Human metabolic phenotype diversity and its association with diet and blood pressure.

Metabolic phenotypes are the products of interactions among a variety of factors-dietary, other lifestyle/environmental, gut microbial and genetic. We use a large-scale exploratory analytical approach to investigate metabolic phenotype variation across and within four human populations, based on 1H NMR spectroscopy. Metabolites discriminating across populations are then linked to data for individuals on blood pressure, a major risk factor for coronary heart disease and stroke (leading causes of mortality worldwide). We analyse spectra from two 24-hour urine specimens for each of 4,630 participants from the INTERMAP epidemiological study, involving 17 population samples aged 40-59 in China, Japan, UK and USA. We show that urinary metabolite excretion patterns for East Asian and western population samples, with contrasting diets, diet-related major risk factors, and coronary heart disease/stroke rates, are significantly differentiated (P < 10(-16)), as are Chinese/Japanese metabolic phenotypes, and subgroups with differences in dietary vegetable/animal protein and blood pressure. Among discriminatory metabolites, we quantify four and show association (P < 0.05 to P < 0.0001) of mean 24-hour urinary formate excretion with blood pressure in multiple regression analyses for individuals. Mean 24-hour urinary excretion of alanine (direct) and hippurate (inverse), reflecting diet and gut microbial activities, are also associated with blood pressure of individuals. Metabolic phenotyping applied to high-quality epidemiological data offers the potential to develop an area of aetiopathogenetic knowledge involving discovery of novel biomarkers related to cardiovascular disease risk.

A nutrient-wide association study on blood pressure.

BACKGROUND: A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. METHODS AND RESULTS: Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. CONCLUSIONS: We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

Estimating 24-hour urinary sodium excretion from casual urinary sodium concentrations in Western populations: the INTERSALT study.

High intakes of dietary sodium are associated with elevated blood pressure levels and an increased risk of cardiovascular disease. National and international guidelines recommend reduced sodium intake in the general population, which necessitates population-wide surveillance. We assessed the utility of casual (spot) urine specimens in estimating 24-hour urinary sodium excretion as a marker of sodium intake in the International Cooperative Study on Salt, Other Factors, and Blood Pressure. There were 5,693 participants recruited in 1984-1987 at the ages of 20-59 years from 29 North American and European samples. Participants were randomly assigned to test or validation data sets. Equations derived from casual urinary sodium concentration and other variables in the test data were applied to the validation data set. Correlations between observed and estimated 24-hour sodium excretion were 0.50 for individual men and 0.51 for individual women; the values were 0.79 and 0.71, respectively, for population samples. Bias in mean values (observed minus estimated) was small; for men and women, the values were -1.6 mmol per 24 hours and 2.3 mmol per 24 hours, respectively, at the individual level and -1.8 mmol per 24 hours and 2.2 mmol per 24 hours, respectively, at the population level. Proportions of individuals with urinary 24-hour sodium excretion above the recommended levels were slightly overestimated by the models. Casual urine specimens may be a useful, low-burden, low-cost alternative to 24-hour urine collections for estimation of population sodium intakes; ongoing calibration with study-specific 24-hour urinary collections is recommended to increase validity.

A comparison of self-reported analgesic use and detection of urinary ibuprofen and acetaminophen metabolites by means of metabonomics: the INTERMAP Study.

Information on dietary supplements, medications, and other xenobiotics in epidemiologic surveys is usually obtained from questionnaires and is subject to recall and reporting biases. The authors used metabolite data obtained from hydrogen-1 (or proton) nuclear magnetic resonance ((1)H NMR) analysis of human urine specimens from the International Study of Macro-/Micro-Nutrients and Blood Pressure (INTERMAP Study) to validate self-reported analgesic use. Metabolic profiling of two 24-hour urine specimens per individual was carried out for 4,630 participants aged 40-59 years from 17 population samples in Japan, China, the United Kingdom, and the United States (data collection, 1996-1999). (1)H NMR-detected acetaminophen and ibuprofen use was low (∼4%) among East Asian population samples and higher (>16%) in Western population samples. In a comparison of self-reported acetaminophen and ibuprofen use with (1)H NMR-detected acetaminophen and ibuprofen metabolites among 496 participants from Chicago, Illinois, and Belfast, Northern Ireland, the overall rate of concordance was 81%-84%; the rate of underreporting was 15%-17%; and the rate of underdetection was approximately 1%. Comparison of self-reported unspecified analgesic use with (1)H NMR-detected acetaminophen and ibuprofen metabolites among 2,660 Western INTERMAP participants revealed similar levels of concordance and underreporting. Screening for urinary metabolites of acetaminophen and ibuprofen improved the accuracy of exposure information. This approach has the potential to reduce recall bias and other biases in epidemiologic studies for a range of substances, including pharmaceuticals, dietary supplements, and foods.

Nutrient and food intakes of middle-aged adults at low risk of cardiovascular disease: the international study of macro-/micronutrients and blood pressure (INTERMAP).

PURPOSE: Individuals with favorable levels of readily measured cardiovascular disease (CVD) risk factors (low risk, LR) experience low long-term rates of CVD mortality and greater longevity. The purpose of the current study was to compare nutrient/food intakes of LR participants with participants not LR in the INTERMAP study. METHODS: Men and women (40-59 years) from 17 population samples in four countries (China, Japan, UK, US) provided four 24-h dietary recalls and two timed 24-h urine collections. LR was defined as meeting all of the following CVD risk criteria: systolic/diastolic blood pressure (BP) ≤ 120/ ≤ 80 mmHg; no drug treatment for high BP, hyperlipidemia, or CVD; non-smoking; BMI <25.0 kg/m(2) (US, UK) or <23.0 kg/m(2) (China, Japan); alcohol consumption <26.0 g/day (men)/<13.0 g/day (women); and no history of diabetes or CVD. Multivariate logistic regression was used to examine associations of nutrient/food intakes with LR. RESULTS: LR individuals reported higher intake of vegetable protein, fiber, magnesium, non-heme iron, potassium; lower energy intake; lower intake of cholesterol, saturated fatty acids, animal protein; and lower 24-h urinary sodium compared with individuals not LR. With regard to foods, LR individuals reported higher intake of fruits, vegetables, grains, pasta/rice, fish; lower intakes of meats, processed meats, high-fat dairy, and sugar-sweetened beverages than individuals not LR. CONCLUSIONS: Lower energy intake and differential intake of multiple specific nutrients and foods are characteristic of individuals at low risk for developing CVD. Identification of dietary habits associated with LR is important for further development of public health efforts aimed at reduction/prevention of CVD.

The role of a changing Arctic Ocean and climate for the biogeochemical cycling of dimethyl sulphide and carbon monoxide.

Dimethyl sulphide (DMS) and carbon monoxide (CO) are climate-relevant trace gases that play key roles in the radiative budget of the Arctic atmosphere. Under global warming, Arctic sea ice retreats at an unprecedented rate, altering light penetration and biological communities, and potentially affect DMS and CO cycling in the Arctic Ocean. This could have socio-economic implications in and beyond the Arctic region. However, little is known about CO production pathways and emissions in this region and the future development of DMS and CO cycling. Here we summarize the current understanding and assess potential future changes of DMS and CO cycling in relation to changes in sea ice coverage, light penetration, bacterial and microalgal communities, pH and physical properties. We suggest that production of DMS and CO might increase with ice melting, increasing light availability and shifting phytoplankton community. Among others, policy measures should facilitate large-scale process studies, coordinated long term observations and modelling efforts to improve our current understanding of the cycling and emissions of DMS and CO in the Arctic Ocean and of global consequences.

Relation of urinary calcium and magnesium excretion to blood pressure: The International Study Of Macro- And Micro-nutrients And Blood Pressure and The International Cooperative Study On Salt, Other Factors, And Blood Pressure.

Data indicate an inverse association between dietary calcium and magnesium intakes and blood pressure (BP); however, much less is known about associations between urinary calcium and magnesium excretion and BP in general populations. The authors assessed the relation of BP to 24-hour excretion of calcium and magnesium in 2 cross-sectional studies. The International Study of Macro- and Micro-Nutrients and Blood Pressure (INTERMAP) comprised 4,679 persons aged 40-59 years from 17 population samples in China, Japan, the United Kingdom, and the United States, and the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT) comprised 10,067 persons aged 20-59 years from 52 samples around the world. Timed 24-hour urine collections, BP measurements, and nutrient data from four 24-hour dietary recalls (INTERMAP) were collected. In multiple linear regression analyses, urinary calcium excretion was directly associated with BP. After adjustment for multiple confounders (including weight, height, alcohol intake, calcium intake, urinary sodium level, and urinary potassium intake), systolic BP was 1.9 mm Hg higher per each 4.1 mmol per 24 hours (2 standard deviations) of higher urinary calcium excretion (associations were smaller for diastolic BP) in INTERMAP. Qualitatively similar associations were observed in INTERSALT analyses. Associations between magnesium excretion and BP were small and nonsignificant for most of the models examined. The present data suggest that altered calcium homoeostasis, as exhibited by increased calcium excretion, is associated with higher BP levels.

Natural variability in air-sea gas transfer efficiency of CO2.

The flux of CO2 between the atmosphere and the ocean is often estimated as the air-sea gas concentration difference multiplied by the gas transfer velocity (K660). The first order driver for K660 over the ocean is wind through its influence on near surface hydrodynamics. However, field observations have shown substantial variability in the wind speed dependencies of K660. In this study we measured K660 with the eddy covariance technique during a ~ 11,000 km long Southern Ocean transect. In parallel, we made a novel measurement of the gas transfer efficiency (GTE) based on partial equilibration of CO2 using a Segmented Flow Coil Equilibrator system. GTE varied by 20% during the transect, was distinct in different water masses, and related to K660. At a moderate wind speed of 7 m s-1, K660 associated with high GTE exceeded K660 with low GTE by 30% in the mean. The sensitivity of K660 towards GTE was stronger at lower wind speeds and weaker at higher wind speeds. Naturally-occurring organics in seawater, some of which are surface active, may be the cause of the variability in GTE and in K660. Neglecting these variations could result in biases in the computed air-sea CO2 fluxes.

Metabolic profiling and the metabolome-wide association study: significance level for biomarker identification.

High throughput metabolic profiling via the metabolome-wide association study (MWAS) is a powerful new approach to identify biomarkers of disease risk, but there are methodological challenges: high dimensionality, high level of collinearity, the existence of peak overlap within metabolic spectral data, multiple testing, and selection of a suitable significance threshold. We define the metabolome-wide significance level (MWSL) as the threshold required to control the family wise error rate through a permutation approach. We used 1H NMR spectroscopic profiles of 24 h urinary collections from the INTERMAP study. Our results show that the MWSL primarily depends on sample size and spectral resolution. The MWSL estimates can be used to guide selection of discriminatory biomarkers in MWA studies. In a simulation study, we compare statistical performance of the MWSL approach to two variants of orthogonal partial least-squares (OPLS) method with respect to statistical power, false positive rate and correspondence of ranking of the most significant spectral variables. Our results show that the MWSL approach as estimated by the univariate t test is not outperformed by OPLS and offers a fast and simple method to detect disease-related discriminatory features in human NMR urinary metabolic profiles.

Metabolome-wide association study identifies multiple biomarkers that discriminate north and south Chinese populations at differing risks of cardiovascular disease: INTERMAP study.

Rates of heart disease and stroke vary markedly between north and south China. A (1)H NMR spectroscopy-based metabolome-wide association approach was used to identify urinary metabolites that discriminate between southern and northern Chinese population samples, to investigate population biomarkers that might relate to the difference in cardiovascular disease risk. NMR spectra were acquired from two 24-h urine specimens per person for 523 northern and 244 southern Chinese participants in the INTERMAP Study of macro/micronutrients and blood pressure. Discriminating metabolites were identified using orthogonal partial least squares discriminant analysis and assessed for statistical significance with conservative family wise error rate < 0.01 to minimize false positive findings. Urinary metabolites significantly (P < 1.2 × 10(-16) to 2.9 × 10(-69)) higher in northern than southern Chinese populations included dimethylglycine, alanine, lactate, branched-chain amino acids (isoleucine, leucine, valine), N-acetyls of glycoprotein fragments (including uromodulin), N-acetyl neuraminic acid, pentanoic/heptanoic acid, and methylguanidine; metabolites significantly (P < 1.1 × 10(-12) to 2 × 10(-127)) higher in the south were gut microbial cometabolites (hippurate, 4-cresyl sulfate, phenylacetylglutamine, 2-hydroxyisobutyrate), succinate, creatine, scyllo-inositol, prolinebetaine, and trans-aconitate. These findings indicate the importance of environmental influences (e.g., diet), endogenous metabolism, and mammalian-gut microbial cometabolism, which may help explain north-south China differences in cardiovascular disease risk.

Glutamic acid, the main dietary amino acid, and blood pressure: the INTERMAP Study (International Collaborative Study of Macronutrients, Micronutrients and Blood Pressure).

BACKGROUND: Data are available that indicate an independent inverse relationship of dietary vegetable protein to the blood pressure (BP) of individuals. Here, we assess whether BP is associated with glutamic acid intake (the predominant dietary amino acid, especially in vegetable protein) and with each of 4 other amino acids that are relatively higher in vegetable than animal protein (proline, phenylalanine, serine, and cystine). METHODS AND RESULTS: This was a cross-sectional epidemiological study with 4680 persons 40 to 59 years of age from 17 random population samples in China, Japan, the United Kingdom, and the United States. BP was measured 8 times at 4 visits; dietary data (83 nutrients, 18 amino acids) were obtained from 4 standardized, multipass, 24-hour dietary recalls and 2 timed 24-hour urine collections. Dietary glutamic acid (percentage of total protein intake) was inversely related to BP. Across multivariate regression models (model 1, which controlled for age, gender, and sample, through model 5, which controlled for 16 possible nonnutrient and nutrient confounders), estimated average BP differences associated with a glutamic acid intake that was higher by 4.72% of total dietary protein (2 SD) were -1.5 to -3.0 mm Hg systolic and -1.0 to -1.6 mm Hg diastolic (z scores -2.15 to -5.11). Results were similar for the glutamic acid-BP relationship with each of the other amino acids also in the model; eg, with control for 15 variables plus proline, systolic/diastolic pressure differences were -2.7/-2.0 mm Hg (z scores -2.51, -2.82). In these 2-amino acid models, higher intake (by 2 SD) of each of the other amino acids was associated with small BP differences and z scores. CONCLUSIONS: Dietary glutamic acid may have independent BP-lowering effects, which may contribute to the inverse relation of vegetable protein to BP.

Dietary starch intake of individuals and their blood pressure: the International Study of Macronutrients and Micronutrients and Blood Pressure.

OBJECTIVE: Data from the Multiple Risk Factor Intervention Trial show an independent direct association between starch intake and blood pressure in American men at higher risk of coronary heart disease. Cross-sectional data from the International Study of Macronutrients and Micronutrients and Blood Pressure (INTERMAP) were used to assess relations of dietary starch intake to blood pressure in men and women from four countries. METHODS: Data include 83 nutrients from four multipass 24-h dietary recalls and two timed 24-h urine collections; eight blood pressure readings; and questionnaire data, for 4680 participants aged 40-59 years from 17 population samples in Japan, People's Republic of China, United Kingdom, and United States of America. RESULTS: In multiple linear regression analyses--adjusted for urinary sodium, urinary potassium, consumption of alcohol, cholesterol, saturated fatty acids, polyunsaturated fatty acids, calcium, and other variables--starch intake higher by two standard deviations (14.1% kJ) was associated with systolic/diastolic blood pressure differences of -1.0/-0.9 mmHg (P = 0.09, P < 0.05). Results were similar with additional control for fiber, magnesium, or phosphorus; reduced to -0.5/-0.7 mmHg (P = 0.47, P = 0.13) with separate adjustment for vegetable protein. Findings were similar for men analyzed separately, for American men, and for American men at higher coronary heart disease risk. CONCLUSION: Our findings indicate that--if any--relations of starch intake to blood pressure are modestly inverse. Current dietary guidelines for hypertension prevention and control remain relevant.

Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

CONTEXT: Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. OBJECTIVE: To investigate association of genetic loci with CRP levels and risk of coronary heart disease. DESIGN, SETTING, AND PARTICIPANTS: We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. MAIN OUTCOME MEASURE: Risk of coronary heart disease. RESULTS: Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. CONCLUSION: The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

The impact of eating frequency and time of intake on nutrient quality and Body Mass Index: the INTERMAP Study, a Population-Based Study.

BACKGROUND: Epidemiologic evidence is sparse on the effect of dietary behaviors and diet quality on body mass index (BMI; calculated as kg/m(2)), which can be important drivers of the obesity epidemic. OBJECTIVE: This study investigated the relationships of frequency of eating and time of intake to energy density, nutrient quality, and BMI using data from the International Study on Macro/Micronutrients and Blood Pressure including 2,696 men and women aged 40 to 59 years from the United States and the United Kingdom. DESIGN: The International Study on Macro/Micronutrients and Blood Pressure is a cross-sectional investigation with four 24-hour dietary recalls and BMI measurements conducted between 1996 and 1999. Consumption of solid foods was aggregated into eating occasion. Nutrient density is expressed using the Nutrient Rich Food Index 9.3. The ratio of evening/morning energy intake was calculated; mean values of four visits were used. STATISTICAL ANALYSES PERFORMED: Characteristics across eating occasion categories are presented as adjusted mean with corresponding 95% CI. Multiple linear regression models were used to examine associations of eating occasions, ratio of evening/morning energy intake, dietary energy density, and Nutrient Rich Food Index 9.3 with BMI. RESULTS: Compared to participants with fewer than four eating occasions in 24 hours, those with six or more eating occasions in 24 hours had lower mean BMI (27.3 vs 29.0), total energy intake (2,129 vs 2,472 kcal/24 hours), dietary energy density (1.5 vs 2.1 kcal/g), and higher Nutrient Rich Food Index 9.3 (34.3 vs 28.1). In multiple regression analyses, higher evening intake relative to morning intake was directly associated with BMI; however, this did not influence the relationship between eating frequency and BMI. CONCLUSIONS: Our results suggest that a larger number of small meals may be associated with improved diet quality and lower BMI. This may have implications for behavioral approaches to controlling the obesity epidemic.

Individual efforts to reduce salt intake in China, Japan, UK, USA: what did people achieve? The INTERMAP Population Study.

OBJECTIVE: Habitual high-salt intake raises blood pressure and risk of cardiovascular diseases. To prevent/control these risks, reduced salt diet (RSD) is recommended in many countries and some people report practicing it; however, little is known about actual achievement. This population-based study assessed level of 24-h dietary sodium intake of participants reporting RSD and others. METHOD: Participants were 4680 men and women ages 40-59 years randomly selected from 17 populations in People's Republic of China (PRC), Japan, UK and USA, for an observational study on diet and blood pressure (INTERMAP). Daily sodium intake was determined by two timed 24-h urine collections. Antihypertensive treatment status and RSD were ascertained by questionnaire. RESULTS: Participants reporting RSD were few; 3.1% (Japan), 1.3% (PRC), 2.5% (UK), 7.2% (USA); 15.1, 7.9, 16.7 and 16.8% of people with treated hypertension. For those reporting RSD, 24-h urinary sodium excretion was significantly, but only modestly lower than for others, by 17.9 mmol/day (Japan), 56.7 (PRC) and 14.7 (USA), but higher by 10.5 in UK. Sodium intakes for participants reporting RSD remained higher than recommended; 181.0 mmol/day (Japan), 171.5 (PRC), 155.2 (UK) and 148.9 (USA). For these people, as for others, main sources of salt were processed foods in Japan, UK and USA; in PRC, salt added in preparation at home. CONCLUSION: Enhanced sustained efforts are needed to raise general awareness of the harmful effects of salt on health and the benefits of salt reduction. Population approaches are needed to reduce salt content of processed foods and restaurant meals.

Blood pressure differences associated with Optimal Macronutrient Intake Trial for Heart Health (OMNIHEART)-like diet compared with a typical American Diet.

The Dietary Approaches to Stop Hypertension-Sodium (DASH-Sodium) trial demonstrated beneficial effects on blood pressure (BP) of the DASH diet with lower sodium intake when compared with typical American diet. The subsequent Optimal Macronutrient Intake Trial for Heart Health (OMNIHEART) trial reported additional BP benefits from replacing carbohydrate in the DASH diet with either protein or monounsaturated fats. The primary aim of this study is to assess possible BP benefits of an OMNIHEART-like diet in free-living Americans using cross-sectional US population data of the International Study of Macronutrients, Micronutrients and Blood Pressure (INTERMAP) study. The INTERMAP data include four 24-hour dietary recalls, 2 timed 24-hour urine collections, 8 BP readings for 2195 individuals aged 40 to 59 years from 8 US INTERMAP population samples. Analyses are conducted using 2 approaches: (1) regression of BP on a linear OMNIHEART nutrient score calculated for each individual and (2) a Bayesian approach comparing estimated BP levels of an OMNIHEART-like nutrient profile with a typical American nutrient profile. After adjustment for potential confounders, an OMNIHEART score higher by 1 point was associated with systolic/diastolic BP differences of -1.0/-0.5 mm Hg (both P<0.001). Mean systolic/diastolic BPs were 111.3/68.4 and 115.2/70.6 mm Hg for Bayesian OMNIHEART and Control profiles, respectively, after controlling for possible confounders, with BP differences of -3.9/-2.2 mm Hg, P(difference≤0)=0.98/0.96. Findings were comparable for men and women, for nonhypertensive participants, and with adjustment for antihypertensive treatment. Our findings from data on US population samples indicate broad generalizability of OMNIHEART results beyond the trial setting and support recommendations for an OMNIHEART-style diet for prevention/control of population-wide adverse BP levels.

Dietary glycine and blood pressure: the International Study on Macro/Micronutrients and Blood Pressure.

BACKGROUND: Available data have indicated independent direct relations of dietary animal protein and meat to the blood pressure (BP) of individuals. OBJECTIVE: In this study, we aimed to assess whether BP is associated with the intake of dietary amino acids higher relatively in animal than in vegetable protein (alanine, arginine, aspartic acid, glycine, histidine, lysine, methionine, and threonine). DESIGN: The study was a cross-sectional epidemiologic study that involved 4680 persons aged 40-59 y from 17 random population samples in the People's Republic of China, Japan, the United Kingdom, and the United States. BP was measured 8 times at 4 visits; dietary data (83 nutrients and 18 amino acids) were from four 24-h dietary recalls and two 24-h urine collections. RESULTS: Dietary glycine and alanine (the percentage of total protein intake) were considered singly related directly to BP; with these 2 amino acids together in regression models (from model 1, which was controlled for age, sex, and sample, to model 5, which was controlled for 16 possible confounders), glycine, but not alanine, was significantly related to BP. Estimated average BP differences associated with a 2-SD higher glycine intake (0.71 g/24 h) were 2.0-3.0-mm Hg systolic BP (z = 2.97-4.32) stronger in Western than in East Asian participants. In Westerners, meat was the main dietary source of glycine but not in East Asians (Chinese: grains/flour and rice/noodles; Japanese: fish/shellfish and rice/noodles). CONCLUSION: Dietary glycine may have an independent adverse effect on BP, which possibly contributes to direct relations of animal protein and meat to BP.

Relationship of dietary monounsaturated fatty acids to blood pressure: the International Study of Macro/Micronutrients and Blood Pressure.

OBJECTIVE: In short-term feeding trials, replacement of other macronutrients with monounsaturated fatty acid reduces blood pressure. However, observational studies have not clearly demonstrated a relationship between monounsaturated fatty acid intake and blood pressure. We report associations of monounsaturated fatty acid intake of individuals with blood pressure in a cross-sectional study. METHODS: The International Study of Macro/Micronutrients and Blood Pressure is a cross-sectional epidemiologic study of 4680 men and women ages 40-59 years from 17 population samples in China, Japan, UK and USA. Nutrient intake data were based on four in-depth multipass 24-h dietary recalls/person and two-timed 24-h urine collections/person. Blood pressure was measured eight times at four visits. RESULTS: Mean monounsaturated fatty acid intake ranged from 8.1%kcal (China) to 12.2%kcal (USA). With sequential models to control for possible confounders (dietary, other), linear regression analyses showed significant inverse relationship of total monounsaturated fatty acid intake with DBP for all participants; for 2238 'nonintervened' individuals, the relationship was stronger. Estimated DBP differences with 2-SD higher monounsaturated fatty acids (5.35%kcal) were -0.82 mmHg (P < 0.05) for all participants and -1.70 mmHg (P < 0.01) for nonintervened individuals. Inverse associations of dietary total oleic acid (main monounsaturated) with blood pressure in nonintervened individuals were not significant, but those of oleic acid from vegetable sources were stronger and significant (P < 0.05). CONCLUSION: Dietary monounsaturated fatty acid intake, especially oleic acid from vegetable sources, may contribute to prevention and control of adverse blood pressure levels in general populations.

Dietary and urinary metabonomic factors possibly accounting for higher blood pressure of black compared with white Americans: results of International Collaborative Study on macro-/micronutrients and blood pressure.

Black compared with non-Hispanic white Americans have higher systolic and diastolic blood pressure and rates of prehypertension/hypertension. Reasons for these adverse findings remain obscure. Analyses here focused on relations of foods/nutrients/urinary metabolites and higher black blood pressure for 369 black compared with 1190 non-Hispanic white Americans aged 40 to 59 years from 8 population samples. Multiple linear regression, standardized data from four 24-hour dietary recalls per person, two 24-hour urine collections, and 8 blood pressure measurements were used to quantitate the role of foods, nutrients, and metabolites in higher black blood pressure. Compared with non-Hispanic white Americans, blacks' average systolic/diastolic pressure was higher by 4.7/3.4 mm Hg (men) and 9.0/4.8 mm Hg (women). Control for higher body mass index of black women reduced excess black systolic/diastolic pressure to 6.8/3.8 mm Hg. Lesser intake of vegetables, fruits, grains, vegetable protein, glutamic acid, starch, fiber, minerals, and potassium, and higher intake of processed meats, pork, eggs, and sugar-sweetened beverages, along with higher cholesterol and higher Na/K ratio, related to in higher black blood pressure. Control for 11 nutrient and 10 non-nutrient correlates reduced higher black systolic/diastolic pressure to 2.3/2.3 mm Hg (52% and 33% reduction in men) and to 5.3/2.8 mm Hg (21% and 27% reduction in women). Control for foods/urinary metabolites had little further influence on higher black blood pressure. Less favorable multiple nutrient intake by blacks than non-Hispanic white Americans accounted, at least in part, for higher black blood pressure. Improved dietary patterns can contribute to prevention/control of more adverse black blood pressure levels.

Quantitative UPLC-MS/MS analysis of the gut microbial co-metabolites phenylacetylglutamine, 4-cresyl sulphate and hippurate in human urine: INTERMAP Study.

The role of the gut microbiome in human health, and non-invasive measurement of gut dysbiosis are of increasing clinical interest. New high-throughput methods are required for the rapid measurement of gut microbial metabolites and to establish reference ranges in human populations. We used ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) -- positive and negative electrospray ionization modes, multiple reaction monitoring transitions -- to simultaneously measure three urinary metabolites (phenylacetylglutamine, 4-cresyl sulphate and hippurate) that are potential biomarkers of gut function, among multi-ethnic US men and women aged 40-59 from the INTERMAP epidemiologic study (n = 2000, two timed 24-hr urine collections/person). Metabolite concentrations were quantified via stable isotope labeled internal standards. The assay was linear in the ranges 1ng/mL (lower limit of quantification) to 1000ng/mL (phenylacetylglutamine and 4-cresyl sulfate) and 3ng/mL to 3000ng/mL (hippurate). These quantitative data provide new urinary reference ranges for population-based human samples: mean (standard deviation) 24-hr urinary excretion for phenylacetylglutamine was: 1283.0 (751.7) µmol/24-hr (men), 1145.9 (635.5) µmol/24-hr (women); for 4-cresyl sulphate, 1002.5 (737.1) µmol/24-hr (men), 1031.8 (687.9) µmol/24-hr (women); for hippurate, 6284.6 (4008.1) µmol/24-hr (men), 4793.0 (3293.3) µmol/24-hr (women). Metabolic profiling by UPLC-MS/MS in a large sample of free-living individuals has provided new data on urinary reference ranges for three urinary microbial co-metabolites, and demonstrates the applicability of this approach to epidemiological investigations.