Associations of Observational and Genetically Determined Caffeine Intake With Coronary Artery Disease and Diabetes Mellitus

Abstract

Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). However, whether these associations are causal remains unknown. This study aimed to identify genetic variants associated with caffeine intake, and to investigate evidence for causal links with CAD or T2DM. In addition, we aimed to replicate previous observational findings. Methods and Results Observational associations were tested within UK Biobank using Cox regression analyses. Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2DM, with the lowest risks at intakes of 121 to 180 mg/day from coffee for CAD (hazard ratio [HR], 0.77 [95% CI, 0.73-0.82; P<1×10^-16]), and 301 to 360 mg/day for T2DM (HR, 0.76 [95% CI, 0.67-0.86]; P=1.57×10^-5). Next, genome-wide association studies were performed on self-reported caffeine intake from coffee, tea, or both in 407 072 UK Biobank participants. These analyses identified 51 novel genetic variants associated with caffeine intake at P<1.67×10^-8. These loci were enriched for central nervous system genes. However, in contrast to the observational analyses, 2-sample Mendelian randomization analyses using the identified loci in independent disease-specific cohorts yielded no evidence for causal links between genetically determined caffeine intake and the development of CAD or T2DM. Conclusions Mendelian randomization analyses indicate genetically determined higher caffeine intake might not protect against CAD or T2DM, despite protective associations in observational analyses.

Keywords: Mendelian randomization; caffeine intake; coronary artery disease; genetics; type 2 diabetes mellitus.

Figure 1. Associations between observational caffeine intake with new‐onset coronary artery disease (A) and type 2 diabetes mellitus (B).

Hazard ratios (HR) with 95% CIs were calculated using Cox regression analyses, adjusted for age, sex, active smoking, body mass index, and log‐transformed weekly alcohol intake. Estimates <1 indicate a beneficial association between caffeine intake and outcome. Sixty milligrams of caffeine is equivalent to 1 cup of instant coffee or 2 cups of tea.

Figure 2. Manhattan plot for combined caffeine intake.

Manhattan plot showing the results for the genome‐wide associations with combined caffeine intake in the UK Biobank with the −log10 P value on the vertical axis. The sentinel single nucleotide polymorphisms that reached genome‐wide significance (P<1.67×10⁻⁸) are colored red.

Figure 3. Venn diagram of candidate genes associated with caffeine intake.

Candidate genes were prioritized based on proximity, data‐driven expression‐prioritized integration for complex traits, and expression quantitative trait locus mapping for combined caffeine intake, caffeine from coffee, and caffeine from tea.

Figure 4. Mendelian randomization results for genetically determined higher caffeine intake (per SD) on coronary artery disease (A) and type 2 diabetes mellitus (B).

Odds ratios (OR) with 95% CIs are provided per standard deviation increase in genetically determined caffeine intake from combined, coffee, or tea. Number of single‐nucleotide polymorphisms (SNPs) included are shown per method. Estimates <1.0 indicate a beneficial association between genetically determined caffeine intake and outcome. MR‐PRESSO indicates Mendelian Randomization Pleiotropy Residual Sum and Outlier.