There are two kinds of people in this world: those who can't imagine life without coffee and those who just don't get what the fuss is about. Now researchers have found two genetic variations that may explain why never the twain shall meet.
Genetic epidemiologist Marilyn Cornelis of the Harvard School of Public Health in Boston knows about coffee addicts first hand—she's got one in the family. Her father drinks 10 cups a day, she says. "He actually needs a cup of coffee before he can go to bed."
Twin studies have shown that genes probably have a lot to do with this, suggesting that they account for between 43% and 58% of the variability in coffee-drinking habits. But no one knew which genes were involved. So Cornelis and colleagues at six institutions scanned the entire genomes of 47,341 adult subjects from five U.S. studies which had collected data on caffeine intake, among other things. They weren't looking for any genes in particular, just for any genetic eccentricities associated with higher caffeine consumption.
This technique, known as a genome-wide association study, turned up two genetic variants. Subjects with two copies drank about 40 mg more caffeine a day than subjects with zero copies—"worth an 8-ounce diet Pepsi," or about half a cup or less of brewed coffee, says co-author and cancer geneticist Neil Caporaso of the National Cancer Institute in Bethesda, Maryland. One variant was right next to a gene called CYP1A2, a familiar face in caffeine research. CYP1A2 is expressed in the liver and "is up to 95% responsible for caffeine metabolism," Cornelis says. The other big hit, the team reports in the journal PLoS Genetics, was a variant near a gene called AHR, which regulates how CYP1A2 is expressed.
But, as evidenced by any outdoor café in Paris, people tend to like coffee with their cigarettes and vice versa. To make sure they’d found genes related to coffee rather than cigarettes, the researchers scanned the population again, this time looking only at nonsmokers. The same two variants popped up. "It wasn't smoking we were picking up," Cornelis says.
These two variants are responsible for just a small fraction—less than 1%—of the variation in caffeine intake among the subjects, suggesting that rarer variants, which this study didn't search for, are still out there, Cornelis says. But the fact that the variants they did find relate to caffeine metabolism "underscores that our findings are for real and not just by chance," she says. When trying to tease out the genetics of behaviors such as overeating or alcoholism, researchers commonly ask whether the genes at play are ones that regulate how a substance is metabolized or ones that mediate the body's response. With caffeine, there is now a clear answer: "It's in the liver, not in your brain," Caporaso says.
That's a marked difference from smoking, the only other consumption behavior that has been linked to certain genes, says Abraham Palmer, a pharmacogeneticist at the University of Chicago in Illinois who studies how genes regulate the effects of amphetamine. The genes linked with smoking were ones that regulated nicotine receptors in the brain. This study's results are "really a contrast" and for that reason "very interesting," he says.
Figuring out what's going on physiologically would take experiments, not just statistics, Cornelis and Caporaso say. One possible hypothesis: coffee hounds have gene variants that increase their metabolism of caffeine, "so to maintain levels that give them [the same] fix, they require more" coffee, Cornelis says. But the study doesn't explain why some people don't seek out caffeine at all. Since these variants tell only part of the story, enterprising coffee moguls should put away their cheek swabs, Palmer cautions: "If you were Starbucks and wanted to know who your customers were, this is not going to be an effective way."