Phytoestrogens are estradiol-like natural compounds found in plants that have been associated with protective effects against chronic diseases, including some cancers, cardiovascular diseases and osteoporosis. The purpose of this study was to estimate the dietary intake of phytoestrogens, identify their food sources and their association with lifestyle factors in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Single 24-hour dietary recalls were collected from 36 037 individuals from 10 European countries, aged 35–74 years using a standardized computerized interview programe (EPIC-Soft). An ad hoc food composition database on phytoestrogens (isoflavones, lignans, coumestans, enterolignans and equol) was compiled using data from available databases, in order to obtain and describe phytoestrogen intakes and their food sources across 27 redefined EPIC centres.
Mean total phytoestrogen intake was the highest in the UK health-conscious group (24.9 mg/day in men and 21.1 mg/day in women) whereas lowest in Greece (1.3 mg/day) in men and Spain-Granada (1.0 mg/day) in women. Northern European countries had higher intakes than southern countries. The main phytoestrogen contributors were isoflavones in both UK centres and lignans in the other EPIC cohorts. Age, body mass index, educational level, smoking status and physical activity were related to increased intakes of lignans, enterolignans and equol, but not to total phytoestrogen, isoflavone or coumestan intakes. In the UK cohorts, the major food sources of phytoestrogens were soy products. In the other EPIC cohorts the dietary sources were more distributed, among fruits, vegetables, soy products, cereal products, non-alcoholic and alcoholic beverages.
There was a high variability in the dietary intake of total and phytoestrogen subclasses and their food sources across European regions.
Phytoestrogens are polyphenolic secondary plant metabolites that induce biological responses in animals and can mimic or modulate the action of endogenous estrogens, usually by binding to estrogen receptors.1, 2 The principal phytoestrogens in foods are isoflavones, lignans, coumestans, enterolignans and equol.
Isoflavones are a subclass of flavonoids that occur mainly in soy products. They are also found in much lower concentrations in other plant products3, 4 and even in animal products.5 Classically, the most studied isoflavones were daidzein, genistein and glycitein. In the last two decades, biochanin A and formononetin have also been considered, because they are converted by the intestinal microbiota into genistein and daidzein, respectively.6
Lignans are a diverse group of nonflavonoid compounds widely distributed in the plant kingdom, especially in seeds, such as flax and sesame.7 A large variety of plant lignans exists, but only a few of them are converted into enterolignans by the intestinal microbiota, and therefore able to be absorbed by the human body.8 Highlighted in this group of bioavailable enterolignans are secoisolariciresinol and matairesinol. More recently, lariciresinol and pinoresinol, have also shown a high degree of conversion into enterolignans (around 55%).9
Along with lignans, isoflavone daidzein is also metabolized by intestinal microbiota and transformed into equol.8 As a result of such isoflavone and lignan microbial metabolism in animal gut, these metabolites may also be present in foods of animal origin.5 However, because their occurrence and biosynthesis are different, some authors classify these enterolignans and equol in separate groups, particularly in epidemiological studies.4
The bioactivity of phytoestrogens is based mostly on their weak affinity to the estrogen receptor β and to a lesser extent estrogen receptor α. Therefore, potential effects on hormone-related diseases such as breast, prostate, colorectal and endometrial cancers; and also on lung cancer, CVD, osteoporosis and menopausal symptoms, have been suggested.4, 8, 10 Furthermore, phytoestrogens may reduce oxidative stress by activating intracellular kinase cascades, leading to acute activation of endothelial nitric oxide synthase and modulating redox-sensitive gene transcription via NF-κB (nuclear factor-κB) and Nrf2 (nuclear factor erythroid 2-related factor 2).11, 12 A meta-analysis investigating the relationship between soy foods, isoflavone intakes and breast cancer showed an inverse association in Asian populations, but not in Western populations (Europe and US),13 which tend to have low phytoestrogen intake.
Several studies have published intake estimations of dietary isoflavones.14, 15, 16, 17, 18 Few descriptive articles exist on lignans,19, 20 and even fewer are available to date on coumestans, enterolignans and equol intakes, especially in Europe.4 Moreover, the assessment methods used in these studies have been quite heterogeneous and some used old food composition databases (FCDB), so it is straightforward comparing phytoestrogen intakes. Therefore, the aim of this study was to estimate the intake of total, subgroups and individual phytoestrogens and to present their main food sources in 10 European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). Intakes were also assessed across geographical regions, sociodemographic, lifestyle and anthropometric strata to determine the factors associated with phytoestrogen intake.
MATERIALS AND METHODS
EPIC is a large multicentre prospective cohort study designed to investigate the role of dietary, environmental and lifestyle factors in the etiology of cancer in 23 centres of 10 European countries: Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, The Netherlands and the United Kingdom.21, 22 The initial 23 EPIC administrative centres were redefined into 27 centres for the analysis of dietary patterns according to geographical south–north gradient.23 Participants were mostly recruited from the general population residing within defined geographical areas, with some exception: female members of a health insurance company for teachers and school workers (France), women attending mammography screening (Utrecht-The Netherlands; and Florence-Italy), and mostly blood donors (centres in Italy and Spain). In the United Kingdom, a ‘health-conscious’ group involving mainly vegetarians, essentially from Oxford, was considered separately from a ‘general population’ group recruited by general practitioners in Cambridge and Oxford.22 The cohorts in France, Norway, Utrecht (The Netherlands) and Naples (Italy) recruited only women. All participants provided written informed consent, and the EPIC study was approved by the ethical review boards of all local recruiting institutions.
The EPIC calibration study designed to correct measurement error on baseline dietary intake measurements was carried out between 1995 and 2000, and has been described elsewhere.23 Briefly, a stratified random sample (n=36 994) by age, sex and centre, and weighted for expected cancer cases in each stratum of the whole cohort was selected for a single 24-hour dietary recall (24-HDR) interview. We excluded 941 participants younger than 35 or older than 74 years of age as participation in these age groups was too low to describe intakes across centres meaningfully. After further exclusion of 16 participants who did not complete food frequency questionnaires, a total of 36 037 participants were finally included in this analysis.
Dietary and lifestyle information
Dietary data of the 24-HDR was administered by trained dieticians using EPIC-Soft, a standardized computerized interview programe developed specifically for the EPIC calibration study.24, 25 The 24-HDR was administered in a face-to-face interview, except in Norway, where it was obtained by telephone interview.
Data on other lifestyle factors, including educational level, total physical activity and smoking history, were collected at baseline through standardized questionnaires, and have been described elsewhere.22, 23, 26 Data on age, body weight and height were self-reported by the participants during the 24-HDR interview. The mean time interval between these baseline questionnaire measures and the 24-HDR interview varied by country, from 1 day to 3 years later.23
We developed an ad hoc phytoestrogen FCDB based on data from the US Department of Agriculture database on isoflavones updated in 20083 and expanded with the Phenol-Explorer database on polyphenols released in 2009,27 which provide exhaustive and worldwide food composition data published to date on flavonoids/polyphenols. Moreover, our FCDB was also expanded with phytoestrogen data from specific countries such as the UK,4 The Netherlands7 and Canada.28 Approximately, 8.6%, 0.1% and 23.1% of our database come from USDA, Phenol-Explorer and the other publications, respectively. Unavailable values were estimated, as far as possible, using recipes (15.7%), estimations by similar food (25.3%) or food group items (2.5%) and logical zeros (16.5%), as in the previous studies.29, 30 The variation in phytoestrogen content of foods after cooking is generally minimal;31 therefore we did not apply any retention factors. Finally, the FCDB created contained a total of 1877 food items and only 8.2% had unknown values, which are calculated as a zero by default.
Dietary phytoestrogen intake was estimated for five major subclasses and their 13 components in each subclass: isoflavones (daidzein, genistein, glycitein, biochanin A and formononetin), lignans (secoisolariciresinol, matairesinol, lariciresinol and pinoresinol), coumestans (coumestrol), enterolignans (enterolactone and enterodiol) and equol. Phytoestrogens are expressed as phytoestrogen aglycones per 100 mg of fresh weight and are calculated as the sum of the available forms (glycosides and aglycones) in the literature.
Dietary intake data are shown as means (least square means) and s.e. stratified by sex and by 27 redefined EPIC centres ordered geographically from south to north. The mean intake data were adjusted for age and weighted by season and day of the recall using generalized linear modelling. The contribution of the individual phytoestrogen to the subgroup and total intake, as well as the contribution of the subgroup to total intake, was calculated as a percentage. The contribution of each food group to the total intake of phytoestrogens was also computed as a percentage. Differences in phytoestrogen intake stratified by sex were also compared by the categories of age (35–44, 45–54, 55–64, 65–74), educational level (none, primary completed, technical/professional, secondary school and university degree), smoking status (never smoker, current smoker and former smoker), level of physical activity (inactive, moderately inactive, moderately active and active), body mass index (BMI; <25, 25 to <30, ⩾30 kg/m2) and European region (Mediterranean (MED) countries: all centres in Greece, Spain, Italy and the South of France; non-MED countries: all centres in the North-East and North-West of France, Germany, The Netherlands, Denmark, Sweden and Norway; United Kingdom general population; and finally United Kingdom health-conscious group). We used these four European regions because in the UK, regular flour is supplemented with soy flour (one of the richest sources of isoflavones) in the elaboration of breads, cakes and biscuits.32 Moreover, the UK health-conscious group form a distinct subgroup with higher consumptions of fruit, vegetables, legumes, nuts and seeds, cereals and soy products compared with the other EPIC centres.33 These models were adjusted for sex, age, centre, BMI and energy intake. All models were weighted by season and day of the week of the 24-HDR using generalized linear models to control for different distributions of 24-HDR interviews across seasons and days of the week. P-values <0.05 (two-tailed) were considered statistically significant. All analyses were conducted using the SPSS Statistics software (version 17.0, SPSS Inc., Chicago, IL, USA).
The mean daily intake of total phytoestrogens ranged from 1.29 mg/day (Greece) to 24.90 mg/day (UK health-conscious cohort) in men (Table 1a) and from 0.99 mg/d (Granada, Spain) to 21.05 mg/d (UK health-conscious cohort) in women (Table 1b). For both sexes, the UK health-conscious group had the highest intake of isoflavones, lignans and coumestans. The highest enterolignan and equol intake was reported in Umea (Sweden) in men. For women, the highest enterolignan and equol intakes were reported in Asturias (Spain) and in North-East of France, respectively. Whereas for both sexes, the UK health-conscious group and Ragussa (Italy) had the lowest intakes of enterolignans and equol. Greek men had the lowest intakes of total isoflavones and coumestans; Spanish (Asturias) of lignans. For women, the lowest intakes of isoflavones, lignans and coumestans were observed in San Sebastian and Asturias of Spain and in Greece, respectively. Annexes 1 and 2 show the mean intakes and s.e. for individual phytoestrogens stratified by centre, adjusted for age and sex and weighted for season and day of the week.
In MED and non-MED countries, the main contributing phytoestrogens were the group of lignans (58.1–67.3%) and isoflavones (30.4–37.9%) then followed by coumestans (1.5–3.3%), enterolignans (0.7–0.8%) and equol (0.2–0.3%) (Table 2). However, in both UK centres, the highest contributors were isoflavones (58.4–86.9%) followed by lignans (11.1–39.0%), coumestans (2.0–2.2%), enterolignans (<0.4%) and equol (<0.12%).
Table 3 shows the evaluation of the effect of sociodemographic, lifestyle and anthropometric characteristics on phytoestrogen intake adjusted for age, sex, centre, energy and BMI and weighted for season and day of the week. Men had a statistically significant higher intake of lignans than women (1.22 vs 1.18 mg/day), but less of enterolignans (0.013 vs 0.014 mg/day) and equol (0.004 vs 0.005 mg/day). There were no statistically significant differences in total phytoestrogen, isoflavone and coumestan intakes between the sexes. Participants who were between 45 and 64 years had the highest intakes of total phytoestrogens, isoflavones, lignans and coumestans. Northern European countries (non-MED countries) had higher intakes of total phytoestrogens, isoflavones, lignans and coumestans than southern countries (MED countries), with a maximum intake in the UK, especially in the UK health-conscious group, was observed. Decreasing intake gradients when assessing total phytoestrogens and some phytoestrogen subgroups in relation to increasing categories of BMI, were observed. Levels of intake of phytoestrogens overall and of isoflavones did not vary significantly by educational level, smoking status and physical activity and phytoestrogen and isoflavone intakes were observed. Physically active individuals, non-smokers and participants with a higher level of education had higher intakes of lignans, enterolignans and equol. However, for coumestans the opposite occurred.
Soy products were the most abundant food sources of phytoestrogens overall (79.6%), isoflavones (89.9%) and coumestans (82.2%) in the UK health-conscious group. In the MED and non-MED countries and UK general population the sources were more varied, with vegetables, fruits, cereals, non-alcoholic (coffee and tea) and alcoholic beverages (wines, beers and ciders), and soy products being important contributors (up to 30% each) (Table 4). For MED countries, the major food sources of lignans were fruits, vegetables, beverages and cereal products, whereas for non-MED countries, they were beverages, vegetables, cereals products and fruits. For both UK centres, they were beverages, vegetables, fruits, nuts and seeds, and cereals products. For MED and non-MED countries, coffee was the most important contributors of coumestans, whereas for the UK general population, the highest food source was the cereal and cereals products. Dairy products were by far the most important contributor to enterolignans and equol intakes in all regions (82.3–92.1%), although intakes of both were low across nearly all centres.
To our knowledge, this is the first study to describe the total, subgroup and individual phytoestrogen intakes and their food sources in a large adult European cohort, comparing intakes within 10 European countries and by individual and lifestyle characteristics. The use of a unique and updated FCDB and a standardized 24-HDR for the entire study facilitated the comparison across countries and thus reduces the error in testing for the potential relationships between phytoestrogen intake and diseases.
The highest intake of phytoestrogen was in the UK health-conscious group (22.41 mg/day). MED countries had the lowest phytoestrogen intake (1.52 mg/day), followed by non-MED countries (2.11 mg/day) and UK general population (4.04 mg/day), showing similar results as those published in individual European countries, such as The Netherlands,34 Sweden35, 36 and UK4 (0.58–3.17 mg/day), and in the US (1.11–2.02 mg/day)37 or Canada (1.17 mg/day).20 The UK health-conscious cohort is made up predominantly of lacto-ovo vegetarians and vegans; therefore they consume more plant foods, especially soy products that are the most abundant food sources of phytoestrogens.33 Despite this, phytoestrogen intake was not statistically associated with healthy lifestyle characteristics, such as be active physical activity or never smoker, in the whole cohort. Our results are in concordance with previous results using plasma phytoestrogen concentrations in a sub-sample within the EPIC-Europe cohort.38
Many publications have estimated isoflavone intake, although most of them have only assessed the main isoflavones (daidzein and genistein). In our study, these contributed between 77 and 91% to the total isoflavone intake. MED countries had the lowest isoflavone intake (0.47 mg/day), but it was higher than previously reported (0.03–0.29 mg/day).39, 40, 41, 42 The lower values obtained in both Greek42 and Spanish39 EPIC studies were probably because of the fact that neither the Phenol-Explorer database27 nor the UK composition data4 were accounted for. Moreover, the present study was based on a single 24 h recall, which may be more efficient in capturing foods rich in major phytoestrogens that are rarely consumed, notably soy-rich products, but only at population level. Non-MED countries had slightly higher, though still relatively low levels of estimated isoflavone intake (0.76 mg/day), which is comparable to other reported data (from 0.23 to 0.96 mg/day).4, 34, 35, 43 These low intakes are consistent with estimates for other Western countries such as Canada (0.31 mg/day)20 and US (around 1.1 mg/day).37, 44 In the UK general population, the isoflavone intake was also higher (2.34 mg/day) compared with other European countries because of the addition of soy flour to regular flour used in baking.32 Therefore, cereals and cereals products, sugar and confectionary, cakes and biscuits contributed 69.1% of the total isoflavone intake. Isoflavone intake in vegetarians is higher than in non-vegetarians, as was observed in the health-conscious cohort in the present study (19.4 mg/day) and in a former UK study (10.1 mg/day), which includes a subset of participants from the current study.43 Nevertheless, Chinese and Japanese populations still have the highest isoflavone intakes worldwide (ranging from 27.1 to 68.6 mg/day).45, 46, 47, 48 Asian populations consume more soy products, which are by far the most important food source of isoflavones in all the studies. However, the dietary habits of Asian immigrant populations living in America and Europe are becomimg more westernized and this may explain a twofold decrease in isoflavone intake observed in Japanese Brazilians46 and a fourfold decrease in intake observed in Japanese women living in the US.49
Lignans were the most abundant contributor of phytoestrogens in those with low phytoestrogen intakes, and the second highest contributor in those with a high intake, such as the UK centres. MED countries had a low lignan intake (1.02 mg/day), but higher than that reported in an Italian study (0.67 mg/day).50 Non-MED countries and the UK general population had slightly higher intakes of lignans (1.26–1.60 mg/day) than MED countries (1.02 mg/day). This is similar to the intake previously reported in The Netherlands (1.24 mg/day),19 Sweden (0.50–2.81 mg/day)35, 36 and Finland (1.22 mg/day).51 In other Western countries such as Mexico, US and Canada, lignan intakes were much lower than our results (from 0.35 to 0.86 mg/day).20, 37, 52 To our knowledge, there are not descriptive data on dietary lignan intake in Asian populations, but probably their contribution to the total phytoestrogen intake would be low like in our UK health-conscious group (<16%). Several papers have reported on intakes of secoisolariciresinol and matairesinol,34, 60 but most of them did not consider lariciresinol and pinoresinol, which contributed >70% to the total lignans in our cohort. Other lignans, such as syringaresinol and medioresinol have also been described, but to date, there is little food composition data for them. These lignans have a low conversion degree into enterolignans (<15%) compared with the other precursors described previously.9 Food sources of lignans varied depending on the region. Fruits, vegetables and wine were the most abundant sources in MED countries. On the other hand, the highest contributors were vegetables, cereal and cereals products, tea coffee and fruits in non-MED countries. Likewise, in Northern European countries (UK, The Netherlands, Sweden and Canada) flaxseed, bread, tea, and some vegetables and fruits have also described in the literature as the main food sources.19, 36, 53, 54
Lignans are the precursors of enterolignans, but enterolignans can also occur in animal-derived foods after their transformation by the intestinal microbiota. Therefore, their main food source was dairy products, so the intake differences across centres were equivalent to the consumption of dairy product previously observed in EPIC.55 Our results were higher than those reported in the literature (0.01–0.02 mg/day).4, 35, 36 Enterolactone is the main contributor in all the studies, whereas enterodiol was an extremely minor enterolignan contributor (<0.3%).
Equol is also a metabolite formed by the intestinal microbiota, but from daidzein. Equol intake (ranged from 0.003 to 0.005 mg/day) in our study was similar to that reported for the EPIC-Norfolk cohort (0.004 mg/day).4 However, two Swedish studies have reported lower equol intakes (about 0.001 mg/day).35, 36 Dairy products were by far the most food source of equol intake in all regions; therefore its intake variance was similar to the dairy product consumption in EPIC centres.55
Coumestrol is the most common coumestan. MED countries had the lowest intake of coumestrol (0.02 mg/day) preceded by non-MED countries (0.07 mg/day) and the UK general population group (0.09 mg/day). Finally, the UK health-conscious group (0.44 mg/day) had the highest coumestrol intake because soy products were the main food sources in their diets. According to our data, coffee is the main source of coumestrol in diets low in soy, which is in line with previously published data from the USDA.3 It is noteworthy that values reported by others are at least 10-fold lower compared with our data, ranging from 0.0005 to 0.006 mg/day,4, 20, 36, 37, 52 except for those reported in a US case-control study (0.19 mg/day).56
The incidence rates for hormone-related cancers, especially breast cancer, in Asian countries have been much lower (up to sixfold) than those in Western countries.57 Soy products and isoflavones/phytoestrogens, which are widely consumed in Asian countries, have been extensively assessed as possibly being responsible for these beneficial effects. Even if phytoestrogens are absorbed from the gut in tiny amounts,8, 58 their effects on health may be significant.59 However, this is not always consistent, especially in populations with low phytoestrogen intakes.8, 13, 60, 61 The possible mechanism of action through which phytoestrogens may act is often related with their weak estrogenic activity,4 but it has even been suggested that phytoestrogens might simply reflect a healthy lifestyle.8 In our study, healthy lifestyle and anthropometric characteristics, which have been associated with risk of hormone-related diseases, were statistically associated with lignans, enterolignans and equol, but no differences were shown for total phytoestrogens, isoflavones or coumestans.
This is a large study estimating the phytoestrogen intake across European countries. However, as not all the EPIC cohorts are population based, the findings on intake cannot be extrapolated to the general population of each region.62 Dietary data was collected ∼10 years ago therefore the current phytoestrogen intake may be higher because soy products and soy-supplemented foods are now more available in Europe. Another limitation of this study is that each person contributed only one 24-HDR, hence variation in intakes cannot be evaluated at the individual level, especially when less frequently consumed foods, such as soy-rich products, are concerned. However, 24-HDRs are considered an acceptable method for estimating population mean intakes.63 Furthermore, the sampling of the EPIC calibration study was designed to control for seasonal and day-of-the-week variations in dietary intake.23 Thus, it is reasonable to expect that the population mean will not be too much influenced by day-to-day or seasonal variability. Underestimation of total phytoestrogen intake may also occur because of the unknown composition data, especially for the newly available soy-supplemented products. However, our database was compiled from the most updated polyphenol databases, with 1877 food items and only 8% of missing values. Indeed, the major strength of the present study is the use of a unique and specifically developed FCDB on phytoestrogens, for that allowed results to be compared across countries. Further underestimation may be due to the omission of herb/plant supplements in this analysis (up to 5% of the consumers in Denmark, the highest consumer country).64
In summary, the data presented in this study show the mean intake of phytoestrogens (isoflavones, lignans, coumestans, enterolignans and equol) and their food sources in 10 European countries. The used FCDB comprises the most updated and available worldwide data on phytoestrogen in foods. Lignan, enterolignan and equol intakes were related with healthy lifestyle habits (non-smoking status, BMI, educational level and physical activity), but not total phytoestrogens (except BMI), isoflavones or coumestans. These data provide a useful basis for the further exploration of associations between phytoestrogen intake and disease risk.
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This work was carried out with the financial support of the European Commission: Public Health and Consumer Protection Directorate 1993 to 2004; Research Directorate-General 2005; Ligue contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM; France); German Federal Ministry of Education and Research; Danish Cancer Society: Health Research Fund (FIS) of the Spanish Ministry of Health (RTICC DR06/0020); the participating regional governments and institutions of Spain; Cancer Research UK; Medical Research Council, UK; the Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; the Wellcome Trust, UK; the Stavros Niarchos Foundation and the Hellenic Health Foundation; Italian Association for Research on Cancer; Compagnia San Paolo, Italy; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Nordforsk - Centre of Excellence programe HELGA; Some authors are partners of ECNIS, a network of excellence of the 6FP of the EC. RZR is thankful for a postdoctoral programe Fondo de Investigación Sanitaria (FIS; no. CD09/00 133) from the Spanish Ministry of Science and Innovation. We thank Raul M. García for developing an application to link the FCDB and the 24-HDR. We would also like to thank Marleen Lentjes, Veronica van Scheltinga, Alison McTaggart and Amit Bhaniani for their invaluable contributions to the creation of the EPIC-Norfolk phytoestrogen database.
The authors declare no conflict of interest.
Contributors: RZ-R and CAG designed the research; RZ-R. and VK conducted the research; RZ-R and LL-B performed the statistical analysis; RZ-R wrote the manuscript; all authors read, critically reviewed and approved the final manuscript.
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Zamora-Ros, R., Knaze, V., Luján-Barroso, L. et al. Dietary intakes and food sources of phytoestrogens in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort. Eur J Clin Nutr 66, 932–941 (2012). https://doi.org/10.1038/ejcn.2012.36
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