In a recent study published in The Lancet Regional Health - Western Pacific, a group of researchers investigated the interaction of caffeine with Leucine rich repeat kinase 2 (LRRK2) genetic risk variants in Asians and assessed Parkinson's disease (PD) risk in caffeine-drinking individuals carrying these variants.
Study: Caffeine intake interacts with Asian gene variants in Parkinson's disease: a study in 4488 subjects. Image Credit: Danijela Maksimovic/Shutterstock.com
Background
PD is a prevalent neurodegenerative condition marked by tremors, slow movement, and balance issues. Its incidence, especially in those over 65 years, increases societal burdens due to aging populations. PD's origins are multifaceted, with both genetic and environmental influences.
Genes like Alpha-synuclein, LRRK2, and Parkin play significant roles in PD progression. LRRK2 mutations, particularly specific variants, are common risk factors in Asians.
Interestingly, studies have shown that caffeine may offer protective effects against PD, reducing risk by 25% through its impact on the adenosine A2A receptor. Although genetics and environmental factors are independently studied in the PD context, research on their interplay, especially caffeine's interaction with PD-related genes, remains sparse.
About the study
The present study identified PD cases from two primary movement disorder centers in Singapore, diagnosed based on United Kingdom PD Society Brain Bank criteria. Healthy participants from a Community Health Screening Programme served as controls. Consent was secured, and the study complied with SingHealth Centralised Institutional Review Board (CIRB) guidelines.
Using a validated questionnaire, participants provided demographics, family history, and caffeine consumption data via clinical interviews. The caffeine source was predominantly coffee and tea.
Non-consumers of caffeine were identified as those with zero lifetime intake. For genetic analysis, blood samples underwent deoxyribonucleic acid (DNA) extraction and genotyping, with verifications via sequencing.
The analysis considered demographics like age, sex, family history, and caffeine usage. Various statistical tests assessed differences and genotype distributions, including Student's t-test and Fisher's exact test.
Odds ratios (OR) assessed each SNP's association, determining the genetic model and SNP-caffeine interactions. Participants were categorized based on genetic risk and caffeine consumption. Adjusted OR accounted for age, sex, and family history.
Logistic regression's appropriateness was verified using the Hosmer–Lemeshow test. R version 3.4.2 and STATA version 14.0 supported the statistical analysis.
SNPassoc assisted in assessing associations and choosing the best-fitting genetic model based on p-values.
Study results
In the present study, of the 5,100 subjects screened, 4,488 participants (88%) were included, with 1,790 PD cases and 2,698 controls. Exclusions were due to incomplete demographic/exposure data (4.5%) or genetic data (7.5%).
Among PD cases, 8.9% had a family history of movement disorders, and 11.2% were non-caffeine-drinkers. The average age for PD onset was 62.3 years, whereas the control group had an average age of 52.5 years.
Significant positive associations with PD were seen for the G2385R and R1628P variants, while the S1647T variant showed a non-significant positive trend.
On evaluating caffeine use, heterozygous carrier status at G2385R and R1628P was significantly associated with PD among caffeine drinkers. Non-caffeine drinkers with homozygous variant carriers of S1647T exhibited a stronger association with PD than caffeine drinkers.
When stratified by genotype, caffeine consumption was linked with decreased odds of PD across all risk variants. Among G2385R mutant carriers, the protective effect of caffeine was more pronounced in mutant carriers.
G2385R mutant carriers who did not consume caffeine had over eight times the odds of developing PD compared to wild-type caffeine drinkers. The combined risk exposure group had greater odds than groups with a single risk exposure.
Positive biological interaction was indicated by the values relative excess risk due to interaction (RERI), synergy index (S), and attributable proportion (AP) due to interaction.
Similar associations were seen for R1628P and S1647T variants, where those with a high genetic risk who did not consume caffeine had about four times increased risk of PD compared to those with low genetic risk who drank caffeine.
Interestingly, among all risk variants, high genetic-risk caffeine drinkers had lower odds of developing PD than low genetic-risk non-caffeine-drinkers. This suggests that caffeine's protective effect might offset the genetic risk posed by the variant.
An analysis of caffeine intake revealed an average consumption of 448.3 mg-decade for PD cases and 473.0 mg-decade for controls. Due to variability in responses, the accuracy of this estimation was limited.
The study further categorized caffeine doses into low, moderate, and high. Among risk variant carriers, a trend was observed linking higher caffeine intake to lower PD odds. Still, it was not statistically significant, likely due to the variability in dose estimation.
Conclusions
The present study explored significant interactions between caffeine intake and three LRRK2 risk variants related to PD.
Non-caffeine-drinking carriers of these risk variants are four to eight times more susceptible to PD than those without the risk variants.
While the exact mechanisms behind these interactions remain unknown, they suggest caffeine's potential neuroprotective role, possibly by influencing the LRRK2 protein.
These findings offer a promising avenue for personalized preventive interventions, emphasizing the potential benefits of caffeine consumption for those at high genetic risk.
However, the results are primarily relevant to the Asian population studied, and further research in different populations is necessary.
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