In a recent study published in BMC Medicine, researchers investigated the effects of caffeine levels in circulation by considering genetically predicted variations in caffeine metabolism.
Study: Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization. Image Credit: portumen/Shutterstock.com
Background
Caffeine, a plant-origin bioactive molecule, is a popular psychoactive stimulant whose therapeutic effects are unclear due to its interaction with consumption behavior and metabolism.
It penetrates through cellular membranes and has rapid effects throughout organ systems, functioning as an antagonist to adenosine receptors in the brain, adipose tissue, cardiovascular, renal, gastrointestinal, and respiratory systems.
Previous studies used genetic variations to determine the causative impact of increased serum caffeine levels on type 2 diabetes and obesity risks; however, epidemiological and genetic studies on the health implications of coffee intake yielded contrasting results.
About the study
In the present study, researchers analyzed phenome-wide association study (PheWAS) data to evaluate the clinical impacts of serum caffeine using genetic variants related to caffeine metabolism that affect its circulating levels.
The team derived a genetic risk score (GRS) for serum caffeine using single-nucleotide polymorphisms (SNPs) within CYP1A2 and AHR genes strongly associated with serum caffeine levels.
They performed logistic regressions for each phenotypic code against standardized serum caffeine genetic risk scores, adjusting for gender, age, and the initial ten principal genetic components.
The PheWAS study included 988 clinical features recorded among United Kingdom Biobank (UKBB) participants to assess health outcomes associated with serum caffeine levels.
They performed a metabolome- and proteome-wide Mendelian randomization analysis to elucidate the mechanisms responsible for the biological effects of serological caffeine on osteoarthritis, postmenopause bleeding, and serum metabolites and proteins.
The team retrieved genetic data for serum caffeine from a previous meta-analysis of genome-wide association studies (GWAS) comprising 9,876 participants, mainly Europeans aged between 47 and 71 years.
They obtained genetic association data for osteoarthrosis and osteoarthritis from a meta-analysis of 177,517 any-site osteoarthritis cases and 649,173 controls across 21 cohorts. The team ascertained post-menopause bleeding cases using the International Classification of Diseases, tenth revision (ICD-10) codes.
To investigate potential pleiotropic effects introducing bias, the researchers stratified the United Kingdom Biobank (UKBB) participants by the type of beverage consumed.
They used the random-effects inverse-variance method to perform bidirectional Mendelian randomization and determine the relationship between caffeine metabolism and caffeine intake.
The team proxied caffeine consumption using self-documented coffee consumption, for which they obtained genetic association information from 428,860 UKBB participants.
To assess the influence of body mass index (BMI) on serum caffeine effects on outcomes, they performed a mediation analysis, multiplying MR estimates for serum caffeine effects on BMI by those for BMI effects on the study outcome.
Results
Higher genetically estimated caffeine levels in caffeinated beverage drinkers were related to lower obesity [odds ratio (OR) for each standard deviation elevation in caffeine level (odds ratio, 0.97) and osteoarthritis (OR, 0.97) risks. Lower body weight mediated 33% of the beneficial effects of serum caffeine against osteoarthritis.
Metabolomic and proteomic analyses indicated improved lipid profiles, lower chronic inflammation, and glycogen and protein metabolism changes as biological pathways associated with caffeine effects.
In the PheWAS analysis, higher estimated levels of circulating caffeine from the genetic risk score significantly lowered the risk of obesity and osteoarthritis outcomes. The weighted GRS for serum caffeine was also related to increased postmenopausal bleeding risk.
Two-sample Mendelian randomization analyses revealed a 10% reduction in the risk of osteoarthritis [odds ratio (OR), 0.9] per standard deviation increase in caffeine. The team found no two-sample Mendelian randomization evidence that serum caffeine levels impacted postmenopausal bleeding risk among FinnGen consortium participants (OR, 1.2).
In the stratified analysis, there was a significant relationship between genetically estimated serum caffeine levels and the risk of osteoarthritis among individuals consuming coffee but not among abstainers.
The team also found a statistically significant association between BMI and genetically estimated serum caffeine levels among self-reported coffee or tea consumers but not among abstainers.
The bi-directional MR investigating the relationship between plasma caffeine and coffee consumption identified evidence of an association between higher genetically estimated serum caffeine and lower coffee consumption but not between genetically estimated coffee consumption and serum caffeine levels.
Conclusion
Overall, the study findings provided evidence from proteome-, phenome-, and metabolome-wide MR analyses of the protective effects of caffeine on osteoarthritis and obesity risks, which is crucial due to the global burden of obesity and osteoarthritis.
The study also found that higher plasma caffeine may reduce caffeine consumption. Future studies, including randomized clinical trials, could improve the understanding of the translational relevance of the study findings.
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