Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization
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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.
Originalsprog | Engelsk |
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Artikelnummer | 81 |
Tidsskrift | BMC Medicine |
Vol/bind | 22 |
Udgave nummer | 1 |
Antal sider | 10 |
ISSN | 1741-7015 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
HTC is supported by the Novo Nordisk Foundation Challenge Programme: Harnessing the Power of Big Data to Address the Societal Challenge of Aging (NNF17OC0027812). SB is supported by the Wellcome Trust (225790/Z/22/Z) and the United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7). SCL is supported by the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123), Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), and Swedish Cancer Society (Cancerfonden). DG is supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College.
Publisher Copyright:
© The Author(s) 2024.
ID: 389842388