriers who consumed caffeine (RERI = 10.01, AP = 0.76, S = 5.70). Similarly, rs356182 risk-variant carriers without caffeine intake had a 9.23-fold increased PD risk [OR 9.23 (5.24–16.24)] (RERI = 3.18, AP = 0.34, S = 1.63) [Table 5, 6].

Conclusion: This study establishes a novel, significant gene-environment interaction, showing that caffeine intake modifies PD risk in genetically susceptible individuals. High genetic-risk individuals may mitigate PD risk through caffeine intake, supporting its role as potential neuroprotective agent. Clinically, these findings could inform personalized PD risk reduction strategies, integrating dietary interventions, genetic counseling, and neurobehavioral therapy into precision medicine frameworks.

Table 1

Table 2

Table 3

Table 4

Table 5

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gene-caffeine-interaction-in-parkinsons-disease-a-case-control-study-of-alpha-synuclein-snps/