In a recent study published in BMJ Medicinethe researchers conducted two randomized Mendelian sample (MR) studies to investigate the effects of long-term exposure to higher plasma concentrations of caffeine on type 2 diabetes (T2D), obesity, and cardiovascular diseases, such as ischemic heart disease, stroke, and atrial fibrillation, For example but not limited to.
Stady: Evaluation of the causal effect of plasma caffeine on obesity, type 2 diabetes, and cardiovascular disease: a randomized, two-sample study. Image credit: ThanaponTH/Shutterstock.com
The caffeine (1,3,7-trimethylxanthine) in coffee and tea has thermogenic and psychostimulant effects.
Several short-term randomized controlled trials (RCTs) have found that caffeine (even in trace amounts) helps reduce weight, fat mass, and body mass index (BMI).
Thus, consuming more caffeine (by drinking tea and coffee) is very likely to reduce the risk of fat-related diseases, such as T2D and cardiovascular disease. However, the long-term effects of caffeine intake remain elusive.
Observational studies have shown an inverse relationship between coffee consumption and T2D risk. However, observational results on its association with cardiovascular disease are inconsistent, indicating positive and negative associations.
Thus, these studies did not reliably infer causation, which may lead to confusing associations.
Furthermore, other compounds found in caffeinated beverages and foods make determining the specific effects of caffeine on cardiovascular disease risk difficult.
In this study, the researchers examined six population studies in 9876 individuals of European ancestry to determine genome-wide associations (GWA) of single nucleotide polymorphisms (SNPs) near cytochrome P450 isoform 1A2 (CYP1A2) and AHR loci.
They selected the strongest polymorphisms near CYP1A2 and AHR loci, that is, rs2472297 in CYP1A2 and rs4410790 in AHR, to use as instrumental variables in this MR analysis.
The researchers hypothesized that the genetic variants used as instrumental variables in the MR analysis fulfilled three assumptions, the relatedness assumption, the independence assumption, and the exclusion restriction assumption.
Genetic differences near CYP1A2, which metabolizes caffeine in the liver, and AHR, which regulates expression of CYP1A2, correlate with plasma caffeine concentrations.
Individuals who carry these genetic variants can help to reliably improve causal inference by serving as unbiased surrogates.
The team obtained estimates of the associations of caffeine SNPs for body mass index, whole-body lean mass, and corresponding summary genetic data for subtypes of T2D, cardiovascular disease, and atrial fibrillation.
It helped them investigate possible causal effects of long-term exposure to higher plasma caffeine concentrations on obesity, T2D, and major cardiovascular diseases.
First, the authors estimated the SNP and score (beta coefficient). They divided it by the estimate of association between the SNP and plasma caffeine concentration to obtain an estimate of MR using standard deviation (SD) unit, which represents the variance in plasma caffeine concentration for each allele.
Next, they combined the MR estimates for these two SNPs for each inverse variance weighting method. To follow up, they conducted a two-step MRI mediation analysis to investigate the extent to which BMI mediates caffeine’s effects on T2D.
The authors noted an association between genetically predicted higher plasma concentrations of caffeine and lower body mass index (beta −0.08 SD) and whole body fat mass (beta −0.06 SD), with one SD being 4.8 kg/m.2 in BMI and 9.5 kg in fat mass, respectively.
The study estimated that a 43% decrease in BMI mediated the effect of caffeine on T2D responsibility. However, for each SD increase in plasma caffeine, the genetically predicted higher plasma caffeine concentrations were not associated with lean body mass (beta −0.01 SD), with one SD being ~11.5 kg.
Furthermore, higher plasma caffeine concentrations were associated with a reduced risk of T2D in the FinnGen and DIAMANTE consortia, with a pooled odds ratio (OR) of 0.81.
Previous observational results were unable to identify a clear association between genetically predicted coffee consumption and T2D in MR analyses. This MR study suggested that caffeine, at least in part, explains the inverse association between coffee consumption and T2D risk.
Although the study’s results for plasma caffeine may appear superficially to be inconsistent and contradictory to previous MR analyses, the authors anticipated such a discrepancy because genetic variants in the two genomic regions associated with high plasma caffeine concentrations are also associated with lower coffee and caffeine consumption.
Furthermore, the genetic method used in this study only used SNPs located in genes encoding enzymes with an established role in caffeine metabolism.
The confidence interval (CI) for cardiovascular outcomes in this study was 95%, indicating that any protective effect of plasma caffeine concentrations on ischemic heart disease and atrial fibrillation is unlikely to be greater than 15% and 12% and more harmful than 1%. and 5%, respectively.
The magnitude of the association was stronger in this MR analysis than in previous MR studies, which may be related to the use of different tools and data sources for BMI and T2D.
This MRI study found strong evidence to support causal associations of plasma caffeine concentrations with reduced obesity and T2D risk.
However, more clinical studies are warranted to investigate the translational potential of these findings toward reducing the burden of metabolic disease. Randomized controlled trials on caffeine consumption and chronic disease are expensive and tedious to implement; Later, a few of them were published.
However, more randomized controlled trials are warranted to evaluate whether no-calorie caffeinated beverages can help reduce the risk of obesity and T2D.