Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization

Abstract

Background: Caffeine is one of the most utilized drugs in the world, yet its clinical effects are not fully understood. Circulating caffeine levels are influenced by the interplay between consumption behaviour and metabolism. This study aimed to investigate the effects of circulating caffeine levels by considering genetically predicted variation in caffeine metabolism.

Methods: Leveraging genetic variants related to caffeine metabolism that affect its circulating levels, we investigated the clinical effects of plasma caffeine in a phenome-wide association study (PheWAS). We validated novel findings using a two-sample Mendelian randomization framework and explored the potential mechanisms underlying these effects in proteome-wide and metabolome-wide Mendelian randomization.

Results: Higher levels of genetically predicted circulating caffeine among caffeine consumers were associated with a lower risk of obesity (odds ratio (OR) per standard deviation increase in caffeine = 0.97, 95% confidence interval (CI) CI: 0.95-0.98, p = 2.47 × 10^-4), osteoarthrosis (OR = 0.97, 95% CI: 0.96-0.98, P=1.10 × 10^-8) and osteoarthritis (OR: 0.97, 95% CI: 0.96 to 0.98, P = 1.09 × 10^-6). Approximately one third of the protective effect of plasma caffeine on osteoarthritis risk was estimated to be mediated through lower bodyweight. Proteomic and metabolomic perturbations indicated lower chronic inflammation, improved lipid profiles, and altered protein and glycogen metabolism as potential biological mechanisms underlying these effects.

Conclusions: We report novel evidence suggesting that long-term increases in circulating caffeine may reduce bodyweight and the risk of osteoarthrosis and osteoarthritis. We confirm prior genetic evidence of a protective effect of plasma caffeine on risk of overweight and obesity. Further clinical study is warranted to understand the translational relevance of these findings before clinical practice or lifestyle interventions related to caffeine consumption are introduced.

Keywords: Caffeine; Mendelian randomization; Obesity; Osteoarthritis; Phenome-wide association study.

Fig. 1

Study design. Abbreviations: AHR: aryl hydrocarbon receptor, CYP1A2: cytochrome P450 isoform 1A2. The schematic was created using Biorender.com

Fig. 2

Disease odds ratio per standard deviation increase in the plasma caffeine genetic risk score (A) and genetically predicted plasma caffeine levels (B). The PheWAS and stratified analysis considered associations of a weighted genetic risk score for plasma caffeine, whereas the two-sample MR performed inverse-variance weighted MR analysis using genetic variants predicting plasma caffeine levels. Abbreviations: CI: confidence interval, GRS: genetic risk score, MR: Mendelian randomization, OA: osteoarthritis OR: odds ratio, PheWAS: Phenome-wide association analysis, PMB: postmenopausal bleeding, SD: standard deviation. Notes: ¹Defined as International Classification of Diseases (ICD) version 10 codes M15–M19, ²Defined as ICD10 codes M19. Estimates are presented as the odds ratios (95% confidence interval) per standard deviation change in the genetic risk score of caffeine (A), and genetically predicted plasma caffeine levels (B). Estimate p-values are presented on the far right

Fig. 3

An illustrative mechanistic diagram showing the protective effect of genetically predicted plasma caffeine levels on osteoarthritis liability^(a), mediated through body mass index^(b). The figure extends to a representation of our findings that genetically predicted caffeine levels drive consumption behaviour^(c), but not vice versa^(d). In keeping with our findings, prior studies have reported a positive association between caffeine consumption and body mass index and osteoarthritis risk^(e). Mendelian randomization estimates are scaled per one standard deviation increase in plasma caffeine levels and are shown with their corresponding 95% confidence intervals in parenthesis. Citations included [1] Cornelis et al. (2016); [2] Nicolopoulos et al. (2020); [3] Lee (2018); [4] Zhang et al. (2021). Abbreviations: AHR: aryl hydrocarbon receptor, BMI: body mass index, CYP1A2: cytochrome P450 isoform 1A2. This figure was created using Biorender.com