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Original Investigation
August 2018

Association of Coffee Drinking With Mortality by Genetic Variation in Caffeine Metabolism: Findings From the UK Biobank

Author Affiliations
  • 1Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
  • 2Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 3Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
  • 4Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
JAMA Intern Med. 2018;178(8):1086-1097. doi:10.1001/jamainternmed.2018.2425
Key Points

Question  Moderate coffee consumption has been inversely associated with mortality; however, does heavy intake, particularly among those with common genetic polymorphisms that impair caffeine metabolism, increase risk of mortality?

Findings  This large prospective cohort study of a half million people found inverse associations for coffee drinking with mortality, including among participants drinking 1 up to 8 or more cups per day. No differences were observed in analyses that were stratified by genetic polymorphisms affecting caffeine metabolism.

Meaning  This study provides further evidence that coffee drinking can be part of a healthy diet and offers reassurance to coffee drinkers.


Importance  Prospective cohorts in North America, Europe, and Asia show consistent inverse associations between coffee drinking and mortality, including deaths from cardiovascular disease and some cancers. However, concerns about coffee, particularly among people with common genetic polymorphisms affecting caffeine metabolism and among those drinking more than 5 cups per day, remain.

Objective  To evaluate associations of coffee drinking with mortality by genetic caffeine metabolism score.

Design, Setting, and Participants  The UK Biobank is a population-based study that invited approximately 9.2 million individuals from across the United Kingdom to participate. We used baseline demographic, lifestyle, and genetic data form the UK Biobank cohort, with follow-up beginning in 2006 and ending in 2016, to estimate hazard ratios (HRs) for coffee intake and mortality, using multivariable-adjusted Cox proportional hazards models. We investigated potential effect modification by caffeine metabolism, defined by a genetic score of previously identified polymorphisms in AHR, CYP1A2, CYP2A6, and POR that have an effect on caffeine metabolism. Of the 502 641 participants who consented with baseline data, we included those who were not pregnant and had complete data on coffee intake and smoking status (n = 498 134).

Exposures  Total, ground, instant, and decaffeinated coffee intake.

Main Outcomes and Measures  All-cause and cause-specific mortality.

Results  The mean age of the participants was 57 years (range, 38-73 years); 271 019 (54%) were female, and 387 494 (78%) were coffee drinkers. Over 10 years of follow-up, 14 225 deaths occurred. Coffee drinking was inversely associated with all-cause mortality. Using non–coffee drinkers as the reference group, HRs for drinking less than 1, 1, 2 to 3, 4 to 5, 6 to 7, and 8 or more cups per day were 0.94 (95% CI, 0.88-1.01), 0.92 (95% CI, 0.87-0.97), 0.88 (95% CI, 0.84-0.93), 0.88 (95% CI, 0.83-0.93), 0.84 (95% CI, 0.77-0.92), and 0.86 (95% CI, 0.77-0.95), respectively. Similar associations were observed for instant, ground, and decaffeinated coffee, across common causes of death, and regardless of genetic caffeine metabolism score. For example, the HRs for 6 or more cups per day ranged from 0.70 (95% CI, 0.53-0.94) to 0.92 (95% CI, 0.78-1.10), with no evidence of effect modification across strata of caffeine metabolism score (P = .17 for heterogeneity).

Conclusions and Relevance  Coffee drinking was inversely associated with mortality, including among those drinking 8 or more cups per day and those with genetic polymorphisms indicating slower or faster caffeine metabolism. These findings suggest the importance of noncaffeine constituents in the coffee-mortality association and provide further reassurance that coffee drinking can be a part of a healthy diet.

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    9 Comments for this article
    Coffee Increases Testosterone
    James Howard, bs | independent biologist
    I suggest the findings of Loftfield, et al., result from increases in testosterone. Coffee is known to increase testosterone. ("Testosterone Controls Human and Great Ape Lifespans;" at: http://anthropogeny.com/Human%20Lifespan%20Testosterone.html )
    Impact of testosterone
    Peter Pressman, MD | The Daedalus Foundation
    Even if coffee is causally associated with a statistically significant increase in testosterone, wouldn't one expect pre-malignant or malignant lesions to be promoted via mitogenic
    What about other correlations?
    Matthias Reinecken, Ph.D. |
    In the end it's probably something trivial such as: People that drink 8 cups of coffee a day (added to their normal water intake) just drink more compared to people that do not drink 8 cups of coffee. Are the researchers sure every person only drank a certain amount of water per day?
    Consideration of bitter taste receptor and immune sytem activity missing
    Imke Kirste, PhD | NIH
    First of all, thank you for the interesting article. However, the causality is not entirely convincing in this study especially given that you studied caffeine related genes only and you found the same effect for decaffeinated and caffeinated drinks. Given that the scientific community had some major findings in recent years how genes for taste receptors are also crucial in respect to immune system functioning, I am hoping you might be able to provide also some data on the genetic variation in this respect. I'd hypothesize that the tolerance of the bitter taste is directly linked to coffee intake as well as immune system reactivity ultimately leading to a confounding effect of the coffee itself, but a potential causal effect between immune activity and longevity, e.g. TNFs role in taste (Feng and Jotaki), polymorphisms in TAS2R38 (Please see the recent review in Front Cell Infect Microbiol by Triantaffilou et al.).
    Caffeine vs increased Mortality
    Andrew Macko, Physician | RI Medical

    I want to thank anybody who is looking.  The studies don't specify other cardiac anomalies associated with caffeine intake. Although safe to a degree they don't take into account for how many milligrams per day. Caffeine can be deadly if taken into excess. Nobody talks about the negative effects. There might be benefits but the negative is also a concern.  

    Although low to moderate doses are generally safe, caffeine is addictive. Users can become dependent on it and find it difficult to quit or even cut back. (Caffeine dependence was even named as a
    new mental disorder this year.) Anyone who's ever quit cold turkey knows it can trigger pounding headaches, mental fuzziness and fatigue for a couple of days until the body adjusts.

    Other effects of too much caffeine:

    It increases anxiety and disrupts sleep patterns, leading to a vicious cycle of restless sleep, relying on caffeine to help with daytime fatigue, followed by more insomnia.

    Caffeine interacts with some medications, including thyroid medication, psychiatric and depression drugs, the antibiotic Cipro and the heartburn drug Tagamet.

    It increases blood sugar levels, making it harder for those with type 2 diabetes to manage their insulin, according to a number of studies; it also can slightly raise blood pressure. 

    The amount of caffeine in a particular coffee drink depends on the brew and beverage size:

    Restaurant espresso (1 oz.) 40-75 mg
    Instant coffee (8 oz.) 27-173 mg
    Typical brewed coffee (8 oz.) 95-200 mg
    McDonald's brewed coffee (16 oz.) 100 mg
    Starbucks brewed coffee (16 oz.) 330 mg
    Source: Mayo Clinic

    Caffeine potentially leads to some spinal bone loss in postmenopausal women, if they typically drink more than three cups, or 300 mg of caffeine, a day, but don't get enough calcium in their diet, says Linda Massey, emeritus professor of nutrition at Washington State University. An older woman should make sure she gets at least 800 mg of calcium daily — through food or supplements — to offset caffeine's effect on calcium, adds Bess Dawson-Hughes, M.D., director of the Bone Metabolism Laboratory at Tufts University in Boston.

    Coffee itself can also lead to stomach upset. If you have problems with acid reflux or heartburn, then coffee and even tea might not be right for you.

    And if you have high cholesterol and you don't want your coffee adding to the problem, you need to use a paper filter to trap the cafestol, a compound in coffee that raises LDL cholesterol levels.

    Caffeine is a drug and every drug has its downfall. So in my opinion I would need more evidence based medicine to prove that caffeine offers a benefit to decrease mortality. 

    CONFLICT OF INTEREST: Is caffeine really the safe alternative, Are we snowed based on studies
    Caffeine vs mortality
    Andrew Macko, Physician Assistant | RI medical
    One question is what caffeine does to the body. Every study is focused on the benefits or disadvantages, but nobody looked at actual symptoms associated with caffeine intake. Caffeine is not a substitute for increased risk of mortality based on the studies; also important are  cardiovascular disease (CVD), coronary heart disease (CHD) and acute myocardial infarction (AMI), effects on arrhythmia, heart failure, sudden cardiac arrest, stroke, blood pressure, hypertension, and other biomarkers of effect, including heart rate, cerebral blood flow, cardiac output, plasma homocysteine levels, serum cholesterol levels, electrocardiogram (EKG) parameters, heart rate variability, endothelial/platelet function and plasma/urine catecholamine levels. Medical personal need to look further into suggesting caffeine as a health benefit. The best water intake has always been pure water and no other derivatives from dating back to 320 AD. Food for thought. Caffeine was introduced based on its ability to increase work stamina just like Adrenal or Amphetamines. Are they any safer?

    CONFLICT OF INTEREST: Caffeine vs increase Mortality
    Other correlations?
    Mike Hirsch |

    I wondered how this study could be conclusive if it didn't mention details on anything added to coffee (i.e., sugar, cream, dairy milk, almond milk, etc.) and the amount of said additions, as well as how many times (every cup or just sometimes) those were added. Also, how many people had straight, black coffee?

    Also, what about the amount of water intake for each individual? And what about exercise?

    Seems many relevant factors were overlooked or left out.

    Coffee, not just caffeine
    Steven Horwitz, DC |
    Key statements:
    1. This was a recall study - participants " answered comprehensive touchscreen questionnaires"
    2. "Participants were asked “How many cups of coffee do you drink each day (including decaffeinated coffee)?” "“What type of coffee do you usually drink?” and were able to select 1 of 6 mutually exclusive responses including “decaffeinated coffee (any type),” “instant coffee,” or “ground coffee (include espresso, filter, etc).”
    3. "We also observed inverse associations for both caffeinated and decaffeinated coffee, further suggesting the importance of noncaffeine compounds in the association."
    4. "The UK Biobank presented a unique opportunity to assess potential differences
    between drinking instant vs ground coffee because 55% of coffee drinkers reported usually drinking instant coffee. Associations for ground coffee and all cause mortality were generally stronger than those for instant coffee" ", instant coffees have been shown to have lower amounts of bioactive compounds, including polyphenols, than ground coffees, which may have an effect on observed associations."

    5. "Information on coffee preparation (ie, filtered, cappuccino, espresso, and latte) is available on a subset

    of approximately 70 000 UK Biobank participants who completed 24-hour dietary recalls at baseline and will be useful as the cohort matures."

    As usual, headlines distort a deeper look into the study. The authors state, "Our results are based on observational data and should be interpreted with caution" For those who enjoy coffee this is certainly promising, but we have much to learn. As this paper (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824984/) states, "coffee is chemically complex, consisting of more than 1,000 different compounds." Nature does it best.

    On the clinical side, if a patient has had an issue with coffee as described by Dr. Macko in the comments, I have asked them to try an organic, fairly traded coffee (fortunately many are now available) brewed in a glass or stainless steel French press and this has frequently mitigated or removed all negative side effects.
    Interpretation of results
    Le Wang, Ph.D | Peking Union Medical College
    Thanks for this interesting article. I'm just feeling worried about the interpretations of some results. Firstly, the results in Table 3 showed a lower hazard ratio in the decaffeinated coffee group than the HRs of other two groups, while the authors did not explain the differences of various coffee groups. From the results, I have a hypothesis that caffeine is associated with a higher risk of all cause mortality. Secondly, similar variations among different groups of smoking status were presented in Table 5. No significant association between coffee intake and mortality was found in never-smokers whereas lower mortality risk was found in both current smokers and former smokers. How to interpret these results of subgroup analysis is a challenge.