Heavy coffee drinkers with slow caffeine metabolism at increased risk of nonfatal MI

March 07, 2006

Toronto, ON - The answer to the coffee conundrum, such as whether or not it increases the risk of MI, appears to lie in the genes. In a new study of Costa Rican coffee drinkers, consumption of the delicious brown bean among people with slow caffeine metabolism was associated with an increased risk of nonfatal MI[1]. Surprisingly, investigators also report that there appeared to be a protective effect with moderate coffee consumption among those able to quickly metabolize caffeine, particularly in younger patients.

"When we looked at the studies that have been done linking coffee and caffeine to heart disease, the results have been really all over the map," said study investigator Dr Ahmed El-Sohemy (University of Toronto, ON). "We know that people metabolize caffeine at different rates, and we also know the gene responsible for that, so we reasoned that this was the cause for the inconsistencies in the data. We also reasoned that among individuals who are slow metabolizers, if caffeine is in fact harmful, maybe they might be at increased risk of MI with coffee consumption because they can't get rid of it efficiently. And this is exactly what we found."

The results of the study are published in the March 8, 2006 issue of the Journal of the American Medical Association.

Fast and slow metabolism of caffeine

Speaking with heart wire , El-Sohemy explained that recent epidemiologic studies examining the association between coffee consumption and MI have been inconclusive. "Some have shown caffeine to be harmful, some have shown no association, and there have even been a couple that suggested moderate intake might lower the risk of heart disease," he said. In addition, although some studies have implicated caffeine in the development of cardiovascular disease, it is not clear whether the caffeine or other chemicals found in coffee are responsible for the increased risk, he said.

Caffeine is metabolized almost wholly by cytochrome P450 1A2 (CYP1A2) in the liver. However, variations in the CYP1A2 gene can alter enzyme activity, resulting in wide variability in how quickly caffeine is metabolized. In this case, carriers of the CYP1A2*1F allele are slow metabolizers of caffeine, whereas individuals who are homozygous for the CYP1A2*1A allele are rapid caffeine metabolizers, he said.

To determine whether the CYP1A2 genotype modified the association between the intake of coffee and nonfatal MI, the investigators, led by Marilyn Cornelis (University of Toronto), obtained genetic data on 2014 patients who had a nonfatal MI between 1994 and 2004 and 2014 controls matched for age, sex, and area of residence. Using a questionnaire, subjects were asked to specify the amount of coffee they consumed, with categories ranging from less than one cup per month to six cups per day or more.

Coffee intake and relative risk of MI by CYP1A2 genotype*

Coffee intake (cups/d) Cases (n) Controls (n) Odds ratio (95% CI)
*1A/*1A 900 932
 <1 94 113 1.00
 1 117 158 0.75 (0.51-1.12)
 2-3 510 538 0.78 (0.56-1.09)
>4 179 123 0.99 (0.66-1.48)
*1A/*1F + *1F/*1F 1114 1082
 <1 108 156 1.00
 1 117 180 0.99 (0.69-1.44)
 2-3 636 595 1.36 (1.01-1.83)
>4 253 151 1.64 (1.14-2.34)
*The results are presented using a dominant 1F allele model with *1A/*1F and *1F/*1F genotypes combined because both groups have a similar rate of caffeine metabolism.

For slow metabolizers of caffeine, the intake of coffee was associated with an increased risk of nonfatal MI. Investigators also report the association was present in men and women, although women appeared to be at a slightly higher risk. El-Sohemy explained that because of hormonal differences, women typically metabolize caffeine slower than men, regardless of genotype. The modifying effect of the CYP1A2 genotype on risk of MI with coffee consumption was similar for smokers and nonsmokers, although it did not reach significance.

Among carriers of the slow CYP1A2*1F allele who were younger than the median 59 years, there was an increasing risk of nonfatal MI with increasing coffee consumption. On the other hand, among fast metabolizers who were younger than 59 years, those who drank a moderate amount of coffee, one cup a day or two to three cups a day, had a 52% and 43%, respectively, lower risk of MI.

El-Sohemy noted that the genetic variant was present in 55% of nonfatal MI subjects and in 54% of controls. He added that while this is a Costa Rican population, the prevalence of a number of other genetic variants in this population is similar to what would be found in a multiethnic population. As such, he suspects the prevalence of the slow CYP1A2*1F allele might be similar in other populations, although this needs to be studied further.

In the paper, the investigators suggest that the inability to metabolize caffeine might increase the risk of MI because the excess caffeine binds to adenosine receptors, thus hindering the ability to promote vasodilation. Despite the adverse association in slow metabolizers, El-Sohemy suggests that one cup of java, even in those with the slow CYP1A2*1F allele, is still allowed.

"We found that the consumption of one cup of coffee doesn't cause any harm, regardless of genetics," said El-Sohemy. "Clearly, moderation, in this respect, is a prudent measure. In terms of a bigger picture, this type of research is telling us why we find conflicting results in nutrition research. This will really help the field of nutrigenomics and will really help in understanding the role of nutrition in health disease."


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