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. 2023 Jan 31;2(1):1-8.
doi: 10.1136/bmjmed-2022-000335. eCollection 2023.

Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study

Susanna C Larsson  1   2 , Benjamin Woolf  3   4   5 , Dipender Gill  6   7
Affiliations

Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study

Susanna C Larsson et al. BMJ Med. .

Abstract

Objective: To investigate the potential causal effects of long term plasma caffeine concentrations on adiposity, type 2 diabetes, and major cardiovascular diseases.

Design: Two sample mendelian randomisation study.

Setting: Genome-wide association study summary data for associations of two single nucleotide polymorphisms associated with plasma caffeine at the genome-wide significance threshold (rs2472297 near the CYP1A2 gene and rs4410790 near the AHR gene) and their association with the outcomes.

Participants: Primarily individuals of European ancestry participating in cohorts contributing to genome-wide association study consortia.

Main outcome measures: Outcomes studied were body mass index, whole body fat mass, whole body fat-free mass, type 2 diabetes, ischaemic heart disease, atrial fibrillation, heart failure, and stroke.

Results: Higher genetically predicted plasma caffeine concentrations were associated with lower body mass index (beta -0.08 standard deviation (SD) (95% confidence interval -0.10 to -0.06), where 1 SD equals about 4.8 kg/m2 in body mass index, for every standard deviation increase in plasma caffeine) and whole body fat mass (beta -0.06 SD (-0.08 to -0.04), 1 SD equals about 9.5 kg; P<0.001) but not fat-free mass (beta -0.01 SD (-0.02 to -0.00), 1 SD equals about 11.5 kg; P=0.17). Higher genetically predicted plasma caffeine concentrations were associated with a lower risk of type 2 diabetes in two consortia (FinnGen and DIAMANTE), with a combined odds ratio of 0.81 ((95% confidence interval 0.74 to 0.89); P<0.001). Approximately half (43%; 95% confidence interval 30% to 61%) of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index reduction. No strong associations were reported between genetically predicted plasma caffeine concentrations and a risk of any of the studied cardiovascular diseases.

Conclusions: Higher plasma caffeine concentrations might reduce adiposity and risk of type 2 diabetes. Further clinical study is warranted to investigate the translational potential of these findings towards reducing the burden of metabolic disease.

Keywords: Cardiology; Diabetes mellitus; Epidemiology; Genetics, medical; Preventive medicine; Public health.

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Conflict of interest statement

Competing interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; DG is employed part-time by Novo Nordisk; the other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic overview of the study design
Figure 2
Figure 2
Genetically predicted higher plasma caffeine concentration and risk of type 2 diabetes and major cardiovascular diseases. The odds ratios with their corresponding 95% confidence intervals (CIs) are scaled per one standard deviation increase in plasma caffeine concentration. Cochran’s Q test statistic for heterogeneity between study specific estimates: Q=2.39 (P=0.12) for type 2 diabetes, Q=0.13 (P=0.72) for ischaemic heart disease, Q=0.48 (P=0.49) for atrial fibrillation, Q=0.08 (P=0.78) for heart failure, and Q=0.11 (P=0.74) for stroke
Figure 3
Figure 3
Causal directed acyclic graph showing the total effect of plasma caffeine on type 2 diabetes risk and the effect mediated by body mass index. The presented mendelian randomisation effect estimates with their corresponding 95% confidence intervals (shown in parenthesis) are scaled per one standard deviation increase in plasma caffeine concentration. BMI=body mass index
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