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

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.