Abstract
Coffee is one of the most widely consumed beverages in the world, and has been implicated in many health conditions. Coffee is a complex exposure with pleiotropic effects, and the physiological response to coffee varies among individuals. Epidemiological studies of gene-coffee interactions may inform causality, parse the constituents of coffee responsible for disease, and identify subgroups most likely to benefit from increasing or decreasing coffee consumption. Cancers, cardiovascular disease, Parkinson’s disease, and pregnancy outcomes have been the subject of gene-coffee interaction studies and have yielded promising preliminary results. Most studies have targeted the caffeine component of coffee and have examined only a limited number of genetic variants. Depending upon the disease of study, coffee appears to exert beneficial, adverse, or no effects, which may be more pronounced when accounting for genetics. With continued investment, studies of gene-coffee interactions promise to provide the necessary foundation for personalized coffee consumption recommendations.
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Introduction
Coffee is one of the most widely consumed beverages and top-traded commodities in the world [1]. Approximately 1.6 billion cups of coffee are consumed every day worldwide [1]. In North America and Europe, coffee drinkers typically consume approximately two and four cups per day, respectively [1]. With the widespread popularity and availability of coffee, there is increasing public and scientific interest in the potential health consequences of its regular consumption. Meta-analyses of epidemiological studies for over 30 health outcomes have been conducted to date, with results suggesting both beneficial and adverse effects (Table 1) [2–43]. Coffee consumption has also recently been linked to basal cell carcinoma of the skin [44], gestational diabetes mellitus [45], depression [46, 47], and suicide [48]. Despite a long history of interest in coffee and its impact on a wide spectrum of health conditions, both positive and negative, there are currently no published guidelines on consumption of coffee, although some nations and some organizations have set upper limits for intake of caffeine, a psychostimulant naturally present in coffee, among special populations such as children and pregnant women [49, 50••].
While epidemiological studies are highly efficient and relevant methods of investigating the role that habitual coffee intake plays in the health of a “real-world” population, they have several limitations that warrant consideration in the interpretation of results [51]. Furthermore, this approach does not provide causal or mechanistic insights into the relationship between coffee and health; hence, epidemiology is often considered a “basic science” of public health [52]. This review discusses how the addition of a genetic component to traditional epidemiological studies of coffee and health may greatly improve data. More specifically, epidemiological studies of gene-coffee interactions may inform causality, parse the constituents of coffee responsible for disease, and identify subgroups most likely to benefit from increasing or decreasing coffee consumption.
Coffee is a Complex Exposure with Pleiotropic Physiological Effects
For most populations, coffee is the main source of caffeine, which is by far the best-characterized naturally occurring component of the beverage. In addition to its well-characterized psychostimulant properties [53], caffeine reportedly enhances the activation and carcinogenic potential of environmental mutagens [54], stimulates and suppresses tumors [55], and modulates stress and sex hormones [56]. Although linked to acute adverse effects on blood pressure [57] and calcium and glucose homeostasis [58•], caffeine reduces neurodegeneration and amyloid-β production and stabilizes the blood-brain barrier [59•, 60].
Caffeine, however, is only one of the hundreds of biologically active chemicals present in coffee [61]. For example, brewed coffee is considered one of the richest dietary sources of natural phenols [62, 63], which have antioxidant activities [64] and favorable roles in fatty acid oxidation and glucose homeostasis [65, 66]. Melanoidins and lipid-soluble heterocyclic compounds such as furans, pyrroles, and maltol also contribute to coffee’s antioxidant content [61, 67, 68]. Boiled or unfiltered coffee contains diterpenoid alcohols, including cafestol and kahweol [69]. These compounds have well-known hypercholesterolemic effects [70] but may also exert anticarcinogenic effects [71, 72]. Roasted coffee beans contain low concentrations of heterocyclic amines and polycyclic aromatic hydrocarbons that may be significant contributors to the total mutagen content of the diet when coffee is consumed in large amounts [61, 73].
The precise chemical composition of a brewed cup of coffee will depend upon a series of factors, from bean species to brewing method [61]. Nevertheless, in light of its complex composition, coffee potentially exerts a multitude of physiological effects that may affect a number of health conditions in different ways.
Individuals Vary in Their Physiological Response to Coffee
Interindividual variation in the metabolism of or physiological response to any of the many chemicals present in coffee may alter the persistence and/or magnitude of their individual effects. For example, the 2- to 12-fold interindividual variation in caffeine metabolism will affect the duration of exposure to caffeine and its effects [74–77]. In humans, CYP1A2 accounts for more than 95 % of caffeine metabolism and is the major source of variability in caffeine pharmacokinetics [78, 79]. Clinical and population pharmacokinetic studies have identified several environmental factors contributing to variation in CYP1A2, including smoking, oral contraceptive use, pregnancy, and habitual alcohol and caffeine intake [78–80]. Genetic factors also play a role [81]. Failure to account for these factors will result in greater variability of response to a given amount of coffee consumed by a population, resulting in potentially different associations across studies.
Gene-Coffee Interactions: Research and Public Health Implications
There is growing enthusiasm for studies of gene-coffee interactions, which are described herein as biological rather than statistical phenomena, and involve gene products that plausibly interact with coffee. The main effect of both genotype and coffee intake may be greater in one stratum, such as level of intake or type of allele, than in the other strata, or it may have the opposite effect in one stratum compared with the others [82].
When carefully designed, gene-coffee interactions may provide causal and mechanistic insight into coffee’s role in disease [81] by separating the biological effects of one compound from those of other compounds present in coffee, or from environmental or personal factors correlated with coffee intake. For example, if caffeine is the causal component of coffee underlying a protective association between coffee and a disease, the association would be most evident among individuals with genotypes corresponding to slower caffeine metabolism or to more favorable physiological responses to caffeine. In addition to pinpointing the precise component of coffee or the biological pathway underlying the association, this approach may also identify subgroups that might benefit from personalized advice concerning their coffee consumption habits.
Approach: Candidate Gene and Variant Selection
Methodological issues in epidemiological studies of gene-environment interactions have been reviewed elsewhere in detail [83]. Selection of genes to consider for testing gene-coffee (or genotype-coffee) interaction will depend upon the scientific question being asked. Generally, the approaches fall into two categories: examining genes related to metabolism or action of coffee constituents, or those related to diseases ostensibly affected by coffee intake. Our knowledge of metabolism of caffeine and its mechanism of action enables reasonable selection of candidate genes when examining the caffeine component of coffee underlying its association with a disease or trait. Considering only genes with common and functional variants is especially attractive, as these may affect study power and interpretation.
Over 300 single-nucleotide polymorphisms (SNPs) have been identified in the CYP1A2 gene [84]. However, the functional significance and/or proportion of CYP1A2 phenotype variability explained by these SNPs remain unclear [85]. The intronic CYP1A2*1F (C734A, rs762551) polymorphism has been considered in most genetic epidemiological studies of coffee, caffeine, and other CYP1A2 substrates. For most populations, the A variant (often referred to as the “rapid” metabolizing allele) is the most common, and has been associated with higher inducibility compared with the C (“slow”) variant, particularly among smokers [86–88].
With the advent of genome-wide association studies (GWAS), our selection of candidate genes and functional SNPs (or SNPs tagging functional SNPs) for a disease or trait has improved substantially. Although this agnostic approach to candidate gene discovery has not been applied to clinical measures of caffeine metabolism or response per se, it has been successfully applied to self-reported habitual coffee and caffeine intake behavior [89••, 90, 91]. Genome-wide meta-analyses of European population-based studies showed significant SNP-coffee intake and SNP-caffeine intake associations upstream of AHR (aryl hydrocarbon receptor, rs4410790, rs6968865) [89••, 90]. A second locus maps to the CYP1A1-CYP1A2 bidirectional promoter (rs2470893, rs2472297), although CYP1A2*1F (rs762551) was also among the genome-wide significant SNPs [89••, 90, 91]. The protein product of AHR is a ligand-activated transcription factor that plays a key role in regulating the expression of a number of genes, including CYP1A1 and CYP1A2 [92, 93]. Although functional studies are warranted, SNPs near CYP1A1-CYP1A2 and AHR may associate with intake behavior because they alter caffeine metabolism and thus levels of physiological exposure to caffeine that elicit the most desirable psychostimulant effects. While variation in taste-related genes has been associated with caffeine- and coffee-taste perception and preferences in candidate and genome-wide studies [94–96], none of these variants was related to coffee or caffeine consumption in previous GWAS [89••, 90, 91]. Interestingly, GWAS of blood pressure have identified significant loci mapping to CYP1A2, including the CYP1A2*1F SNP [97, 98].
The main psychological effects of caffeine in humans are reportedly due to competitive inhibition of central A1 and A2A adenosine receptors [53, 99]. By inhibiting these receptors, caffeine indirectly promotes the release of dopamine, norepinephrine, serotonin, acetylcholine, γ-aminobutyric acid, and glutamate [53, 99]. As such, gene members of pathways involving these neurotransmitters are candidates for studies of the relationship between caffeine and health. Candidate gene studies on caffeine and caffeine-related traits have focused on variants in ADORA2A (rs5751876) encoding the A2A receptor, ADORA1 (rs10920568) encoding the A1 receptor, and DRD2 (rs1079597, rs1110976) encoding D2R, but their functions are unclear, possibly due to differences in study design [100–104]. In the GWAS of caffeine intake [89••] and caffeine-related sleep disturbance [105], novel SNPs in ADORA2A were nominally significant, but may warrant further study regarding other outcomes.
Genetic variation in xenobiotic metabolism (NAT2, CYP1A2, CYP1A1, UGTs) has been examined in relation to the mutagen content of coffee. Variation in genes reportedly involved in metabolism of other coffee constituent classes, such as diterpenes (UGTs, SULTs), flavonoids (CYP1A2, CYP2D6, CYP2C09, CYP3A4, CYP1A1, CYP2E1, UGTs, SULTs), and polyphenols (UGTs, GSTs, SULTs), have thus far received limited attention [51]. Likewise, genes or pathways targeted by these and other non-caffeine constituents of coffee have not been examined, in part because our knowledge of these is quite limited.
An alternate approach to gene and variant selection for gene-coffee interaction studies has been to focus on candidates directly associated with disease [106–108]. While these studies are important, many are exploratory in nature and do not inform the biology connecting coffee and disease. With the exception of one study of Parkinson’s disease [109•], they are not further discussed in this review.
Progress: Epidemiological Studies of Gene-Coffee Interactions and Health
Table 2 provides details of genetic epidemiological investigations linking coffee or caffeine intake to various health conditions [109•, 110–125, 126•, 127–142]. Most have been case-control studies based in populations of European ancestry. The caffeine and mutagen components of coffee have been the focus of most studies, and accordingly, caffeine or xenobiotic pathway genes have been the primary candidates selected for analysis.
Breast Cancer
A recent meta-analysis reported no overall association between coffee or caffeine and breast cancer risk, but a significant inverse association among postmenopausal women or BRCA1 mutation carriers [3]. One of the three studies contributing to the latter association also examined whether the protective effect of coffee among BRCA1 mutation carriers was modified by CYP1A2: Kotsopoulos et al. [110] reported a significantly lower risk of breast cancer with “ever” consuming coffee only among CYP1A2 C (“slow”, rs762551) carriers, suggesting that the lower risk may be attributable to the prolonged exposure of caffeine among slow metabolizers. Although CYP1A2 may also activate carcinogens in coffee, this role is less likely to explain the protective effect of a slow CYP1A2 genotype, since the same carcinogens are present at higher concentrations in tobacco smoke, and no interaction between CYP1A2 and smoking was observed. To provide insight into the generalizability of these earlier findings, Lowcock et al. [113] conducted a larger population-based study. High coffee consumption, but not total caffeine, was associated with reduced risk of estrogen receptor (ER)-negative and postmenopausal breast cancer, independent of CYP1A2 genotype. Whether the CYP1A2-coffee interaction is specific to BRCA1 mutation carriers warrants further study.
In a case-only study [111], moderate to high coffee consumption was associated with ER-negative tumors and a later age at diagnosis compared with low coffee consumption, but only among patients with the “rapid” CYP1A2 genotype. In addition to its role in metabolizing over 95 % of caffeine, CYP1A2 is also a key enzyme in the 2-hydroxylation of the main estrogens, estrone and estradiol [143], yielding potentially protective estrogen metabolites [144]. Since caffeine and coffee also induce CYP1A2 [78], the slower growth of ER-positive tumors in rapid CYP1A2 genotype patients consuming coffee may be mediated by altered estrogen exposure [145].
Rabstein et al. [112] explored associations between coffee consumption, acetylation status (defined by NAT2 haplotypes), and receptor-defined breast cancer. Coffee consumption increased the risk of breast cancer among “slow” acetylators but decreased the risk among “fast” acetylators. N-acetyltransferases play a dual role in xenobiotic metabolism, which can render a product metabolite more or less active than its substrate [146]. Thus, an adverse constituent of coffee that is potentially inactivated by NAT2, and thus directly mediating this interaction, while plausible, warrants further study.
Ovarian Cancer
Epidemiological studies do not support a significant overall association between coffee consumption and ovarian cancer [13, 14]. Goodman et al. [114] evaluated associations between CYP1A2 (rs762551), coffee/caffeine consumption, and epithelial ovarian cancer among a population of predominately Asian and Pacific Islanders. High regular coffee and total caffeine consumption were associated with an increased risk of cancer, but effect sizes were greater among women with the AA (rapid) genotype than among women carrying the C (slow) allele. In their larger study of Caucasians, Kotsopoulos et al. [116] reported no overall effect of coffee on ovarian cancer and no effect modification by SNPs in CYP1A2, CYP1A1, CYP2A6, or CYP19 [116]. Terry et al. [115] examined two SNPs in CYP1A1 and their interaction with various potential mutagens, including caffeine, on risk of ovarian cancer. An elevated risk associated with an Ile-to-Val substitution (rs1048943, not examined by Kotsopoulos et al. [116]), conferring increased activity, was observed only among high caffeine consumers. No interaction was observed between the second SNP (rs4646903, also examined by Kotsopoulos et al. [116]) and caffeine intake [115].
Bladder Cancer
A recent meta-analysis of coffee intake and bladder cancer reported no overall association, suggesting that any support for an increased risk with coffee consumption originated from case-control studies [2]. Three studies investigated gene-coffee interactions and risk of bladder cancer [119–121]. The first study framed coffee as a source of carcinogens, and investigated variants in genes encoding xenobiotic-metabolizing and DNA-repair enzymes [119]. Heavy lifetime coffee consumption enhanced the risk associated with a more active GSTP1 variant, but no statistical test for interaction was provided. The second [120] and third [121] studies focused on genetic variation in caffeine metabolism (CYP1A2, CYP1A1, and CYP2E1) and reported no significant SNP-coffee interactions with bladder cancer.
Colorectal Cancers
Case-control, but not cohort, studies support a protective effect of coffee intake on risk of colorectal and colon cancer [4]. Only two studies of gene-coffee interactions have been conducted to date, and neither report an overall protective effect of coffee or effect modification by genetic variation in GSTM1, NAT2, or CYP1A2 [117, 118].
Pregnancy Outcomes
The unknown or potential adverse consequences of maternal coffee and caffeine consumption on the developing fetus have resulted in recommendations that pregnant women limit their caffeine intake. For example, Health Canada advises women who are planning to become pregnant, are pregnant, or are breast-feeding to limit their caffeine intake to <300 mg/day [50••]. The March of Dimes Foundation recommends a more rigorous limit of <200 mg/day [49]. Epidemiological evidence of an effect of caffeine on human reproductive health and fetal development, however, is limited [147, 148]. A recent Cochran Review, which was based on one random controlled trial [149], concluded that there was insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on improved birth weight or other pregnancy outcomes [150].
Interactions between genetic variation in xenobiotic metabolism and maternal coffee and/or total caffeine were tested in three studies of recurrent pregnancy loss [128, 129, 132], one study of fecundability [133], and one study of acute childhood leukemia [134], but no consistent and/or interpretable results were reported. Four studies specifically examined whether any relationship between coffee intake and pregnancy outcomes were modified by genetic variation in caffeine metabolism. Sata et al. [129] reported an increased risk of recurrent pregnancy loss associated with caffeine only among women with the CYP1A2 AA (rapid, rs762551) genotype, suggesting that pregnancy is adversely affected by either a metabolite of caffeine or some other compound present in dietary sources of caffeine that is activated by CYP1A2. Bech et al. [127] considered the same CYP1A2 SNP, as well as SNPs in NAT2 and GSTA1, in their study of caffeine intake and risk of stillbirth, but no SNP-caffeine interaction was reported. Infante-Rivard et al. [130] reported no main effect of maternal caffeine intake or CYP1A2/1E2-caffeine interactions for risk of small-for-gestational-age babies. Finally, Schmidt et al. [131] examined the association between maternal exposure to caffeine and risk of neural tube defects, taking into consideration both the mother’s and child’s CYP1A2 and NAT2 genotype. Maternal pre-pregnancy exposure to caffeine increased risk among infants with CYP1A2 AA genotype, but it is unclear how variation in the infant’s CYP1A2 gene may affect predisposition, given the time of exposure, and because expression of this enzyme is very low in infants relative to adults.
Parkinson’s Disease
Consistent epidemiologic evidence supports a linear protective effect of coffee and caffeine intake on risk of Parkinson’s disease (PD). One hypothesis underling this relationship, as well as that of the inverse association between smoking and PD, is that PD patients have premorbid personality traits associated with dislike for coffee drinking (and smoking). A second hypothesis is that caffeine and nicotine are neuroprotective. A third, more recent hypothesis implicates a protective effect of coffee and tobacco smoke on the microbiota in the gut [151]. These hypotheses could be tested in genetic epidemiology studies of coffee and PD.
Earlier studies by Tan et al. [135, 136] and Facheris et al. [137] investigated variation in ADORA2A and CYP1A2, reporting no significant SNP-coffee interactions for risk of PD. Palacios et al. [138] observed an increased risk of PD associated with CYP1A2 C (slow, rs762551) variant among females (but not males), but no interaction with caffeine consumption. The main effect of CYP1A2 may be due to CYP1A2’s role in metabolism of neurotoxins, such as the synthetic opioid contaminant MPTP [152], but the prevalence of these exposures and the sex-specific associations reported are unclear. The largest candidate gene study of coffee and PD reported a stronger inverse association between coffee and PD among individuals homozygous for the CYP1A2 rs762551 C (slow) allele or the moderately correlated (r2 = 0.66) rs2470890 C allele, a finding consistent with a protective effect of caffeine.
These CYP1A2-coffee interactions, however, were not replicated in a study by the NeuroGenetics Research Consortium [140]. More recently, this consortium performed genome-wide joint tests of SNP main effects and SNP-coffee interactions to exploit the role caffeine plays in PD development as a means for disease gene discovery [109•]. The most significant signals came from rs4998386 and neighboring SNPs in GRIN2A. This gene encodes an NMDA glutamate receptor subunit that can regulate excitatory neurotransmission in the brain and is a plausible candidate in PD etiology. GRIN2A may also be a target for caffeine, and thus a novel candidate worthy of further investigation.
Cardiovascular Disease
Randomized controlled trials demonstrate significant but modest elevations in blood pressure with regular coffee intake [57, 153]. Population studies generally do not support an association between habitual coffee consumption and elevated risk of hypertension (HTN) or other cardiovascular outcomes (Table 1). These generalizations, however, should be tempered in light of results from gene-coffee interactions. Palatini et al. [125] tested the CYP1A2-coffee interaction among Italians and reported an increased risk of HTN among CYP1A2 C (slow, rs762551) carriers but not among those homozygous for the A (rapid) allele. Similarly, Cornelis et al. [124] reported an increased risk of nonfatal myocardial infarction associated with regular coffee intake only among carriers of the CYP1A2 C (slow) allele. A trend toward a protective effect with moderate coffee consumption was observed among those homozygous for the A allele.
Motivated by GWAS reporting associations between CYP1A2 variants and both caffeine intake [89••] and blood pressure [97, 98], Guessous et al. [126•] designed a thoughtful study to explore, in part, the effects of CYP1A2 variants on blood pressure and HTN, focusing on caffeine as the potential mediator of CYP1A2 effects. The CYP1A2 AA (rapid) genotype was associated with a lower risk of HTN among nonsmokers, and this was mediated by caffeine intake, which was also inversely associated with HTN. These associations were not observed among smokers, possibly due to the strong CYP1A2-inducing effect of smoking, which may supersede the effect of genotype.
Taken together, these studies suggest that the caffeine component of coffee may have adverse cardiovascular effects but that these effects are limited to individuals with impaired or slower caffeine metabolism (i.e., CYP1A2 C and nonsmokers). Further, individuals who can rapidly metabolism caffeine (i.e., CYP1A2 AA and smokers) may benefit from other compounds present in coffee. The discrepant pattern of results across studies may be due to differences in study design or exposure distribution.
Happonen et al. [123] examined a non-synonymous SNP in the gene encoding catechol-O-methyl transferase (COMT), the main enzyme responsible for metabolism of catecholamines. An increased risk of acute myocardial infarction in heavy coffee drinkers was found in subjects possessing the COMT rs4680 allele conferring lower COMT activity [123]. Elevated catecholamine levels have been linked to both coffee intake and increased risk of coronary heart disease [154].
Conclusions and Future Directions
Given the widespread popularity and availability of coffee, modulating its intake represents a significant opportunity to affect health outcomes. While epidemiology has largely laid the groundwork for continued studies of this modifiable risk factor, the discipline, in its most basic form, has clearly reached its limit. With our growing knowledge of the composition of coffee and factors underlying interindividual variability in the metabolism of and response to its separate constituents, it is reasonable to apply this knowledge to investigations of coffee and health. Indeed, we are now seeing progress in this regard, with over 30 gene-coffee interaction studies published to date. While these efforts are promising, the findings are not conclusive. Most have targeted the caffeine component of coffee and have examined a limited number of SNPs, many with unclear functional significance.
While the addition of a genetic component provides an advantage over traditional epidemiology, it is not a panacea, and all studies of gene-coffee interactions should be held to the same level of methodological rigor as any epidemiological study. Specific to tests of gene-environment interactions are issues concerning population stratification and gene-environment correlations that may violate assumptions underlying certain methods [83]. Pleiotropic effects of candidate genes, including those targeted for studies of coffee, will also affect the interpretation of significant gene-environment interactions. The need for information on both DNA and coffee consumption clearly poses limits to designing a sufficiently powered study, not to mention an adequate replication study. Interaction meta-analyses may improve power and type 1 error, but warrant careful consideration for the scale and distribution of coffee intake and confounders in participating populations.
Thus far, studies of gene-coffee interactions appear most rewarding for gaining insight into causality and mechanisms linking coffee to health. Coffee appears to exert beneficial, adverse, and no effects, depending upon the disease of study (Table 1), and these effects may be more pronounced when accounting for genetics (Table 2). As such, coffee is not amenable to a one-size-fits-all paradigm; rather, it is ideally suited for personalization. Ultimately, such studies promise to provide the necessary foundation for personalized coffee consumption recommendations.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
International Coffee Organization. Annual review; 2009–2010. [www.ico.org]
Zhou Y, Tian C, Jia C. A dose-response meta-analysis of coffee consumption and bladder cancer. Prev Med. 2012;55(1):14–22.
Jiang W, Wu Y, Jiang X. Coffee and caffeine intake and breast cancer risk: an updated dose-response meta-analysis of 37 published studies. Gynecol Oncol. 2013;129(3):620–9.
Li G, Ma D, Zhang Y, et al. Coffee consumption and risk of colorectal cancer: a meta-analysis of observational studies. Public Health Nutr. 2013;16(2):346–57.
Je Y, Giovannucci E. Coffee consumption and risk of endometrial cancer: findings from a large up-to-date meta-analysis. Int J Cancer. 2012;131(7):1700–10.
Zheng JS, Yang J, Fu YQ, et al. Effects of green tea, black tea, and coffee consumption on the risk of esophageal cancer: a systematic review and meta-analysis of observational studies. Nutr Cancer. 2013;65(1):1–16.
Botelho F, Lunet N, Barros H. Coffee and gastric cancer: systematic review and meta-analysis. Cadernos De Saude Publica. 2006;22(5):889–900.
Malerba S, Galeone C, Pelucchi C, et al. A meta-analysis of coffee and tea consumption and the risk of glioma in adults. Cancer Causes Control. 2013;24(2):267–76.
Bravi F, Bosetti C, Tavani A, et al. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin Gastroenterol Hepatol. 2013;11(11):1413.e1–21.e1.
Turati F, Galeone C, La Vecchia C, et al. Coffee and cancers of the upper digestive and respiratory tracts: meta-analyses of observational studies. Ann Oncol. 2011;22(3):536–44.
Wang Y, Yu X, Wu Y, et al. Coffee and tea consumption and risk of lung cancer: a dose-response analysis of observational studies. Lung Cancer (Amsterdam, Netherlands). 2012;78(2):169–70.
Tang N, Wu Y, Ma J, et al. Coffee consumption and risk of lung cancer: a meta-analysis. Lung Cancer (Amsterdam, Netherlands). 2010;67(1):17–22.
Braem MG, Onland-Moret NC, Schouten LJ, et al. Coffee and tea consumption and the risk of ovarian cancer: a prospective cohort study and updated meta-analysis. Am J Clin Nutr. 2012;95(5):1172–81.
Steevens J, Schouten LJ, Verhage BA, et al. Tea and coffee drinking and ovarian cancer risk: results from the Netherlands Cohort Study and a meta-analysis. Br J Cancer. 2007;97(9):1291–4.
Turati F, Galeone C, Edefonti V, et al. A meta-analysis of coffee consumption and pancreatic cancer. Ann Oncol. 2012;23(2):311–8.
Dong J, Zou J, Yu XF. Coffee drinking and pancreatic cancer risk: a meta-analysis of cohort studies. World J Gastroenterol. 2011;17(9):1204–10.
Zhong S, Chen W, Yu X, et al. Coffee consumption and risk of prostate cancer: an up-to-date meta-analysis. Eur J Clin Nutr. 2014;68(3):330–7.
Zeegers MP, Tan FE, Goldbohm RA, et al. Are coffee and tea consumption associated with urinary tract cancer risk? A systematic review and meta-analysis. Int J Epidemiol. 2001;30(2):353–62.
Caldeira D, Martins C, Alves LB, et al. Caffeine does not increase the risk of atrial fibrillation: a systematic review and meta-analysis of observational studies. Heart. 2013;99(19):1383–9.
Ding M, Bhupathiraju SN, Satija A, et al. Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies. Circulation. 2014;129(6):643–59.
Wu JN, Ho SC, Zhou C, et al. Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies. Int J Cardiol. 2009;137(3):216–25.
Sofi F, Conti AA, Gori AM, et al. Coffee consumption and risk of coronary heart disease: a meta-analysis. Nutr Metab Cardiovasc Dis. 2007;17(3):209–23.
Mostofsky E, Rice MS, Levitan EB, et al. Habitual coffee consumption and risk of heart failure: a dose-response meta-analysis. Circ Heart Fail. 2012;5(4):401–5.
Steffen M, Kuhle C, Hensrud D, et al. The effect of coffee consumption on blood pressure and the development of hypertension: a systematic review and meta-analysis. J Hypertens. 2012;30(12):2245–54.
Zhang Z, Hu G, Caballero B et al: Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies. Am J Clin Nutr 2011.
Fernandes O, Sabharwal M, Smiley T, et al. Moderate to heavy caffeine consumption during pregnancy and relationship to spontaneous abortion and abnormal fetal growth: a meta-analysis. Reprod Toxicol. 1998;12(4):435–44.
Maslova E, Bhattacharya S, Lin SW, et al. Caffeine consumption during pregnancy and risk of preterm birth: a meta-analysis. Am J Clin Nutr. 2010;92(5):1120–32.
Santos IS, Victora CG, Huttly S, et al. Caffeine intake and pregnancy outcomes: a meta-analytic review. Cadernos De Saude Publica. 1998;14(3):523–30.
Cheng J, Su H, Zhu R et al: Maternal coffee consumption during pregnancy and risk of childhood acute leukemia: a metaanalysis. Am J Obstet Gynecol 2014; 210(2):151 e151–151 e110.
Lee DR, Lee J, Rota M, et al. Coffee consumption and risk of fractures: A systematic review and dose-response meta-analysis. Bone. 2014;63:20–8.
Sheng J, Qu X, Zhang X, et al. Coffee, tea, and the risk of hip fracture: a meta-analysis. Osteoporos Int. 2014;25(1):141–50.
Malerba S, Turati F, Galeone C, et al. A meta-analysis of prospective studies of coffee consumption and mortality for all causes, cancers and cardiovascular diseases. Eur J Epidemiol. 2013;28(7):527–39.
Je Y, Giovannucci E. Coffee consumption and total mortality: a meta-analysis of twenty prospective cohort studies. Br J Nutr. 2013;111(7):1162–73.
Chiaffarino F, Bravi F, Cipriani S et al: Coffee and caffeine intake and risk of endometriosis: a meta-analysis. Eur J Nutr 2014.
Santos C, Costa J, Santos J, et al. Caffeine intake and dementia: systematic review and meta-analysis. J Alzheimers Dis. 2010;20 Suppl 1:S187–204.
Kim J, Oh SW, Myung SK et al: Association between coffee intake and gastroesophageal reflux disease: a meta-analysis. Dis Esophagus 2013.
Sang LX, Chang B, Li XH, et al. Consumption of coffee associated with reduced risk of liver cancer: a meta-analysis. BMC Gastroenterol. 2013;13:34.
Qi H, Li S: Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson’s disease. Geriatr Gerontol Int 2013.
Lee YH, Bae SC, Song GG: Coffee or tea consumption and the risk of rheumatoid arthritis: a meta-analysis. Clin Rheumatol 2014.
Kim B, Nam Y, Kim J, et al. Coffee consumption and stroke risk: a meta-analysis of epidemiologic studies. Korean J Family Med. 2012;33(6):356–65.
Larsson SC, Orsini N. Coffee consumption and risk of stroke: a dose-response meta-analysis of prospective studies. Am J Epidemiol. 2011;174(9):993–1001.
Ding M, Bhupathiraju SN, Chen M, et al. Caffeinated and decaffeinated coffee consumption and risk of type 2 diabetes: a systematic review and a dose-response meta-analysis. Diabetes Care. 2014;37(2):569–86.
Wang S, Zhang Y, Mao Z et al: A meta-analysis of coffee intake and risk of urolithiasis. Urol Int 2014.
Song F, Qureshi AA, Han J. Increased caffeine intake is associated with reduced risk of basal cell carcinoma of the skin. Cancer Res. 2013;72(13):3282–9.
Adeney KL, Williams MA, Schiff MA, et al. Coffee consumption and the risk of gestational diabetes mellitus. Acta Obstet Gynecol Scand. 2007;86(2):161–6.
Guo X, Park Y, Freedman ND, et al. Sweetened beverages, coffee, and tea and depression risk among older US adults. PLoS ONE. 2014;9(4):e94715.
Lucas M, Mirzaei F, Pan A, et al. Coffee, caffeine, and risk of depression among women. Arch Intern Med. 2011;171(17):1571–8.
Lucas M, O’Reilly EJ, Pan A et al: Coffee, caffeine, and risk of completed suicide: Results from three prospective cohorts of American adults. World J Biol Psychiatry 2013.
March of Dimes Foundation [http://www.marchofdimes.com/pregnancy/print/caffeine-in-pregnancy.html]
Health Canada [http://www.hc-sc.gc.ca/fn-an/securit/addit/caf/food-caf-aliments-eng.php]. This site summarizes Health Canada’s decision to provide population-level recommended maximum caffeine intake levels.
Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Curr Opin Clin Nutr Metab Care. 2007;10(6):745–51.
Institute of Medicine Committee for the Study of the Future of Public Health. The future of public health. Washington, DC: National Academy Press; 1988.
Fredholm BB, Battig K, Holmen J, et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51(1):83–133.
Zhou T, Chen Y, Huang C et al: Caffeine induction of sulfotransferases in rat liver and intestine. J Appl Toxicol 2011.
World Cancer Research Fund/American Institute for Cancer Research: Food, nutrition, physical activity and the prevention of cancer: a global perspective. In. Washington, DC: American Institute for Cancer Research; 2007.
Nagata C, Kabuto M, Shimizu H. Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenopausal Japanese women. Nutr Cancer. 1998;30(1):21–4.
Jee SH, He J, Whelton PK, et al. The effect of chronic coffee drinking on blood pressure: a meta-analysis of controlled clinical trials. Hypertension. 1999;33(2):647–52.
Beaudoin MS, Graham TE: Methylxanthines and human health: epidemiological and experimental evidence. Handb Exp Pharmacol 2011(200):509–548. This book chapter provides an excellent summary of both epidemiological and experimental research on caffeine and its methylxanthine metabolites.
Arendash GW, Cao C. Caffeine and coffee as therapeutics against Alzheimer’s disease. J Alzheimers Dis. 2010;20 Suppl 1:S117–26. This article provides a thorough summary of the mechanisms by which caffeine and coffee may protect against Alzheimer’s disease, and is one of a series of articles in this excellent supplement entitled “Therapeutic Opportunities for Caffeine in Alzheimer’s Disease and Other Neurodegenerative Disease’.”.
Chen X, Gawryluk JW, Wagener JF, et al. Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer’s disease. J Neuroinflammation. 2008;5:12.
Spiller MA. The chemical components of coffee. In: Spiller GA, editor. Caffeine. Boca Raton: CRC; 1998. p. 97–161.
Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr. 2000;130(8S Suppl):2073S–85S.
Clifford MN. Chlorogenic acids and other cinnamates – nature, occurrence, dietary burden, absorption and metabolism. J Sci Food Agric. 2000;80:1033–43.
Natella F, Nardini M, Giannetti I, et al. Coffee drinking influences plasma antioxidant capacity in humans. J Agric Food Chem. 2002;50(21):6211–6.
de Sotillo DV R, Hadley M, Sotillo JE. Insulin receptor exon 11+/- is expressed in Zucker (fa/fa) rats, and chlorogenic acid modifies their plasma insulin and liver protein and DNA. J Nutr Biochem. 2006;17(1):63–71.
Johnston KL, Clifford MN, Morgan LM. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine. Am J Clin Nutr. 2003;78(4):728–33.
Borrelli RC, Visconti A, Mennela C, et al. Chemical characterization and antioxidant properties of coffee melanoidins. J Agric Food Chem. 2002;50:6527–33.
Yanagimoto K, Ochi H, Lee KG, et al. Antioxidative activities of fractions obtained from brewed coffee. J Agric Food Chem. 2004;52:592–6.
Urgert R. Levels of the cholesterol-elevating diterpenes cafestol and kahweol in various coffee brews. J Agric Food Chem. 1995;43:2167–72.
Urgert R, Katan MB. The cholesterol-raising factor from coffee beans. Annu Rev Nutr. 1997;17:305–24.
Huber WW, Rossmanith W, Grusch M, et al. Effects of coffee and its chemopreventive components kahweol and cafestol on cytochrome P450 and sulfotransferase in rat liver. Food Chem Toxicol. 2008;46(4):1230–8.
Majer BJ, Hofer E, Cavin C, et al. Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2). Food Chem Toxicol. 2005;43(3):433–41.
Coffee, tea, mate, methylxanthines and methylglyoxal. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 27 February to 6 March 1990. IARC monographs on the evaluation of carcinogenic risks to humans / World Health Organization, International Agency for Research on Cancer 1991; 51:1–513.
Benowitz NL. Clinical pharmacology of caffeine. Annu Rev Med. 1990;41:277–88.
Birkett DJ, Miners JO. Caffeine renal clearance and urine caffeine concentrations during steady state dosing. Implications for monitoring caffeine intake during sports events. Br J Clin Pharmacol. 1991;31:405–8.
Lelo A, Birkett DJ, Robson RA, et al. Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine, and theophylline in man. Br J Clin Pharmacol. 1986;22:177–82.
Kashuba AD, Bertino Jr JS, Kearns GL, et al. Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin Pharmacol Ther. 1998;63(5):540–51.
Gunes A, Dahl ML. Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics. 2008;9(5):625–37.
Zhou SF, Wang B, Yang LP, et al. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev. 2010;42(2):268–354.
Thorn CF, Aklillu E, Klein TE, et al. PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenet Genomics. 2012;22(1):73–7.
Cornelis MC. Coffee intake. Prog Mol Biol Transl Sci. 2012;108:293–322.
Rothman KJ, Greenland S, editors. Modern epidemiology. Philadelphia: Lippincott Williams and Wilkins; 1998.
Kraft P, Hunter D. Integrating epidemiology and genetic association: the challenge of gene-environment interaction. Philos Trans R Soc Lond B Biol Sci. 2005;360(1460):1609–16.
Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11.
Jiang Z, Dragin N, Jorge-Nebert LF, et al. Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype. Pharmacogenet Genomics. 2006;16(5):359–67.
Sachse C, Brockmoller J, Bauer S, et al. Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999;47(4):445–9.
Ghotbi R, Christensen M, Roh HK, et al. Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol. 2007;63(6):537–46.
Gunes A, Ozbey G, Vural EH, et al. Influence of genetic polymorphisms, smoking, gender and age on CYP1A2 activity in a Turkish population. Pharmacogenomics. 2009;10(5):769–78.
Cornelis MC, Monda KL, Yu K, et al. Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption. PLoS Genet. 2011;7(4):e1002033. This article presents one of the first successful genome-wide assocation studies of dietary behavior. Candidate genes identified were those related to caffeine metabolism. Index polymorphisms were novel and have thus far never been examined in gene-coffee interaction studies.
Sulem P, Gudbjartsson DF, Geller F, et al. Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption. Hum Mol Genet. 2011;20(10):2071–7.
Amin N, Byrne E, Johnson J, et al. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM. Mol Psychiatry. 2011;17(11):1116–29.
Nukaya M, Bradfield CA. Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster. Biochem Pharmacol. 2009;77(4):654–9.
Nukaya M, Moran S, Bradfield CA. The role of the dioxin-responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hydrocarbon receptor biology. Proc Natl Acad Sci U S A. 2009;106(12):4923–8.
Hayes JE, Wallace MR, Knopik VS, et al. Allelic variation in TAS2R bitter receptor genes associates with variation in sensations from and ingestive behaviors toward common bitter beverages in adults. Chem Senses. 2011;36(3):311–9.
Ledda M, Kutalik Z, Souza Destito MC et al: GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics. Hum Mol Genet 2013.
Pirastu N, Kooyman M, Traglia M, et al. Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking. PLoS ONE. 2014;9(3):e92065.
Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41(6):677–87.
Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41(6):666–76.
Ferre S. Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine. J Alzheimers Dis. 2010;20 Suppl 1:S35–49.
Alsene K, Deckert J, Sand P, et al. Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 2003;28(9):1694–702.
Childs E, Hohoff C, Deckert J, et al. Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 2008;33(12):2791–800.
Retey JV, Adam M, Khatami R, et al. A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther. 2007;81(5):692–8.
Cornelis MC, El-Sohemy A, Campos H. Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption. Am J Clin Nutr. 2007;86(1):240–4.
Rogers PJ, Hohoff C, Heatherley SV, et al. Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology. 2010;35(9):1973–83.
Byrne EM, Johnson J, McRae AF, et al. A genome-wide association study of caffeine-related sleep disturbance: confirmation of a role for a common variant in the adenosine receptor. Sleep. 2012;35(7):967–75.
McCulloch CC, Kay DM, Factor SA, et al. Exploring gene-environment interactions in Parkinson’s disease. Hum Genet. 2008;123(3):257–65.
Hancock DB, Martin ER, Vance JM, et al. Nitric oxide synthase genes and their interactions with environmental factors in Parkinson’s disease. Neurogenetics. 2008;9(4):249–62.
Kokaze A, Ishikawa M, Matsunaga N, et al. NADH dehydrogenase subunit-2 237 Leu/Met polymorphism modulates the effects of coffee consumption on the risk of hypertension in middle-aged Japanese men. J Epidemiol/ Japan Epidemiol Assoc. 2009;19(5):231–6.
Hamza T, Chen H, Hill-Burns E, et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson’s disease modifier gene via interaction with coffee. PLoS Genet. 2011;7(8):e1002237. This article describes one of the first successful genome-wide interaction studies. The authors exploit the well-established association between coffee consumption and Parkinson’s disease in efforts to identify additional disease loci.
Kotsopoulos J, Ghadirian P, El-Sohemy A, et al. The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2007;16(5):912–6.
Bageman E, Ingvar C, Rose C, et al. Coffee consumption and CYP1A2*1F genotype modify age at breast cancer diagnosis and estrogen receptor status. Cancer Epidemiol Biomarkers Prev. 2008;17(4):895–901.
Rabstein S, Bruning T, Harth V, et al. N-acetyltransferase 2, exposure to aromatic and heterocyclic amines, and receptor-defined breast cancer. Eur J Cancer Prev. 2010;19(2):100–9.
Lowcock EC, Cotterchio M, Anderson LN, et al. High coffee intake, but not caffeine, is associated with reduced estrogen receptor negative and postmenopausal breast cancer risk with no effect modification by CYP1A2 genotype. Nutr Cancer. 2013;65(3):398–409.
Goodman MT, Tung KH, McDuffie K, et al. Association of caffeine intake and CYP1A2 genotype with ovarian cancer. Nutr Cancer. 2003;46(1):23–9.
Terry KL, Titus-Ernstoff L, Garner EO, et al. Interaction between CYP1A1 polymorphic variants and dietary exposures influencing ovarian cancer risk. Cancer Epidemiol Biomarkers Prev. 2003;12(3):187–90.
Kotsopoulos J, Vitonis AF, Terry KL, et al. Coffee intake, variants in genes involved in caffeine metabolism, and the risk of epithelial ovarian cancer. Cancer Causes Control. 2009;20(3):335–44.
Slattery ML, Kampman E, Samowitz W, et al. Interplay between dietary inducers of GST and the GSTM-1 genotype in colon cancer. Int J Cancer. 2000;87(5):728–33.
Dik VK, Bueno-de-Mesquita HB, Van Oijen MG et al: Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk-Results from the EPIC cohort study. Int J Cancer 2014.
Covolo L, Placidi D, Gelatti U, et al. Bladder cancer, GSTs, NAT1, NAT2, SULT1A1, XRCC1, XRCC3, XPD genetic polymorphisms and coffee consumption: a case-control study. Eur J Epidemiol. 2008;23(5):355–62.
Villanueva CM, Silverman DT, Murta-Nascimento C, et al. Coffee consumption, genetic susceptibility and bladder cancer risk. Cancer Causes Control. 2009;20(1):121–7.
Pavanello S, Mastrangelo G, Placidi D, et al. CYP1A2 polymorphisms, occupational and environmental exposures and risk of bladder cancer. Eur J Epidemiol. 2010;25(7):491–500.
Fortes C, Mastroeni S, Boffetta P, et al. The protective effect of coffee consumption on cutaneous melanoma risk and the role of GSTM1 and GSTT1 polymorphisms. Cancer Causes Control. 2013;24(10):1779–87.
Happonen P, Voutilainen S, Tuomainen TP, et al. Catechol-o-methyltransferase gene polymorphism modifies the effect of coffee intake on incidence of acute coronary events. PLoS ONE. 2006;1:e117.
Cornelis MC, El-Sohemy A, Kabagambe EK, et al. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006;295(10):1135–41.
Palatini P, Ceolotto G, Ragazzo F, et al. CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension. J Hypertens. 2009;27(8):1594–601.
Guessous I, Dobrinas M, Kutalik Z, et al. Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension. Hum Mol Genet. 2012;21(14):3283–92. CYP1A2 is a confirmed locus in GWAS of caffeine intake and blood pressure. This article explores the effects of CYP1A2 variants and CYP1A2 enzyme activity on blood pressure, focusing on caffeine as the potential mediator of CYP1A2 effects. The observational and quasi-experimental results strongly support a causal role of CYP1A2 in blood pressure control via caffeine intake.
Bech BH, Autrup H, Nohr EA, et al. Stillbirth and slow metabolizers of caffeine: comparison by genotypes. Int J Epidemiol. 2006;35(4):948–53.
Zusterzeel PL, Nelen WL, Roelofs HM, et al. Polymorphisms in biotransformation enzymes and the risk for recurrent early pregnancy loss. Mol Hum Reprod. 2000;6(5):474–8.
Sata F, Yamada H, Suzuki K, et al. Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. Mol Hum Reprod. 2005;11(5):357–60.
Infante-Rivard C. Caffeine intake and small-for-gestational-age birth: modifying effects of xenobiotic-metabolising genes and smoking. Paediatr Perinat Epidemiol. 2007;21(4):300–9.
Schmidt RJ, Romitti PA, Burns TL, et al. Caffeine, selected metabolic gene variants, and risk for neural tube defects. Birth Defects Res. 2010;88(7):560–9.
Nonaka T, Takakuwa K, Tanaka K: Analysis of the polymorphisms of genes coding biotransformation enzymes in recurrent miscarriage in the Japanese population. J Obstet Gynaecol Res 2011.
Taylor KC, Small CM, Dominguez CE et al: Alcohol, smoking, and caffeine in relation to fecundability, with effect modification by NAT2. Ann Epidemiol 2011.
Clavel J, Bellec S, Rebouissou S, et al. Childhood leukaemia, polymorphisms of metabolism enzyme genes, and interactions with maternal tobacco, coffee and alcohol consumption during pregnancy. Eur J Cancer Prev. 2005;14(6):531–40.
Tan EK, Chua E, Fook-Chong SM, et al. Association between caffeine intake and risk of Parkinson’s disease among fast and slow metabolizers. Pharmacogenet Genomics. 2007;17(11):1001–5.
Tan EK, Lu ZY, Fook-Chong SM, et al. Exploring an interaction of adenosine A2A receptor variability with coffee and tea intake in Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(6):634–6.
Facheris MF, Schneider NK, Lesnick TG, et al. Coffee, caffeine-related genes, and Parkinson’s disease: a case-control study. Mov Disord. 2008;23(14):2033–40.
Palacios N, Weisskopf M, Simon K, et al. Polymorphisms of caffeine metabolism and estrogen receptor genes and risk of Parkinson’s disease in men and women. Parkinsonism Relat Disord. 2010;16(6):370–5.
Popat RA, Van Den Eeden SK, Tanner CM, et al. Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson’s disease. Eur J Neurol. 2011;18(5):756–65.
Hill-Burns EM, Hamza TH, Zabetian CP, et al. An attempt to replicate interaction between coffee and CYP1A2 gene in connection to Parkinson’s disease. Eur J Neurol. 2011;18(9):e107–108.
Hallstrom H, Melhus H, Glynn A, et al. Coffee consumption and CYP1A2 genotype in relation to bone mineral density of the proximal femur in elderly men and women: a cohort study. Nutrition & Metabolism. 2010;7:12.
Kiyohara C, Washio M, Horiuchi T et al: The modifying effect of NAT2 genotype on the association between systemic lupus erythematosus and consumption of alcohol and caffeine-rich beverages. Arthritis Care Res 2014.
Lee AJ, Cai MX, Thomas PE, et al. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003;144(8):3382–98.
Schneider J, Huh MM, Bradlow HL, et al. Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem. 1984;259(8):4840–5.
Jernstrom H, Klug TL, Sepkovic DW, et al. Predictors of the plasma ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone among pre-menopausal, nulliparous women from four ethnic groups. Carcinogenesis. 2003;24(5):991–1005.
Boukouvala S, Fakis G. Arylamine N-acetyltransferases: what we learn from genes and genomes. Drug Metab Rev. 2005;37(3):511–64.
Peck JD, Leviton A, Cowan LD. A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: a 2000–2009 update. Food Chem Toxicol. 2010;48(10):2549–76.
Leviton A, Cowan L. A review of the literature relating caffeine consumption by women to their risk of reproductive hazards. Food Chem Toxicol. 2002;40(9):1271–310.
Bech BH, Obel C, Henriksen TB, et al. Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial. BMJ. 2007;334(7590):409.
Jahanfar S, Jaafar SH: Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome. The Cochrane database of systematic reviews 2013; 2:CD006965
Derkinderen P, Shannon KM, Brundin P: Gut feelings about smoking and coffee in Parkinson’s disease. Mov Disord 2014.
Coleman T, Ellis SW, Martin IJ, et al. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-demethylated by cytochromes P450 2D6, 1A2 and 3A4–implications for susceptibility to Parkinson’s disease. J Pharmacol Exp Ther. 1996;277(2):685–90.
Noordzij M, Uiterwaal CS, Arends LR, et al. Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized trials. J Hypertens. 2005;23:921–8.
Abraham J, Mudd JO, Kapur NK, et al. Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J Am Coll Cardiol. 2009;53(15):1320–5.
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Marilyn Cornelis is supported, in part, by the American Diabetes Association Grant 7-13-JF-15.
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Marilyn C. Cornelis declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent
All cited studies involving human subjects were performed after approval by the appropriate Institutional Review Boards. Written or verbal informed consent was obtained from all participants.
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Cornelis, M.C. Gene-Coffee Interactions and Health. Curr Nutr Rep 3, 178–195 (2014). https://doi.org/10.1007/s13668-014-0087-1
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DOI: https://doi.org/10.1007/s13668-014-0087-1