Glutamic Acid, the Main Dietary Amino Acid, and
Blood Pressure
The INTERMAP Study (International Collaborative Study of
Macronutrients, Micronutrients and Blood Pressure)
Jeremiah Stamler, MD*; Ian J. Brown, PhD*; Martha L. Daviglus, MD, PhD; Queenie Chan, MPhil;
Hugo Kesteloot, MD, PhD; Hirotsugu Ueshima, MD, PhD;
Liancheng Zhao, MD; Paul Elliott, MB, PhD;
for the INTERMAP Research Group
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
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. (Circulation. 2009;120:221-228.)
Key Words: amino acids 䡲 glutamic acid 䡲 blood pressure 䡲 nutrition 䡲 epidemiology
T
he population-based International Collaborative Study
of Macronutrients, Micronutrients and Blood Pressure
(INTERMAP) found a significant inverse relation of vegetable protein intake to blood pressure (BP) for individuals.1
Among those who consumed predominantly vegetable protein compared with animal protein, intake of glutamic acid,
the most common dietary amino acid, made up a higher
percentage of total protein, as did (to a lesser degree) cystine,
proline, phenylalanine, and serine. We therefore hypothesized
that the higher the intake of these 5 amino acids, and in
particular, glutamic acid, the lower the BP. Results are
presented here.
Clinical Perspective on p 228
Methods
Basic Premises, Population Samples, and Field
Methods (1996 –1999)
Basic INTERMAP premises are as follows: Multiple nutrients have
small, independent influences on BP that in combination summate as
Received November 27, 2008; accepted May 15, 2009.
From the Department of Preventive Medicine (J.S., M.L.D.), Feinberg School of Medicine, Northwestern University, Chicago, Ill; Department of
Epidemiology and Public Health (I.J.B., Q.C., P.E.), Faculty of Medicine, St Mary’s Campus, Imperial College London, United Kingdom; Central
Laboratory (H.K.), Akademisch Ziekenhuis St. Rafael, Leuven, Belgium; Department of Health Science (H.U.), Shiga University of Medical Science,
Otsu, Japan; and Department of Epidemiology (L.Z.), Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Beijing,
People’s Republic of China.
*Drs Stamler and Brown contributed equally to this work.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.839241/DC1.
Correspondence to Jeremiah Stamler, MD, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N Lake
Shore Dr, Suite 1102, Chicago, IL 60611. E-mail [email protected]
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.839241
221
222
Circulation
July 21, 2009
Table 1. Estimated Mean Difference in BP With Consumption
of Foods Higher by 2 SD in Glutamic Acid (as % Total Protein):
Multiple Regression Analyses
Model
SBP Difference,
mm Hg (z Score)
DBP Difference,
mm Hg (z Score)
Main analyses: All 4680
participants
Table 1.
Continued
SBP Difference,
mm Hg (z Score)
DBP Difference,
mm Hg (z Score)
4
⫺1.20 (⫺2.20)
⫺0.76* (⫺1.88)
5b-Mg
⫺1.65 (⫺2.86)
⫺1.17 (⫺2.75)
Model
Nonhypertensive persons
(n⫽3671)
1
⫺3.03* (⫺5.11)
⫺1.44 (⫺3.67)
2
⫺2.78* (⫺4.73)
⫺1.39 (⫺3.58)
3
⫺2.08* (⫺3.51)
⫺1.02 (⫺2.60)
4
⫺1.94 (⫺2.95)
⫺1.19 (⫺2.73)
5a-P
⫺2.43 (⫺3.59)
⫺1.48 (⫺3.28)
4
⫺2.45 (⫺3.06)
⫺1.28 (⫺2.42)
⫺1.63 (⫺3.57)
5b-Mg
⫺2.83 (⫺3.43)
⫺1.65 (⫺2.99)
4⫹Total energy (kJ/d)
⫺1.62 (⫺1.96)
⫺1.05 (⫺1.86)
5b-Mg⫹total energy (kJ/d)
⫺0.18 (⫺0.19)
⫺0.45 (⫺0.74)
4⫹Total energy⫹height⫹
weight
⫺1.87 (⫺2.36)
⫺1.21 (⫺2.23)
5b-Mg⫹total energy⫹
height⫹weight
⫺1.48 (⫺1.70)
⫺1.24 (⫺2.10)
5b-Mg
⫺2.50 (⫺3.66)
5c-Ca
⫺1.48 (⫺2.21)
⫺0.96 (⫺2.15)
5d-Fe
⫺1.81 (⫺2.73)
⫺1.15 (⫺2.59)
5e-Fiber
⫺1.95 (⫺2.93)
⫺1.21 (⫺2.72)
Sensitivity analyses
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Also adjusted for education
(years) and current smoking
(yes/no; n⫽4680)
Excluding persons with high
day-to-day variability in
nutrient intake and/or BP
(n⫽3473)
Glutamic acid expressed as g/d
(instead of % total protein;
n⫽4680)
4
⫺1.88 (⫺2.86)
⫺1.23 (⫺2.81)
5b-Mg
⫺2.46 (⫺3.59)
⫺1.68 (⫺3.67)
4
⫺1.95 (⫺2.96)
⫺1.21 (⫺2.77)
4
⫺1.06 (⫺2.33)
⫺0.66 (⫺2.15)
5b-Mg
⫺2.52 (⫺3.67)
⫺1.64 (⫺3.56)
5b-Mg
⫺0.22 (⫺0.44)
⫺0.35 (⫺1.02)
4⫹Height⫹weight
⫺1.08 (⫺2.48)
⫺0.66 (⫺2.22)
5b-Mg⫹height⫹weight
⫺0.86 (⫺1.76)
⫺0.72 (⫺2.17)
Also adjusted for month
of field survey (n⫽4680)
Also adjusted for season
of field survey (n⫽4680)
4
⫺1.93 (⫺2.93)
⫺1.19 (⫺2.74)
5b-Mg
⫺2.49 (⫺3.64)
⫺1.63 (⫺3.56)
4
⫺1.96 (⫺2.98)
⫺1.19 (⫺2.72)
5b-Mg
⫺2.53 (⫺3.70)
⫺1.64 (⫺3.58)
4
⫺1.99 (⫺3.05)
⫺1.20 (⫺2.76)
5b-Mg
⫺2.54 (⫺3.72)
⫺1.60 (⫺3.49)
4
⫺1.74 (⫺2.56)
⫺1.19* (⫺2.64)
5b-Mg
⫺2.07 (⫺2.91)
⫺1.57 (⫺3.30)
4
⫺1.50 (⫺2.12)
⫺0.81 (⫺1.73)
5b-Mg
⫺2.27 (⫺3.07)
⫺1.35 (⫺2.71)
Also adjusted for total
energy (kJ/d; n⫽4680)
Adjusted for urinary Na/creatinine
and K/creatinine ratio (mmol/
mmol) instead of urinary Na and
urinary K (mmol/24 h; n⫽4680)
Also adjusted for total available
carbohydrate (% kJ; n⫽4680)
Also adjusted for starch
(% kJ; n⫽4680)
Censored normal regression
to adjust for antihypertensive
treatment (n⫽4680)
4
⫺2.29 (⫺3.10)
⫺1.40 (⫺2.89)
5b-Mg
⫺2.82 (⫺3.66)
⫺1.81 (⫺3.55)
(Continued)
Glutamic acid expressed as %
kJ (instead of % total protein;
n⫽4680)
Model 1: Controlled for sample, age, and gender.
Model 2: Model 1 variables plus special diet (yes/no), supplement intake
(yes/no), diagnosis of cardiovascular disease/diabetes mellitus (yes/no), physical activity (medium and heavy, hours per day), family history of high BP (yes,
no, or unknown).
Model 3: Model 2 variables plus urinary Na and urinary K (mmol/24 h),
14-day alcohol consumption (g/d).
Model 4: Model 3 variables plus cholesterol (mg/1000 kJ), total saturated
fatty acids, and total polyunsaturated fatty acids (% kJ).
Models 5a through 5e, main analyses: Controlled for model 4 variables plus
each stipulated nutrient (expressed per 1000 kJ).
Sensitivity analyses: Controlled for model 4 variables plus each stipulated
variable, or variables in model 5b-Mg plus each stipulated variable.
Month of field survey represents the midpoint between first and fourth clinic
visit; season of field survey is Winter (December/January/February), Spring
(March/April/May), Summer (June/July/August), or Fall (September/October/
November).
z Score⫽regression coefficient/standard error; z score ⱖ1.96: uncorrected
Pⱕ0.05; z score ⱖ2.58: uncorrected Pⱕ0.01; and z score ⱖ3.29: uncorrected
Pⱕ0.001.
2-SD higher glutamic acid intake for % total protein, 4.72%; for grams per
day, 9.60; for % total kilocalories, 1.00%.
*Test for cross-country heterogeneity significant, P⬍0.05.
sizable (clinically relevant) effects. To detect the impact of single
nutrients on the BP of individuals, standardized high-quality data are
needed on large population samples. Accordingly, INTERMAP
surveyed 4680 men and women 40 to 59 years of age from 17
random population samples in Japan (4 samples), the People’s
Republic of China (3 samples), the United Kingdom (2 samples), and
the United States (8 samples).2 Participants were selected randomly
from community or workplace population lists, arrayed into 4
age/gender strata. Staff were trained and certified by senior col-
Stamler et al
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
leagues based on a common protocol. Each participant attended 4
times, with visits 1 and 2 on consecutive days and visits 3 and 4 on
consecutive days an average of 3 weeks later. BP was measured
twice per visit with a random-zero sphygmomanometer and averaged. Measurements of height and weight and data on daily alcohol
consumption over the previous 7 days were obtained at 2 visits.
Dietary data were collected at each visit by multipass 24-hour
recall.2,3 All foods, drinks, and supplements consumed in the
previous 24 hours were recorded. For participants from the People’s
Republic of China and the United States, monosodium glutamate
(66% and 46% glutamic acid, respectively) was quantitated4; for
Japan and UK participants, monosodium glutamate use was negligible and was not quantitated. Questionnaire data were obtained on
demographic, biomedical, and other possible confounders. Each
participant provided two 24-hour urine collections, start- and endtimed at the research center (visits 1 to 2 and visits 3 to 4);
measurements included urinary volume, sodium, potassium, creatinine, and urea nitrogen, a biomarker of total protein intake.3,5 Eight
percent of the specimens were split locally and sent in a blinded
fashion to the central laboratory to estimate technical error.2
Individuals were excluded if they did not attend all 4 visits; if diet
data were considered unreliable; if energy intake from any 24-hour
dietary recall was ⬍2092 or ⬎20 920 kJ/d for women or 33 472 kJ/d
for men; if 2 urine collections were not available; or if other data
were incomplete or indicated protocol violation (total⫽215 people).
For each exclusion, an alternative participant was recruited. The
study received institutional ethics committee approval for each site,
and all participants gave written informed consent.
Statistical Methods
Food data for individuals were converted into nutrients (83 nutrients,
including 18 amino acids) with the use of country-specific tables on
the nutrient composition of foods, updated and standardized across
countries by the Nutrition Coordinating Center, University of Minnesota.2,6 For nutrients that supplied energy, intake was calculated as
percentage of total energy; for other nutrients, intake was calculated
as intake per 1000 kJ and as amount per 24 hours. For amino acids,
intake was also calculated as a percentage of total protein intake.
Main food groups supplying each amino acid were assessed. Urinary
values per 24 hours were calculated as products of urinary concentrations and volumes, were standardized to 24 hours. Measurements
per person were averaged, for BP and nutrients, across the 4 visits;
for urinary excretions, they were averaged across the 2 collections.
For descriptive statistics, means and SDs or numbers and percentages were calculated by country and studywide. The reliability of BP
and amino acid intakes (mean of 4 visits) was estimated from the
formula 1/[1⫹(ratio/4)]⫻100, where the ratio was intraindividual
variance/interindividual variance, estimated separately for 8 gender/
country strata and pooled by weighting each stratum-specific estimate by (sample size⫺1). This gives a first approximation of the
effect of random error due to day-to-day variability on the reliability
of amino acid associations with BP; the statistic is the estimated size
of an observed coefficient as a percentage of the theoretical coefficient in univariate regression analysis.7–10
Associations among nutrients were explored by partial correlation,
adjusted for sample, age, and gender; pooled across countries; and
weighted by sample size. Multiple regression analyses were used to
examine relations of each of the 5 dietary amino acids (grams per
day, percentage of kilojoules, and percentage of total protein) to
systolic BP (SBP) and diastolic BP (DBP). Adjustment for confounders was done sequentially with the use of 9 models (3 to 15
covariates; Table 1), with and without height and weight.1,2 Regression models were fit by country, and coefficients were pooled across
countries, weighted by the inverse of the variance, to estimate the
overall association. The cross-country heterogeneity of regression
coefficients was tested by ␹2 analysis. Interactions were assessed for
age and gender, and departures from linearity were tested with
quadratic terms. Regression coefficients were expressed as mm Hg
for a 2-SD difference in amino acid intake from overall SDs adjusted
for across-country variation. Statistical significance is presented as
Dietary Glutamic Acid and Blood Pressure
223
the z score (z score⫽regression coefficient/standard error); equivalent probability values are given in the Table footnotes. Sensitivity
analyses were also done (Table 1; online-only Data Supplement
Tables VI, VII, and VIII) that included censored normal regression
to adjust for potential antihypertensive treatment bias.11 Adjusted
mean SBP and DBP by country-specific quartiles of glutamic acid
(% total protein) were calculated by ANOVA and plotted. Analyses
were performed (by I.J.B. and Q.C.) with SAS version 9.1 (SAS
Institute, Inc, Cary, NC).
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the manuscript
as written.
Results
Descriptive Statistics
Multiple characteristics of the study population samples are
provided in online-only Data Supplement Table I. Mean SBP
ranged from 117.2 mm Hg (Japan) to 121.3 mm Hg (People’s
Republic of China), and mean DBP ranged from 73.2 mm Hg
(People’s Republic of China) to 77.3 mm Hg (United Kingdom). Consistently, glutamic acid was the predominant dietary amino acid, averaging 15.7 g/d, 3.0% kJ, and 20.1%
total protein for all 4680 INTERMAP participants. As grams
per day and percent kilojoules, these values were higher for
persons from the United Kingdom and the United States than
for those from Japan or the People’s Republic of China; as a
percentage of total protein, glutamic acid intake was highest
for People’s Republic of China participants (24.1%) and
lowest for Japanese (17.8%; for the United Kingdom and the
United States, the respective values were 20.5% and 19.8%).
Only 2% of women and men reported use of dietary supplements containing glutamic acid; intake from supplements and
from foods plus supplements among supplement users averaged 0.5 and 16.4 g/d, respectively.
Univariate estimates of the reliability of glutamic acid
intake, based on mean values from the four 24-hour recalls
per participant, were as follows: 68% of theoretical coefficient (g/d), 61% (% kJ), and 61% (% total protein; onlineonly Data Supplement Table II). These were similar for men
and women, across the 4 countries, and for the 4 other amino
acids. BP reliability estimates were 94% (SBP) and 93%
(DBP) and were high across all 8 gender/country subgroups.
Partial Correlations
Expressed as grams per day or percentage of kilojoules,
partial correlations (adjusted for sample, age, and gender) for
glutamic acid with proline, phenylalanine, serine, and cystine
were of a high order (0.83 to 0.90; online-only Data Supplement Tables III and IV) and were smaller for amino acids
expressed as a percentage of total dietary protein (0.37 to
0.47, except for the correlation of glutamic acid with proline
[0.80]; online-only Data Supplement Table V). Glutamic acid
expressed as grams per day and as percentage of kilojoules
was positively correlated with dietary calcium, copper, iron,
magnesium, phosphorus, and selenium (partial r from 0.21
for copper to 0.62 for phosphorus; online-only Data Supplement Tables III and IV); with glutamic acid expressed as a
percentage of total protein, partial r values with these micronutrients (expressed as caloric density) were small, ranging
from 0.09 (calcium) to ⫺0.10 (magnesium and selenium),
224
Circulation
July 21, 2009
except for phosphorus (⫺0.18; online-only Data Supplement
Table V). Glutamic acid as a percentage of total protein was
positively correlated with total carbohydrate (0.33) and starch
(0.39) and inversely correlated with alcohol (⫺0.17 to
⫺0.19). Partial correlation (r) data were similar for the 4
other amino acids.
Multiple Regression Analyses: Glutamic Acid
and BP
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
The glutamic acid–BP relation was stronger when expressed
as a percentage of total protein than as grams per day or as a
percentage of kilojoules. With glutamic acid intake (percentage of total protein) from food higher by 2 SD (4.72% total
protein), in multivariate controlled models (models 4 to 5e in
Table 1), average SBP was lower by 1.5 to 2.5 mm Hg (z
score ⫺2.21 to ⫺3.66), and average DBP was lower by 1.0 to
1.6 mm Hg (z score ⫺2.15 to ⫺3.57). Results were qualitatively similar, with smaller BP differences, in corresponding
analyses that included height and weight; for example, in
model 5b-Mg, SBP was lower by 1.8 mm Hg (z score ⫺2.73)
and DBP by 1.2 mm Hg (z score ⫺2.70; data not tabulated).
Compared with model 4 findings, coefficients in models that
also adjusted for phosphorus or magnesium (models 5a-P and
5b-Mg) were larger for both SBP and DBP; results for those
that adjusted for iron or fiber (models 5d-Fe and 5e-fiber)
were similar to model 4; and results for the model that
adjusted for calcium (model 5c-Ca) were lower, particularly
for SBP. With adjustment for vegetable protein, associations
of glutamic acid and BP remained qualitatively similar, and
BP differences and z scores were quantitatively weaker (data
not tabulated).
Sensitivity analyses yielded results similar to the foregoing, including for nonhypertensive persons and after adjustment for antihypertensive treatment, seasonality, and additional sociodemographic characteristics (smoking and
education; Table 1). BP differences and z scores were largest
with the exclusion of persons with high day-to-day variability
in nutrient intake or BP. Tests for age/gender interaction and
quadratic nonlinearity consistently yielded nonsignificant results; most cross-country heterogeneity tests were nonsignificant. Despite the lack of significant interaction terms, the
inverse relationship of glutamic acid to SBP was stronger for
women than for men; also, in models 4 and 5a through 5e, it
was stronger in those 50 to 59 years of age than in those 40
to 49 years old (online-only Data Supplement Tables X and
XI). All analyses yielded almost identical results with the
independent variable of glutamic acid from foods plus supplements (data not tabulated).
The Figure demonstrates successively lower mean SBP
and DBP across quartiles 1 to 4 of country-specific glutamic
acid intake, controlled for model 5b-Mg covariates (P for
trend ⬍0.001 for SBP, 0.12 for DBP).
Proline, phenylalanine, and serine (but not cystine) were
related to BP in a qualitatively similar way, with smaller BP
differences and z scores (online-only Data Supplement Tables
VI, VII, and VIII). In multivariate models that included
glutamic acid and 1 of the other 4 amino acids (2 SD higher
as a percentage of total protein), glutamic acid intake was
Figure. Mean SBP (A) and DBP (B) by country-specific quartiles
of glutamic acid intake (% total protein), adjusted for model
5b-Mg covariates, for all 4680 participants. Whiskers are 99%
CIs. A, P for trend ⬍0.001; B, P for trend⫽0.12. Countryspecific quartile cutoffs for glutamic acid intake (% total protein)
were as follows: for Japan, 16.8 (25th percentile), 17.6 (50th
percentile), and 18.6 (75th percentile); for People’s Republic of
China, 19.4, 25.1, and 27.4; for the United Kingdom, 19.4, 20.3,
and 21.5; and for the United States, 18.6, 19.7, and 20.9. Model
5b-Mg covariates were estimated by ANOVA, overall (coefficients not pooled by country). Adjusted for country (not sample),
age, gender, special diet, supplement intake, diagnosis of cardiovascular disease/diabetes mellitus, physical activity, family
history of high BP, urinary sodium, urinary potassium, 14-day
alcohol consumption, cholesterol, total saturated fatty acids,
total polyunsaturated fatty acids, and magnesium (see Table 1
footnote for units).
associated with 2.0 to 2.9 mm Hg lower SBP and 1.2 to 2.0
mm Hg lower DBP (z score ⫺2.32 to ⫺3.63; Table 2); For
each of the other amino acids in these analyses, BP differences and z scores were of low order. With height and weight
included in these regressions, BP differences and z scores for the
glutamic acid–BP relation were ⫺1.4 to ⫺2.2 mm Hg for SBP
and ⫺0.8 to ⫺1.7 mm Hg for DBP, z score ⫺1.65 to ⫺2.44
(data not tabulated). Sensitivity analyses for these 2-amino acid
assessments yielded findings generally similar to those in Table
2 (online-only Data Supplement Table IX). The relation was
generally less strong with amino acids expressed as grams per
day or percentage of kilojoules. Results were nonsignificant for
tests of age/gender interaction and quadratic nonlinearity with
these 2-amino acid models, as were most tests for cross-country
Stamler et al
Table 2. Estimated Mean Difference in BP With Consumption
of Foods Higher by 2 SD in Amino Acids (% Total Protein), 2
Amino Acids in Same Model, Model 5b-Mg, All Participants
(nⴝ4680)
Variable (2 SD)
SBP Difference,
mm Hg (z Score)
DBP Difference,
mm Hg (z Score)
Glutamic acid (4.72)
⫺2.72 (⫺2.51)
⫺2.00 (⫺2.82)
Proline (2.54)
0.30 (0.26)
0.55* (0.72)
Glutamic acid (4.72)
⫺1.99 (⫺2.48)
⫺1.24 (⫺2.32)
⫺0.72 (⫺1.32)
⫺0.63 (⫺1.71)
⫺2.27 (⫺2.84)
⫺1.37 (⫺2.58)
⫺0.51 (⫺0.96)
⫺0.40 (⫺1.12)
Phenylalanine (0.35)
Glutamic acid (4.72)
Serine (0.45)
Glutamic acid (4.72)
⫺2.88 (⫺3.63)
⫺1.56 (⫺2.95)
Cystine (0.27)
0.57 (1.00)
⫺0.09* (⫺0.25)
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Model 5b-Mg: Controlled for sample, age, gender, special diet, supplement
intake, diagnosis of cardiovascular disease/diabetes mellitus, physical activity,
family history of high BP, urinary Na, urinary K, 14-day alcohol consumption,
cholesterol, total saturated fatty acids, total polyunsaturated fatty acids, and
magnesium (see Table 1 footnote for units).
z Score⫽regression coefficient/standard error; z score ⱖ1.96: uncorrected
Pⱕ0.05; z score ⱖ2.58: uncorrected Pⱕ0.01; and z score ⱖ3.29: uncorrected
Pⱕ0.001.
*Cross-country heterogeneity significant, P⬍0.05.
heterogeneity for the glutamic acid–BP relation (data not
tabulated).
Food Sources of Glutamic Acid
Seven food groups (4 vegetable, Table 3, rows 2–5; 3 animal,
Table 3, rows 9 –11) supplied most (83.6%; vegetable 41.9%,
animal 41.7%) of the glutamic acid.
Discussion
Our main finding was a consistent inverse relation of glutamic acid intake (as a percentage of total protein) to BP that
Table 3.
Dietary Glutamic Acid and Blood Pressure
225
prevailed in repeated regression models with control for
multiple confounders, both nondietary and dietary (including
variables previously demonstrated to relate significantly and
independently to BP [eg, sodium, potassium, alcohol intake,
and weight adjusted for height]);12 also with control for intake
of each of the 4 other amino acids that are more common in
vegetable than animal protein. This relationship prevailed for
women and men; for those ages 40 to 49 and 50 to 59 years;
across 4 countries; for nonhypertensive persons; and with
control for month or season of dietary survey and for
sociodemographic characteristics. It was strongest with the
exclusion of individuals who manifested marked intraindividual variability in nutrient intake or BP, results that are
concordant with the tentative inference that dietary glutamic
acid may have an etiologically significant favorable effect on
BP. This novel finding needs replication in other populations
and in trials.
Of 18 dietary amino acids quantified in the present study,
glutamic acid intake was consistently and by far the most
common. For predominantly vegetable versus predominantly
animal protein consumers, glutamic acid constituted 23%
versus 18% of total protein intake. Thus, given the previous
INTERMAP finding of an independent inverse relation of
vegetable protein intake to BP,1 it was an expected result that
this most common amino acid (especially in vegetable protein) would be inversely related to BP.
To the best of our knowledge, this is the first report of the
relation of glutamic acid (or proline, phenylalanine, serine, or
cystine) intake to BP. Previous literature reporting lower BP
in vegetarian than omnivorous populations did not deal with
specific nutrients,13 and more recent reports (from observational studies or controlled trials) did not report on glutamic
acid or the other 4 amino acids predominant in vegetable
protein.1 In the 2 DASH (Dietary Approaches to Stop
Hypertension) trials and the OMNIHEART (Optimal Macro-
Food Groups Supplying the Most Dietary Glutamic Acid, by Country
Japan (n⫽1145)
Food Group
PRC (n⫽839)
UK (n⫽501)
USA (n⫽2195)
All (n⫽4680)
g/d
%
g/d
%
g/d
%
g/d
%
g/d
%
14.19
100.0
14.97
100.0
16.83
100.0
16.54
100.0
15.72
100.0
Pasta, rice, noodles*
3.03
21.3
3.01
20.2
0.31
1.8
0.85
5.1
1.71
10.9
Bread, rolls, biscuits*
1.06
7.5
0.15
1.0
4.19
24.9
2.22
13.4
1.77
11.3
Vegetables, beans
0.96
6.8
1.47
9.8
1.21
7.2
1.10
6.6
1.14
7.3
Grains, flour, cereals
0.13
0.9
6.30
42.1
0.66
3.9
1.50
9.0
1.94
12.4
Vegetarian meat substitutes
1.07
7.5
0.33
2.2
0.04
0.2
0.11
0.6
0.37
2.4
All
Cakes, puddings, cookies, sweet snacks*
0.37
2.6
0.99
6.6
1.07
6.4
0.39
2.4
0.56
3.6
Nuts, seeds
0.12
0.8
0.27
1.8
0.13
0.8
0.33
2.0
0.25
1.6
Fish, shellfish
3.20
22.6
0.36
2.4
0.64
3.8
0.69
4.2
1.24
7.9
Meat
1.91
13.5
1.25
8.4
4.59
27.3
5.09
30.8
3.57
22.7
Milk, cheese, dairy†
0.87
6.2
0.03
0.2
2.76
16.4
2.63
15.9
1.75
11.1
Eggs
0.61
4.3
0.31
2.1
0.24
1.4
0.43
2.6
0.44
2.8
Sum–vegetable (rows 2–8)
6.73
47.4
11.53
77.1
7.60
45.2
6.48
39.2
7.76
49.4
Sum–animal (rows 9–12)
6.60
46.5
1.95
13.0
8.22
48.9
8.85
53.5
6.99
44.5
PRC indicates People’s Republic of China; UK, United Kingdom; and USA, United States of America.
*May include small quantities of glutamic acid of animal origin (eg, from egg white).
†Does not include ice cream.
226
Circulation
July 21, 2009
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
nutrient Intake Trial for Heart Health) feeding trials, dietary
protein, particularly vegetable protein, was increased, and
hence, so was glutamic acid,14 –16 but this modification was
for protein overall, so that no inference is possible as to
whether the individual nutrient glutamic acid produced BP
reduction with the DASH/OMNIHEART eating pattern. Correspondingly, there are no data on total glutamic acid intake
and BP in the 39 papers from a recent international symposium on glutamate.17 The only related information is from
small (11 to 52 persons), short-term, randomized, controlled
trials dealing with monosodium glutamate,18 –22 with an
amount ranging from a 1.5-g tablet given with breakfast to
12 g given after an overnight fast, without effects on BP. In
3 East Asian studies,23–25 inverse relations were reported with
regard to SBP for the urinary ratio of sulfate to urea (an index
of intake of sulfur-containing amino acids from animal
protein) and of serum phenylalanine and serine; overnight
urinary cysteine; and 24-hour urinary 3-methylhistidine (a
marker for animal protein intake). These articles reported no
dietary-BP relationship data on the 5 amino acids considered
in the present report.
Glutamate has been characterized as “an amino acid of
particular distinction . . . an abundant biomolecule [with]
involvement in multiple metabolic processes that play major
roles . . . .”26 Therefore, multiple mechanisms can be invoked
as possibly accounting for a favorable effect of dietary
glutamic acid on BP; for example, oxidized in the intestinal
tissues, glutamic acid may serve as an energy-yielding or
glutathione substrate.26 Glutathione in its redox state can
counteract oxidative injury from free radicals27 and can
enhance the hypotensive effects of nitric oxide.28 Dietary
glutamate may also be a substrate for arginine,29 a precursor
of nitric oxide and a potent vasodilator.30 Glutamate is an
excitatory neurotransmitter; areas of the brain most sensitive
to increased plasma glutamate (potentially from dietary intake) are those that are relatively unprotected by the bloodbrain barrier, notably the hypothalamus, linking the nervous
system to the endocrine system via the pituitary gland.26,31
Glutamate excitation of hypothalamus neurons could affect
vasoactive hormone production, although findings in human
studies to date are negative.32 Another possible pathway for a
favorable BP influence of higher glutamate intake is enhanced kidney size and function.33–35
The inverse relation between dietary glutamic acid and BP
is 1 of several independent associations of nutrients with BP
found by the INTERMAP study (as expected).1,36 –39 The
relation between glutamic acid and BP is stronger with
glutamic acid expressed as a percentage of total protein than
when it is expressed as grams per day or as a percentage of
kilojoules. This may be because glutamic acid expressed as a
percentage of total protein correlates much less strongly with
other possibly confounding variables than glutamic acid
expressed as grams per day or as a percentage of kilojoules.
Compared with model 4, glutamic acid–BP associations were
larger in models that also adjusted for phosphorus or magnesium, similar in models that adjusted for iron or fiber, and
smaller in models that adjusted for calcium. This may reflect
the different sign of the correlation between these variables
and glutamic acid, but all partial r values are of low order, and
hence, any inference is conjectural. Another possibility is
chance variation. For all models, the glutamic acid–BP
relationship remains qualitatively the same, ie, inverse, with
all z scores ⬎2.
Bias toward the null of exposure-BP associations induced
by reduced BPs of treated hypertensive participants is a
concern for all studies that include such individuals.11 Glutamic acid–BP associations were quantitatively similar in
models that adjusted for antihypertensive treatment effect
compared with main analyses, which indicates that bias of
this kind is not substantial.
Limitations of our findings in the present study include the
following: Their cross-sectional nature (although they are the
only population-based data available); effect-size underestimation due to limited reliability in nutrient measurement
(regression-dilution bias), despite multiple standardized stateof-the-art measurements; ability to control only partially
(albeit considerably) for high-order collinearity among dietary variables of concern, which is less of a problem in
analyses with amino acids expressed as percentage of total
dietary protein than as grams per day or percent total
kilocalories; limited generalizability to persons younger than
40 years and older than 59 years; and the apparently small
effect size. This last limitation, anticipated by INTERMAP,2
must be kept in perspective: With “small” independent
influences of multiple nutrients,1,36 –39 combined effects become substantial, ie, improved nutrition is capable of preventing/reducing unfavorable BP levels for most people, as
the DASH and OMNIHEART feeding trial findings demonstrate.14 –16 Also, long-term BP effects of habitual eating
patterns, from childhood into middle age, may be greater, as
data on salt intake and BP indicate.12 Moreover, reduction of
a population’s average SBP by small amounts (eg, 2 mm Hg),
is estimated to result in mortality rates that are lower by 6%
for stroke and 4% for coronary heart disease.12,40 Finally,
eating patterns based mainly on foods with predominantly
vegetable protein (those high in glutamic acid, ␻-3/␻-6
polyunsaturated fatty acids, calcium, magnesium, phosphorus, iron, and other micronutrients; low/moderate in fats/
saturated fats/cholesterol/refined sugars/caloric density; and
low in salt/alcohol) have multiple favorable influences on BP,
serum lipids, cardiovascular disease risk, and general health.
In conclusion, we found an independent inverse relation of
dietary glutamic acid to BP with control for multiple possible
confounders. Glutamic acid, the most common dietary amino
acid, especially in vegetable protein, may be a key component
accounting for the previously reported inverse relation of
vegetable protein intake to BP.
Acknowledgments
We thank all INTERMAP staff at local, national, and international
centers for their invaluable efforts; a partial listing of these colleagues is given in Reference 2 of this article. We dedicate this paper
to the memory of Vernon R. Young, world-renowned amino acid
investigator, whose exchange with the senior author years ago was
seminal in setting the stage for the research reported here.
Sources of Funding
This study was supported by grant 2-ROI-HL50490 from the
National Heart, Lung, and Blood Institute, National Institutes of
Stamler et al
Health, and by the National Institutes of Health Office on Dietary
Supplements (Bethesda, Md); and by national agencies in China,
Japan (the Ministry of Education, Science, Sports, and Culture,
grant-in-aid for scientific research [A] No. 090357003), and the
United Kingdom.
Dietary Glutamic Acid and Blood Pressure
17.
18.
Disclosures
None.
References
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
1. Elliott P, Stamler J, Dyer AR, Appel L, Dennis B, Kesteloot H, Ueshima
H, Okayama A, Chan Q, Garside DB, Zhou B; for the INTERMAP
Cooperative Research Group. Association between protein intake and
blood pressure: the INTERMAP Study. Arch Intern Med. 2006;166:
79 – 87.
2. Stamler J, Elliott P, Dennis B, Dyer AR, Kesteloot H, Liu K, Ueshima H,
Zhou B, for the INTERMAP Research Group. INTERMAP: background,
aims, design, methods, and descriptive statistics (nondietary). J Hum
Hypertens. 2003;17:591– 608.
3. Dennis B, Stamler J, Buzzard M, Conway R, Elliott P, Moag-Stahlberg A,
Okayama A, Okuda N, Robertson C, Robinson F, Schakel S, Stevens M,
Van Heel N, Zhao LC, Zhou BF; for the INTERMAP Research Group.
INTERMAP: the dietary data: process and quality control. J Hum
Hypertens. 2003;17:609 – 622.
4. He K, Zhao L, Daviglus ML, Dyer AR, Van Horn L, Garside D, Zhu L,
Guo D, Wu Y, Zhou B, Stamler J; for the INTERMAP Cooperative
Research Group. Association of monosodium glutamate intake with overweight in Chinese adults: the INTERMAP Study. Obesity. 2008;16:
1875–1880.
5. Dyer A, Elliott P, Chee D, Stamler J. Urinary biochemical markers of
dietary intake in the INTERSALT Study. Am J Clin Nutr. 1997;65(suppl):
1246S–1253S.
6. Schakel SF, Dennis B, Wold AC, Conway R, Zhao L, Okuda N, Okayama
A, Moag-Stahlberg A, Robertson C, Van Heel N, Buzzard IM, Stamler J.
Enhancing data on nutrient composition of foods eaten by participants in
the INTERMAP study in China, Japan, the United Kingdom, and the
United States. J Food Comp Anal. 2003;16:395– 408.
7. Grandits GA, Bartsch GE, Stamler J. Chapter 4: method issues in dietary
data analyses in the Multiple Risk Factor Intervention Trial. Am J Clin
Nutr. 1997;65(suppl):211S–227S.
8. Dyer AR, Shipley M, Elliott P; for the INTERSALT Cooperative
Research Group. Urinary electrolyte excretion in 24 hours and blood
pressure in the INTERSALT Study, I: estimates of reliability. Am J
Epidemiol. 1994;139:927–939.
9. Dyer AR, Elliott P, Shipley M; for the INTERSALT Cooperative Research
Group. Urinary electrolyte excretion in 24 hours and blood pressure in the
INTERSALT Study, II: estimates of electrolyte-blood pressure associations
corrected for regression dilution bias. Am J Epidemiol. 1994;139:940–951.
10. Dyer AR, Liu K, Sempos CT. Nutrient data analysis techniques and
strategies. In: Berdanier CD, Dwyer J, Feldman EB, eds. Handbook of
Nutrition and Food, Second Edition. Boca Raton, Fla: CRC Press; 2005:
93–103.
11. Tobin MD, Sheehan NA, Scurrah KJ, Burton PR. Adjusting for treatment
effects in studies of quantitative traits: antihypertensive therapy and
systolic blood pressure. Stat Med. 2005;24:2911–2935.
12. Stamler J The INTERSALT Study: background, methods, findings, and
implications. Am J Clin Nutr. 1997;65(suppl):626S– 642S.
13. Sacks FM, Rosner B, Kass EH. Blood pressure in vegetarians. Am J
Epidemiol. 1974;100:390 –398.
14. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks
FM, Bray GA, Vogt TM, Cutler JA, Windhauser MM, Lin PH,
Karanja N; for the DASH Collaborative Research Group. A clinical
trial on the effects of dietary patterns on blood pressure. N Engl J Med.
1997;336:1117–1124.
15. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D,
Obarzanek E, Conlin PR, Miller ER, Simons-Morton DG, Karanja N,
Lin PH; for the DASH-Sodium Collaborative Research Group. Effects
on blood pressure of reduced dietary sodium and the Dietary
Approaches to Stop Hypertension (DASH) diet. N Engl J Med. 2001;
344:3–10.
16. Appel LJ, Sacks FM, Carey VJ, Obarzanek E, Swain JF, Miller ER,
Conlin PR, Erlinger TP, Rosner BA, Laranjo NM, Charleston J,
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
227
McCarron P, Bishop LM; for the OmniHeart Collaborative Research
Group. Effects of protein, monounsaturated fat, and carbohydrate intake
on blood pressure and serum lipids: results of the OmniHeart Randomized
Trial. JAMA. 2005;294:2455–2464.
Fernstrom JD, Garattini S, eds. International symposium on glutamate.
J Nutr. 2000;130(suppl):891S–1079S.
Morselli PL, Garattini S. Monosodium glutamate and the Chinese restaurant syndrome. Nature. 1970;227:611– 612.
Rosenblum I, Bradley JD, Coulston F. Single and double blind studies
with oral monosodium glutamate in man. Toxicol Appl Pharmacol. 1971;
18:367–373.
Zanda G, Franciosi P, Tognoni G, Rizzo M, Standen SM, Morselli PL,
Garattini S. A double blind study on the effects of monosodium glutamate
in man. Biomedicine. 1973;19:202–204.
Yang WH, Drouin MA, Herbert M, Mao Y, Karsh J. The monosodium
glutamate symptom complex: assessment in a double-blind, placebocontrolled, randomized study. J Allergy Clin Immunol. 1997;99:
757–762.
Prawirohardjono W, Dwiprahasto I, Astuti I, Hadiwandowo S, Kristin E,
Muhammad M, Kelly MF. The administration to Indonesians of
monosodium L-glutamate in Indonesian foods: an assessment of adverse
reactions in a randomized double-blind, crossover, placebo-controlled
study. J Nutr. 2000;130(suppl):1074S–1076S.
Yamori Y, Kihara M, Nara Y, Ohtaka M, Horie R, Tsunematsu T, Note
S. Hypertension and diet: multiple regression analysis in a Japanese
farming community. Lancet. 1981;1:1204 –1205.
Zhou B, Zhang X, Zhu A, Zhao L, Zhu S, Ruan L, Zhu L, Liang S. The
relationship of dietary animal protein and electrolytes to blood
pressure: a study on three Chinese populations. Int J Epidemiol.
1994;23:716 –722.
Liu L, Ikeda K, Yamori Y; for the WHO-CARDIAC Study Group.
Inverse relationship between urinary markers of animal protein intake and
blood pressure in Chinese: results from the WHO Cardiovascular
Diseases and Alimentary Comparison (CARDIAC) Study. Int J Epidemiol. 2002;31:227–233.
Young VR, Ajami AM. Glutamate: an amino acid of particular distinction. J Nutr. 2000;130(suppl):892S–900S.
Beutler E. Nutritional and metabolic aspects of glutathione. Ann Rev Nutr.
1989;9:287–302.
Prasad A, Andrews NP, Padder FA, Husain M, Quyyumi AA. Glutathione
reverses endothelial dysfunction and improves nitric oxide bioavailability. J Am Coll Cardiol. 1999;34:507–514.
Reeds PJ, Burrin DG, Stoll B, Jahoor F. Intestinal glutamate metabolism.
J Nutr. 2000;130:978S–982S.
Bode-Böger SM, Böger RH, Galland A, Tsikas D, Frölich JC.
L-arginine–induced vasodilation in healthy humans: pharmacokineticpharmacodynamic relationship. Br J Clin Pharmacol. 1998;46:489 – 497.
Food and Nutrition Board, National Academy of Sciences. Protein and
amino acids. In: Dietary Reference Intakes for Energy, Carbohydrate,
Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: National Academies Press; 2005:589 –768.
Fernstrom JD. Pituitary hormone secretion in normal male humans: acute
responses to a large, oral dose of monosodium glutamate. J Nutr. 2000;
130:1053S–1057S.
Smith HW. The Kidney: Structure and Function in Health and Disease.
New York, NY: Oxford University Press; 1951.
Wilson HEC. An investigation of the cause of renal hypertrophy in rats
fed on a high protein diet. Biochem J. 1933;27:1348 –1356.
Bosch JP, Saccaggi A, Lauer A, Ronco C, Belledonne M, Glabman S.
Renal functional reserve in humans: effect of protein intake on glomerular
filtration rate. Am J Med. 1983;75:943–950.
Ueshima H, Stamler J, Elliott P, Chan Q, Brown IJ, Carnethon M,
Daviglus ML, He K, Moag-Stahlberg A, Rodriguez BL, Steffen LM, Van
Horn L, Yarnell J, Zhou B; for the INTERMAP Research Group. Food
omega-3 fatty acid intake of individuals (total, linolenic acid, long-chain)
and their blood pressure: INTERMAP Study. Hypertension. 2007;50:
313–319.
Elliott P, Kesteloot H, Appel LJ, Dyer AR, Ueshima H, Chan Q,
Brown IJ, Zhao L, Stamler J; for the INTERMAP Cooperative
Research Group. Dietary phosphorus and blood pressure: international
population study on macronutrients and blood pressure. Hypertension.
2008;51:669 – 675.
Miura K, Stamler J, Nakagawa H, Elliott P, Ueshima H, Chan Q, Brown
IJ, Tzoulaki I, Saitoh S, Dyer AR, Daviglus ML, Kesteloot H, Okayama
A, Curb JD, Rodriguez BL, Elmer PJ, Steffen LM, Robertson C, Zhao L;
228
Circulation
July 21, 2009
for the International Study of Macro-Micronutrients and Blood Pressure
Research Group. Relationship of dietary linoleic acid to blood pressure:
the International Study of Macro-Micronutrients and Blood Pressure.
Hypertension. 2008;52:408 – 414.
39. Tzoulaki I, Brown IJ, Chan Q, Van Horn L, Ueshima H, Zhao L, Stamler
J, Elliott P; for the International Collaborative Research Group on Mac-
ro-/Micronutrients and Blood Pressure. Relation of iron and red meat
intake to blood pressure: cross sectional epidemiological study. BMJ.
2008;337:a258.
40. Stamler J, Rose G, Stamler R, Elliott P, Dyer A, Marmot M.
INTERSALT Study findings: public health and medical care implications. Hypertension. 1989;14:570 –577.
CLINICAL PERSPECTIVE
These data showing an independent inverse relationship of dietary glutamic acid (the most common dietary amino acid,
especially in vegetable protein) to blood pressure are consistent with previous findings on the inverse relationship of dietary
vegetable protein to blood pressure and lend further weight to those results. They generally reinforce current
recommendations for a high intake of vegetable products as a part of comprehensive nutritional/lifestyle approaches to
preventing and controlling major established cardiovascular risk factors and epidemic cardiovascular disease.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Glutamic Acid, the Main Dietary Amino Acid, and Blood Pressure: The INTERMAP
Study (International Collaborative Study of Macronutrients, Micronutrients and Blood
Pressure)
Jeremiah Stamler, Ian J. Brown, Martha L. Daviglus, Queenie Chan, Hugo Kesteloot, Hirotsugu
Ueshima, Liancheng Zhao and Paul Elliott
for the INTERMAP Research Group
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Circulation. 2009;120:221-228; originally published online July 6, 2009;
doi: 10.1161/CIRCULATIONAHA.108.839241
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2009 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/120/3/221
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2009/07/07/CIRCULATIONAHA.108.839241.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/
SUPPLEMENTAL MATERIAL
Glutamic Acid – the Main Dietary Amino Acid – and Blood Pressure: The INTERMAP Study
Stamler J, Brown IJ, Daviglus ML, Chan Q, Kesteloot H, Ueshima H, Zhao L, Elliott P for the
INTERMAP Research Group
Supplemental Tables
Table S.1. Descriptive Statistics by Country and for All 4,680 INTERMAP participants
Table S.2. Reliability and its Potential Effect on Regression Coefficients for Dietary Amino Acids and
Blood Pressure, for Participants of the INTERMAP Study, Men and Women Combined and Separately
Table S.3. Partial correlation of dietary amino acids (grams/day) and other variables
Table S.4. Partial correlation of dietary amino acids (% kJ) and other variables
Table S.5. Partial correlation of dietary amino acids (% Total Protein) and other variables
Table S.6. Estimated Mean Difference in Blood Pressure, Proline Intake (% Total Protein) from Foods
Higher by 2 s.d., Multiple Regression Analyses
Table S.7. Estimated Mean Difference in Blood Pressure, Phenylalanine Intake (% Total Protein) from
Foods Higher by 2 s.d., Multiple Regression Analyses
1
Table S.8. Estimated Mean Difference in Blood Pressure, Serine Intake (% Total Protein) from Foods
Higher by 2 s.d., Multiple Regression Analyses
Table S.9. Sensitivity Analyses: Two Amino Acids Regressed Simultaneously, Model 5b - Mg
Table S.10. Estimated Mean Difference in Blood Pressure, by Gender, Glutamic Acid Intake (% Total
Protein) from Foods Higher by 2 s.d., Multiple Regression Analyses
Table S.11. Estimated Mean Difference in Blood Pressure, by Age Group (40-49 and 50-59 years),
Glutamic Acid Intake (% Total Protein) from Foods Higher by 2 s.d., Multiple Regression Analyses
2
Table S.1. Descriptive Statistics by Country and for All 4,680 INTERMAP participants
Variable
Japan
P.R. China
UK
USA
All
(N=1,145)
(N=839)
(N=501)
(N=2,195)
(N=4,680)
Mean
(s.d.)
Mean
(s.d.)
Mean
(s.d.)
Mean
(s.d.)
Mean
(s.d.)
Age (years)
49.4
(5.3)
49.0
(5.8)
49.1
(5.6)
49.1
(5.4)
49.2
(5.5)
Systolic BP (mm Hg)
117
(14)
121
(17)
120
(15)
119
(14)
119
(15)
Diastolic BP (mm Hg)
74
(10)
73
(10)
77
(10)
73
(10)
74
(10)
Glutamic Acid, g/day
14.2
(3.2)
15.0
(5.1)
16.8
(4.9)
16.5
(5.3)
15.7
(4.9)
Cystine, g/day
1.26
(0.28)
1.33
(0.38)
1.15
(0.34)
1.14
(0.37)
1.20
(0.36)
Proline, g/day
4.50
(1.07)
3.93
(1.89)
5.69
(1.69)
5.45
(1.83)
4.97
(1.79)
Phenylalanine, g/day
3.57
(0.83)
3.07
(0.95)
3.68
(1.09)
3.69
(1.22)
3.55
(1.10)
Serine, g/day
3.54
(0.83)
2.99
(0.93)
3.76
(1.11)
3.80
(1.26)
3.59
(1.14)
Glutamic Acid, % kJ
2.81
(0.36)
2.94
(0.48)
3.19
(0.54)
3.02
(0.56)
2.97
(0.51)
Cystine, % kJ
0.25
(0.03)
0.26
(0.04)
0.22
(0.04)
0.21
(0.04)
0.23
(0.04)
Proline, % kJ
0.89
(0.14)
0.76
(0.27)
1.08
(0.19)
0.99
(0.20)
0.94
(0.22)
Phenylalanine, % kJ
0.71
(0.09)
0.61
(0.10)
0.70
(0.13)
0.67
(0.13)
0.67
(0.12)
Serine, % kJ
0.70
(0.10)
0.59
(0.10)
0.71
(0.13)
0.69
(0.14)
0.68
(0.13)
continued on next page
3
Table S.1. continued, page 2
Glutamic Acid, % total protein
17.8
(1.4)
24.1
(4.4)
20.5
(1.6)
19.8
(1.7)
20.1
(3.1)
Cystine, % total protein
1.59
(0.12)
2.16
(0.21)
1.39
(0.11)
1.35
(0.10)
1.56
(0.33)
Proline, % total protein
5.67
(0.77)
6.32
(2.47)
6.93
(0.75)
6.53
(0.82)
6.32
(1.33)
Phenylalanine, % total protein
4.45
(0.17)
4.90
(0.20)
4.43
(0.16)
4.36
(0.17)
4.48
(0.26)
Serine, % total protein
4.41
(0.18)
4.76
(0.24)
4.54
(0.23)
4.49
(0.24)
4.52
(0.25)
Energy, kJ/day
8530
(1879)
8518
(2413)
9070
(2644)
9390
(2923)
8989
(2613)
Total Protein, g/day
80.7
(19.9)
63.0
(19.7)
83.5
(25.1)
84.9
(28.4)
79.8
(26.0)
Animal Protein, g/day
45.1
(16.0)
12.8
(13.2)
51.4
(20.7)
55.9
(23.6)
45.1
(25.4)
Vegetable Protein, g/day
35.6
(8.4)
50.2
(15.6)
32.1
(10.7)
28.0
(10.8)
34.3
(13.9)
Total Fat, g/day
56.8
(16.6)
45.9
(20.4)
81.0
(31.7)
84.4
(33.9)
70.4
(32.3)
Total SFA, g/day
15.0
(5.1)
11.5
(5.9)
29.4
(13.6)
28.0
(12.5)
22.1
(12.7)
Total MFA, g/day
20.6
(6.7)
18.5
(8.6)
27.3
(11.0)
31.9
(13.5)
26.2
(12.5)
Oleic Acid, g/day
18.3
(6.2)
15.4
(8.2)
24.8
(10.0)
29.8
(12.6)
23.8
(12.0)
Total PFA, g/day
14.6
(4.6)
13.5
(7.0)
15.2
(6.9)
17.9
(8.1)
16.0
(7.3)
Linoleic Acid, g/day
11.3
(3.9)
12.2
(6.6)
13.3
(6.3)
15.8
(7.3)
13.8
(6.7)
Total Omega-3, g/day
3.06
(1.12)
1.24
(0.92)
1.76
(0.80)
1.87
(0.93)
2.04
(1.15)
continued on next page
4
Table S.1. continued, page 3
Total Omega-6, g/day
11.5
(3.9)
12.2
(6.7)
13.5
(6.3)
16.0
(7.3)
13.9
(6.7)
Total TFA, g/day
0.99
(0.67)
0.42
(0.80)
3.34
(1.93)
5.03
(2.83)
3.03
(2.92)
Total Carbohydrate, g/day
273
(64)
327
(99)
253
(77)
274
(92)
281
(88)
Starch, g/day
179
(54)
283
(90)
145
(49)
125
(45)
169
(82)
Estimated Total Sugars, g/day
93
(27)
44
(31)
108
(43)
149
(66)
112
(64)
Total Dietary Fiber, g/day
15.6
(4.8)
28.1
(9.5)
25.5
(9.2)
19.1
(7.9)
20.6
(8.9)
Calcium, mg/day
606
(221)
303
(143)
933
(319)
791
(372)
674
(362)
Magnesium, mg/day
269
(66)
308
(115)
320
(94)
319
(112)
305
(103)
Phosphorus, mg/day
1134
(282)
879
(307)
1392
(410)
1295
(441)
1192
(416)
Total Iron, mg/day
10.7
(2.8)
15.8
(5.7)
13.1
(4.2)
16.9
(7.1)
14.8
(6.3)
Non-Heme Iron, mg/day
9.6
(2.6)
15.3
(5.4)
12.3
(4.1)
15.8
(6.9)
13.8
(6.1)
Copper, mg/day
1.36
(0.41)
2.37
(0.72)
1.37
(0.45)
1.46
(0.57)
1.59
(0.67)
Selenium, μg/day
171
(75)
34
(14)
95
(38)
132
(65)
120
(75)
14-day Alcohol, g/day
17.0
(22.6)
8.6
(21.4)
14.7
(19.2)
6.9
(13.7)
10.5
(18.8)
Total Protein, % kJ
16.0
(2.3)
12.4
(1.9)
15.8
(3.1)
15.5
(3.2)
15.1
(3.1)
Animal Protein, % kJ
8.9
(2.4)
2.5
(2.4)
9.8
(3.3)
10.2
(3.2)
8.4
(4.1)
continued on next page
5
Table S.1. continued, page 4
Vegetable Protein, % kJ
7.1
(1.1)
9.9
(1.3)
6.1
(1.4)
5.2
(1.6)
6.6
(2.2)
Total Fat, % kJ
24.9
(5.0)
20.0
(6.1)
32.8
(6.5)
32.9
(6.9)
28.6
(8.2)
Total SFA, % kJ
6.6
(1.8)
5.0
(2.0)
12.1
(3.3)
10.7
(2.8)
8.8
(3.6)
Total MFA, % kJ
9.0
(2.2)
8.1
(2.8)
11.0
(2.5)
12.2
(2.9)
10.5
(3.2)
Oleic Acid, % kJ
8.0
(2.0)
6.7
(2.8)
10.0
(2.3)
11.6
(2.8)
9.6
(3.2)
Total PFA, % kJ
6.4
(1.5)
5.8
(2.2)
6.2
(1.9)
7.0
(2.2)
6.5
(2.1)
Linoleic Acid, % kJ
4.9
(1.3)
5.3
(2.1)
5.4
(1.8)
6.2
(2.0)
5.7
(2.0)
Total Omega-3, % kJ
1.35
(0.38)
0.55
(0.37)
0.73
(0.26)
0.75
(0.31)
0.86
(0.44)
Total Omega-6, % kJ
5.0
(1.3)
5.3
(2.1)
5.5
(1.8)
6.3
(2.0)
5.7
(2.0)
Total TFA, % kJ
0.44
(0.30)
0.18
(0.34)
1.36
(0.61)
1.94
(0.80)
1.20
(0.98)
Total Carbohydrate, % kJ
54.2
(7.3)
65.0
(10.0)
44.5
(6.6)
49.4
(8.1)
52.9
(10.3)
Starch, % kJ
35.5
(7.3)
56.5
(10.3)
25.5
(5.2)
22.8
(5.7)
32.2
(14.3)
Estimated Total Sugars, % kJ
18.7
(4.7)
8.5
(5.2)
20.3
(6.0)
16.7
(8.2)
20.8
(9.5)
Total Dietary Fiber, g/1,000 kJ
1.9
(0.5)
3.4
(0.9)
2.9
(0.9)
2.2
(0.8)
2.4
(1.0)
Calcium, mg/1,000 kJ
73.0
(26.0)
35.7
(13.4)
106.5
(28.4)
86.8
(33.9)
76.3
(35.6)
Magnesium, mg/1,000 kJ
32.1
(6.0)
37.0
(11.1)
36.6
(8.4)
35.4
(9.6)
35.0
(9.2)
continued on next page
6
Table S.1. continued, page 5
Phosphorus, mg/1,000 kJ
135
(23)
105
(27)
158
(30)
141
(30)
135
(32)
Total Iron, mg/1,000 kJ
1.3
(0.3)
1.9
(0.4)
1.5
(0.4)
1.9
(0.6)
1.7
(0.6)
Non-Heme Iron, mg/1,000 kJ
1.1
(0.3)
1.8
(0.4)
1.4
(0.4)
1.7
(0.6)
1.6
(0.5)
Copper, mg/1,000 kJ
0.16
(0.04)
0.28
(0.04)
0.16
(0.04)
0.16
(0.05)
0.18
(0.06)
Selenium, μg/1,000 kJ
20.2
(7.8)
4.0
(1.0)
10.7
(3.4)
14.3
(6.0)
13.5
(7.8)
Urinary Sodium, mmol/24-hr
198
(56)
228
(100)
145
(49)
163
(59)
181
(72)
Urinary Potassium, mmol/24-hr
49
(14)
38
(13)
68
(20)
58
(21)
53
(20)
Urinary Sodium/Potassium Ratio
4.23
(1.24)
6.32
(2.83)
2.23
(0.80)
3.04
(1.20)
3.83
2.07
Height, m
1.61
(0.09)
1.59
(0.08)
1.69
(0.09)
1.68
(0.10)
1.65
(0.10)
Weight, kg
61.2
(10.2)
58.9
(10.0)
78.2
(15.3)
82.3
(19.6)
72.5
(19.0)
Body Mass Index, kg/m2
23.4
(2.9)
23.1
(3.4)
27.5
(4.6)
28.9
(5.9)
26.4
(5.5)
2.5
(3.6)
6.0
(3.8)
2.2
(2.4)
3.2
(3.1)
3.4
(3.5)
Physical Activity, hours/day
moderate + heavy activity
continued on next page
7
Table S.1. continued, page 6
n
(%)
n
(%)
n
(%)
n
(%)
n
(%)
-Yes
528
(46.1)
298
(35.5)
242
(48.3)
1,491
(67.9)
2,559
(54.7)
-Unknown
406
(35.5)
188
(22.4)
188
(37.5)
489
(22.3)
1,271
(27.2)
1,039
(90.7)
382
(45.5)
444
(88.6)
1,533
(69.8)
3,398
(72.6)
diabetic, fat modified, or other
76
(6.6)
45
(5.4)
106
(21.2)
401
(18.3)
628
(13.4)
Taking dietary supplement
243
(21.2)
34
(4.1)
191
(38.1)
1,136
(51.8)
1,604
(34.3)
High blood pressure*
153
(13.4)
145
(17.3)
116
(23.2)
595
(27.1)
1,009
(21.6)
131
(11.4)
59
(7.0)
54
(10.8)
343
(15.6)
587
(12.5)
124
(10.8)
86
(10.3)
98
(19.6)
644
(29.3)
952
(20.3)
Family history of hypertension in
any first degree relative
Current alcohol drinkers
Special diet: weight loss, weight
gain, vegetarian, salt reduced,
History of heart attack, other heart
disease, stroke, or diabetes
Taking prescribed drug treatment
for high BP, CVD†, diabetes, or
affecting cardiovascular system
continued on next page
8
Table S.1. continued, page 7
BP: blood pressure; SFA: saturated fatty acids; MFA: monounsaturated fatty acids; PFA: polyunsaturated fatty acids; TFA: trans fatty acids; CVD:
cardiovascular diseases.
*Systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg or reporting use of medication for high BP
†
Includes lipid-lowering drugs
9
Table S.2. Reliability and its Potential Effect on Regression Coefficients† for Dietary Amino Acids and Blood Pressure, for Participants of the
INTERMAP Study, Men and Women Combined and Separately
Variable (units)
Japan
Ratio*
PR China
(%)†
Ratio
(%)
UK
Ratio
USA
Overall
(%)
Ratio
(%)
Ratio
(%)
Men and women combined (N=4,680)
Glutamic Acid
Cystine
Proline
Phenylalanine
(g/day)
1.97
(67.0)
1.41
(73.9)
2.00
(66.7)
1.97
(67.0)
1.87
(68.1)
(% kJ)
3.28
(55.0)
2.13
(65.2)
2.23
(64.2)
2.50
(61.5)
2.59
(60.7)
(% Protein)
2.90
(58.0)
0.56
(87.7)
3.53
(53.1)
3.01
(57.1)
2.60
(60.6)
(g/day)
1.80
(69.0)
1.57
(71.8)
2.28
(63.7)
2.20
(64.5)
2.00
(66.7)
(% kJ)
3.61
(52.6)
1.45
(73.4)
2.20
(64.6)
2.62
(60.4)
2.61
(60.5)
(% Protein)
2.61
(60.6)
2.09
(65.6)
2.85
(58.4)
3.97
(50.2)
3.18
(55.7)
(g/day)
2.04
(66.3)
0.76
(84.0)
1.82
(68.8)
1.82
(68.8)
1.68
(70.4)
(% kJ)
2.53
(61.3)
0.59
(87.2)
2.06
(66.0)
2.32
(63.3)
2.03
(66.3)
(% Protein)
2.63
(60.3)
0.25
(94.1)
3.11
(56.2)
2.47
(61.8)
2.18
(64.7)
(g/day)
1.86
(68.3)
1.97
(67.0)
2.15
(65.0)
2.12
(65.3)
2.03
(66.3)
(% kJ)
3.07
(56.6)
1.95
(67.3)
2.35
(63.0)
2.69
(59.8)
2.61
(60.5)
(% Protein)
2.33
(63.2)
1.91
(67.7)
2.53
(61.3)
2.71
(59.6)
2.46
(61.9)
continued on next page
10
Table S.2. continued, page 2
Serine
(g/day)
1.88
(68.0)
1.82
(68.8)
2.05
(66.1)
2.09
(65.7)
1.99
(66.8)
(% kJ)
3.16
(55.9)
1.72
(69.9)
2.29
(63.5)
2.57
(60.9)
2.53
(61.2)
(% Protein)
3.52
(53.2)
2.01
(66.5)
3.33
(54.5)
3.88
(50.8)
3.40
(54.1)
Systolic BP
(mm Hg)
0.22
(94.9)
0.23
(94.5)
0.24
(94.4)
0.26
(94.0)
0.24
(94.3)
Diastolic BP
(mm Hg)
0.27
(93.7)
0.32
(92.6)
0.31
(92.8)
0.31
(92.9)
0.30
(93.0)
Men (N=2,359)
Glutamic Acid
Cystine
Proline
(g/day)
1.56
(71.9)
1.50
(72.7)
1.91
(67.7)
1.81
(68.8)
1.56
(71.9)
(% kJ)
1.85
(68.3)
2.18
(64.7)
2.30
(63.5)
2.32
(63.3)
1.85
(68.3)
(% Protein)
0.48
(89.4)
2.52
(61.4)
2.72
(59.5)
2.40
(62.5)
0.48
(89.4)
(g/day)
1.78
(69.1)
1.66
(70.7)
2.18
(64.7)
1.96
(67.1)
1.78
(69.1)
(% kJ)
1.30
(75.4)
2.03
(66.3)
2.43
(62.2)
2.35
(63.0)
1.30
(75.4)
(% Protein)
1.93
(67.5)
2.11
(65.5)
3.82
(51.2)
2.91
(57.9)
1.93
(67.5)
(g/day)
0.82
(83.0)
1.37
(74.5)
1.75
(69.6)
1.62
(71.2)
0.82
(83.0)
(% kJ)
0.56
(87.7)
1.94
(67.4)
2.06
(66.0)
1.80
(68.9)
0.56
(87.7)
(% Protein)
0.24
(94.3)
2.52
(61.3)
2.30
(63.5)
2.10
(65.5)
0.24
(94.3)
continued on next page
11
Table S.2. continued, page 3
Phenylalanine
(g/day)
2.31
(63.4)
1.60
(71.5)
2.06
(66.1)
2.01
(66.5)
2.31
(63.4)
(% kJ)
1.88
(68.0)
2.22
(64.3)
2.44
(62.1)
2.44
(62.1)
1.88
(68.0)
(% Protein)
1.89
(67.9)
2.37
(62.8)
2.51
(61.5)
2.22
(64.3)
1.89
(67.9)
(g/day)
2.10
(65.6)
1.53
(72.3)
2.09
(65.7)
1.99
(66.8)
2.10
(65.6)
(% kJ)
1.59
(71.5)
2.23
(64.2)
2.38
(62.7)
2.39
(62.6)
1.59
(71.5)
(% Protein)
1.75
(69.6)
2.73
(59.4)
3.44
(53.7)
2.88
(58.2)
1.75
(69.6)
Systolic BP
(mm Hg)
0.23
(94.6)
0.21
(94.9)
0.22
(94.9)
0.29
(93.3)
0.25
(94.1)
Diastolic BP
(mm Hg)
0.27
(93.7)
0.30
(93.1)
0.33
(92.4)
0.31
(92.9)
0.30
(93.1)
Serine
Women (N=2,321)
Glutamic Acid
Cystine
(g/day)
2.00
(66.7)
1.26
(76.0)
2.56
(61.0)
2.03
(66.3)
1.93
(67.4)
(% kJ)
3.80
(51.3)
2.40
(62.5)
2.28
(63.7)
2.70
(59.7)
2.87
(58.2)
(% Protein)
2.67
(60.0)
0.64
(86.2)
4.67
(46.1)
3.30
(54.8)
2.80
(58.8)
(g/day)
1.81
(68.9)
1.36
(74.6)
2.99
(57.2)
2.22
(64.3)
2.04
(66.2)
(% kJ)
4.12
(49.2)
1.60
(71.5)
2.38
(62.7)
2.81
(58.8)
2.87
(58.2)
(% Protein)
2.97
(57.4)
2.26
(63.9)
3.68
(52.1)
4.11
(49.3)
3.45
(53.7)
continued on next page
12
Table S.2. continued, page 4
Proline
(g/day)
2.00
(66.7)
0.70
(85.0)
2.33
(63.2)
1.89
(68.0)
1.74
(69.6)
(% kJ)
2.91
(57.9)
0.61
(86.8)
2.21
(64.4)
2.59
(60.7)
2.27
(63.8)
(% Protein)
2.39
(62.6)
0.27
(93.8)
3.78
(51.4)
2.63
(60.3)
2.26
(63.9)
(g/day)
1.82
(68.8)
1.64
(71.0)
2.78
(59.0)
2.19
(64.6)
2.06
(66.0)
(% kJ)
3.19
(55.6)
2.01
(66.6)
2.49
(61.6)
2.94
(57.6)
2.79
(58.9)
(% Protein)
2.84
(58.5)
1.93
(67.4)
2.71
(59.6)
2.92
(57.8)
2.70
(59.7)
(g/day)
1.84
(68.5)
1.54
(72.2)
2.64
(60.3)
2.09
(65.7)
1.98
(66.8)
(% kJ)
3.26
(55.1)
1.86
(68.3)
2.37
(62.8)
2.76
(59.2)
2.68
(59.9)
(% Protein)
4.38
(47.7)
2.28
(63.7)
4.01
(49.9)
4.32
(48.1)
3.93
(50.4)
Systolic BP
(mm Hg)
0.20
(95.2)
0.26
(94.0)
0.26
(93.9)
0.23
(94.6)
0.23
(94.6)
Diastolic BP
(mm Hg)
0.26
(93.8)
0.34
(92.2)
0.29
(93.2)
0.30
(92.9)
0.30
(93.0)
Phenylalanine
Serine
* Ratio of intra-individual to inter-individual variance estimated separately for 8 country-gender subgroups and pooled by N-1, to prevent
between-country and -gender differences from inflating between-person variance and spuriously reducing the ratio
†
Observed regression coefficient as a percentage of a theoretical regression coefficient in univariate regression analysis, based on 4 repeat
measures (for BP, 4× mean of 2 consecutive readings), calculated from the formula 1/[1+(reliability ratio/4)]×100
13
Table S.3. Partial correlation* of dietary amino acids (grams/day) and other variables
Variable
Glutamic Acid,
Cystine,
Proline,
Phenylalanine,
Serine,
g/day
g/day
g/day
g/day
g/day
1
0.84
0.90
0.88
0.87
Cystine, g/day
0.84
1
0.65
0.88
0.87
Proline, g/day
0.90
0.65
1
0.74
0.74
Phenylalanine, g/day
0.88
0.88
0.74
1
0.98
Serine, g/day
0.87
0.87
0.74
0.98
1
Total Protein, g/day
0.86
0.86
0.71
0.97
0.96
Animal Protein, g/day
0.62
0.63
0.54
0.80
0.80
Vegetable Protein, g/day
0.33
0.32
0.23
0.19
0.16
Total Fat, g/day
0.04
0.03
0.04
0.11
0.13
Total SFA, g/day
0.06
-0.02
0.12
0.10
0.12
Total MFA, g/day
0.01
0.03
-0.01
0.08
0.10
Oleic Acid, g/day
-0.01
0.01
-0.02
0.06
0.08
Total PFA, g/day
0.002
0.02
-0.04
0.04
0.03
Linoleic Acid, g/day
-0.02
-0.01
-0.05
-0.004
-0.01
Glutamic Acid, g/day
continued on next page
14
Table S.3. continued, page 2
Total Omega-3, g/day
0.08
0.10
0.01
0.14
0.14
Total Omega-6, g/day
-0.02
-0.001
-0.05
0.004
-0.001
Total TFA, g/day
-0.05
-0.08
0.001
-0.09
-0.09
Total Carbohydrate, g/day
-0.18
-0.16
-0.16
-0.31
-0.31
0.12
0.19
0.05
-0.02
-0.04
-0.31
-0.37
-0.20
-0.31
-0.29
Total Dietary Fiber, g/day
0.14
0.16
0.12
0.11
0.10
Calcium, mg/day
0.40
0.17
0.52
0.39
0.42
Magnesium, mg/day
0.32
0.34
0.28
0.38
0.36
Phosphorus, mg/day
0.60
0.56
0.60
0.70
0.71
Total Iron, mg/day
0.36
0.35
0.31
0.38
0.37
Non-Heme Iron, mg/day
0.32
0.31
0.28
0.32
0.31
Copper, mg/day
0.21
0.28
0.12
0.23
0.22
Selenium, μg/day
0.38
0.40
0.29
0.40
0.42
-0.13
-0.17
-0.10
-0.08
-0.09
Starch, g/day
Estimated Total Sugars, g/day
14-day Alcohol, g/day
continued on next page
15
Table S.3. continued, page 3
Urinary Sodium, mmol/24-hr
0.17
0.17
0.14
0.16
0.16
Urinary Potassium, mmol/24-hr
0.22
0.15
0.24
0.22
0.22
Urinary Sodium/Potassium Ratio
-0.03
0.02
-0.07
-0.05
-0.04
Height, m
0.02
0.02
0.04
0.02
0.02
Weight, kg
0.09
0.11
0.07
0.12
0.11
Body Mass Index, kg/m2
0.08
0.10
0.06
0.11
0.11
Systolic BP, mm Hg
-0.02
0.003
-0.02
-0.001
0.001
Diastolic BP, mm Hg
-0.03
-0.02
-0.02
-0.01
-0.01
SFA: saturated fatty acids; MFA: monounsaturated fatty acids; PFA: polyunsaturated fatty acids; TFA: trans fatty acids; BP: blood pressure.
* Pooled by country (weighted by N), adjusted for age, gender, center, energy
16
Table S.4. Partial correlation* of dietary amino acids (% kJ) and other variables
Variable
Glutamic Acid,
Cystine,
Proline,
Phenylalanine,
Serine,
% kJ
% kJ
% kJ
% kJ
% kJ
1
0.84
0.89
0.89
0.88
Cystine, % kJ
0.84
1
0.65
0.88
0.88
Proline, % kJ
0.89
0.65
1
0.75
0.75
Phenylalanine, % kJ
0.89
0.88
0.75
1
0.98
Serine, % kJ
0.88
0.88
0.75
0.98
1
Total Protein, % kJ
0.87
0.86
0.73
0.97
0.96
Animal Protein, % kJ
0.65
0.64
0.57
0.81
0.81
Vegetable Protein, % kJ
0.35
0.35
0.24
0.23
0.20
Total Fat, % kJ
0.01
-0.01
0.02
0.06
0.08
Total SFA, % kJ
0.02
-0.07
0.10
0.05
0.07
Total MFA, % kJ
-0.03
-0.02
-0.03
0.02
0.04
Oleic Acid, % kJ
-0.04
-0.03
-0.03
0.01
0.03
Total PFA, % kJ
-0.02
-0.01
-0.06
0.01
0.001
Linoleic Acid, % kJ
-0.04
-0.03
-0.07
-0.03
-0.03
Glutamic Acid, % kJ
continued on next page
17
Table S.4. continued, page 2
Total Omega-3, % kJ
0.07
0.10
-0.01
0.14
0.14
Total Omega-6, % kJ
-0.04
-0.02
-0.06
-0.02
-0.03
Total TFA, % kJ
-0.08
-0.12
-0.03
-0.13
-0.12
Total Carbohydrate, % kJ
-0.19
-0.15
-0.17
-0.28
-0.29
0.12
0.21
0.04
0.002
-0.02
Estimated Total Sugars, % kJ
-0.30
-0.38
-0.19
-0.31
-0.28
Total Dietary Fiber, g/1,000 kJ
0.17
0.19
0.16
0.16
0.14
Calcium, mg/1,000 kJ
0.39
0.17
0.53
0.38
0.41
Magnesium, mg/1,000 kJ
0.35
0.36
0.32
0.40
0.38
Phosphorus, mg/1,000 kJ
0.62
0.57
0.62
0.71
0.72
Total Iron, mg/1,000 kJ
0.37
0.35
0.33
0.39
0.38
Non-Heme Iron, mg/1,000 kJ
0.33
0.31
0.31
0.33
0.32
Copper, mg/1,000 kJ
0.24
0.30
0.16
0.26
0.25
Selenium, μg/1,000 kJ
0.40
0.42
0.31
0.43
0.44
14-day Alcohol, g/day
-0.14
-0.18
-0.10
-0.11
-0.11
Starch, % kJ
continued on next page
18
Table S.4. continued, page 3
Urinary Sodium, mmol/24-hr
0.10
0.11
0.08
0.10
0.10
Urinary Potassium, mmol/24-hr
0.18
0.10
0.21
0.18
0.18
Urinary Sodium/Potassium Ratio
-0.05
0.01
-0.09
-0.06
-0.06
Height, m
-0.01
-0.01
0.01
-0.001
0.003
Weight, kg
0.06
0.07
0.05
0.09
0.08
Body Mass Index, kg/m2
0.06
0.08
0.05
0.09
0.09
Systolic BP, mm Hg
-0.03
-0.01
-0.03
-0.01
-0.01
Diastolic BP, mm Hg
-0.03
-0.03
-0.03
-0.02
-0.02
SFA: saturated fatty acids; MFA: monounsaturated fatty acids; PFA: polyunsaturated fatty acids; TFA: trans fatty acids; BP: blood pressure.
* Pooled by country (weighted by N), adjusted for age, gender, center
19
Table S.5. Partial correlation* of dietary amino acids (% Total Protein) and other variables
Variable
Glutamic Acid,
Cystine,
Proline,
Phenylalanine,
Serine,
% Total Protein
% Total Protein
% Total Protein
% Total Protein
% Total Protein
1
0.45
0.80
0.47
0.37
Cystine, % Total Protein
0.45
1
0.16
0.43
0.39
Proline, % Total Protein
0.80
0.16
1
0.39
0.36
Phenylalanine, % Total Protein
0.47
0.43
0.39
1
0.80
Serine, % Total Protein
0.37
0.39
0.36
0.80
1
Total Protein, % kJ
-0.37
-0.41
-0.30
-0.28
-0.23
Animal Protein, % kJ
-0.53
-0.54
-0.35
-0.42
-0.30
0.36
0.35
0.14
0.34
0.18
Total Fat, % kJ
-0.08
-0.11
-0.04
0.02
0.08
Total SFA, % kJ
-0.02
-0.20
0.11
0.05
0.13
Total MFA, % kJ
-0.09
-0.06
-0.08
-0.02
0.06
Oleic Acid, % kJ
-0.08
-0.04
-0.06
-0.01
0.06
Total PFA, % kJ
-0.02
0.03
-0.07
0.05
0.03
0.03
0.07
-0.03
0.08
0.05
Glutamic Acid, % Total Protein
Vegetable Protein, % kJ
Linoleic Acid, % kJ
continued on next page
20
Table S.5. continued, page 2
Total Omega-3, % kJ
-0.16
-0.12
-0.20
-0.07
-0.07
Total Omega-6, % kJ
0.02
0.07
-0.04
0.08
0.05
Total TFA, % kJ
0.14
0.08
0.15
0.07
0.08
Total Carbohydrate, % kJ
0.33
0.37
0.21
0.27
0.20
Starch, % kJ
0.39
0.55
0.15
0.37
0.21
Estimated Total Sugars, % kJ
0.001
-0.14
0.11
-0.08
0.01
Total Dietary Fiber, g/1,000 kJ
0.06
0.09
0.03
0.11
0.03
Calcium, mg/1,000 kJ
0.09
-0.35
0.31
0.23
0.27
Magnesium, mg/1,000 kJ
-0.10
-0.12
-0.07
0.04
-0.04
Phosphorus, mg/1,000 kJ
-0.18
-0.32
-0.03
0.07
0.10
Total Iron, mg/1,000 kJ
-0.01
-0.05
-0.01
0.02
-0.01
0.05
0.004
0.04
0.09
0.05
Copper, mg/1,000 kJ
-0.05
0.04
-0.13
0.02
-0.02
Selenium, μg/1,000 kJ
-0.10
-0.05
-0.12
-0.15
-0.05
14-day Alcohol, g/day
-0.17
-0.21
-0.08
-0.23
-0.22
Non-Heme Iron, mg/1,000 kJ
continued on next page
21
Table S.5. continued, page 3
Urinary Sodium, mmol/24-hr
-0.04
-0.02
-0.05
-0.04
-0.03
Urinary Potassium, mmol/24-hr
-0.06
-0.21
0.01
-0.05
-0.04
Urinary Sodium/Potassium Ratio
0.01
0.16
-0.05
0.01
0.01
Height, m
-0.01
-0.02
0.02
0.01
0.01
Weight, kg
-0.08
-0.05
-0.06
-0.04
-0.04
Body Mass Index, kg/m2
-0.08
-0.05
-0.07
-0.04
-0.04
Systolic BP, mm Hg
-0.08
-0.03
-0.06
-0.07
-0.05
Diastolic BP, mm Hg
-0.06
-0.04
-0.03
-0.07
-0.05
SFA: saturated fatty acids; MFA: monounsaturated fatty acids; PFA: polyunsaturated fatty acids; TFA: trans fatty acids; BP: blood pressure.
* Pooled by country (weighted by N), adjusted for age, gender, center
22
Table S.6. Estimated Mean Difference in Blood Pressure, Proline Intake (% Total Protein) from Foods Higher by 2 s.d., Multiple Regression
Analyses
Model
Systolic BP
Diastolic BP
Difference, mm Hg
(Z-value)
Difference, mm Hg
(Z- value)
4
-1.56
(-2.16)
-0.81*
(-1.67)
5a - P
-1.50
(-2.03)
-0.76
(-1.52)
5b - Mg
-1.88
(-2.58)
-1.05*
(-2.13)
5c - Ca
-0.28
(-0.35)
-0.05
(-0.10)
5d - Fe
-1.45
(-2.00)
-0.79*
(-1.62)
5e - Fiber
-1.61
(-2.24)
-0.83*
(-1.72)
Main Analyses – All 4,680 Participants
continued on next page
23
Table S.6. continued, page 2
Sensitivity Analyses
Adjusted also for Education (years), and
Current Smoking (yes/no) – N=4,680
4
-1.52
(-2.11)
-0.85
(-1.76)
5b - Mg
-1.85
(-2.53)
-1.10
(-2.23)
4
-1.52
(-2.11)
-0.75
(-1.54)
5b - Mg
-1.85
(-2.53)
-0.97
(-1.98)
4
-1.52
(-2.11)
-0.76
(-1.57)
5b - Mg
-1.85
(-2.53)
-1.00
(-2.03)
Adjusted also for Month of Field Survey –
N=4,680
Adjusted also for Season of Field Survey –
N=4,680
continued on next page
24
Table S.6. continued, page 3
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
4
-1.61
(-2.24)
-0.81*
(-1.68)
5b - Mg
-1.92
(-2.63)
-1.05*
(-2.14)
4
-1.38
(-1.92)
-0.68*
(-1.40)
5b - Mg
-1.68
(-2.30)
-0.88
(-1.79)
4
-1.30
(-1.73)
-0.76*
(-1.52)
5b - Mg
-1.35
(-1.78)
-0.90*
(-1.77)
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) instead of
Urinary Na and Urinary K (mmol/24-h) –
(N=4,680)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
continued on next page
25
Table S.6. continued, page 4
Adjusted also for Starch (% kJ) – (N=4,680)
4
-1.22
(-1.66)
-0.54*
(-1.10)
5b - Mg
-1.64
(-2.20)
-0.83
(-1.65)
4
-2.18*
(-2.72)
-1.14*
(-2.14)
5b - Mg
-2.49
(-3.06)
-1.37*
(-2.51)
4
-1.49
(-2.53)
-0.48
(-1.09)
5b - Mg
-1.75
(-2.92)
-0.69
(-1.55)
4
-2.10
(-2.44)
-1.25
(-2.15)
5b - Mg
-2.29
(-2.64)
-1.44
(-2.45)
Censored normal regression adjusting for
antihypertensive treatment – (N=4,680)
Nonhypertensive Persons – (N=3,671)
Excluding Persons with High Day-to-day
Variability in Nutrient Intake and/or BP –
(N=3,473)
continued on next page
26
Table S.6. continued, page 5
Proline Expressed as grams/day (instead of %
Total Protein) – (N=4,680)
4 + Total Energy (kJ/day)
-1.74
(-2.18)
-0.96
(-1.78)
5b - Mg + Total Energy (kJ/day)
-0.60
(-0.70)
-0.48*
(-0.84)
4 + Total Energy + Height + Weight
-1.80
(-2.37)
-1.00
(-1.93)
5b - Mg + Total Energy + Height + Weight
-1.47
(-1.81)
-1.01
(-1.81)
4
-1.18
-2.32
-0.70*
-2.03
5b - Mg
-0.34
-0.61
-0.38*
-1.00
4 + Height + Weight
-1.11
-2.28
-0.64*
-1.91
5b - Mg + Height + Weight
-0.85
-1.60
-0.66*
-1.82
Proline Expressed as % kJ (instead of % Total
Protein) – (N=4,680)
continued on next page
27
Table S.6. continued, page 6
Model 4: Controlled for Sample, Age, Gender, Diet (Yes/No), Supplement Intake (Yes/No), CVD-DM Diagnosis (Yes/No), Physical Activity
(Medium + Heavy, hours/day), Family History of High BP (Yes, No or Unknown), Urinary Na and Urinary K (mmol/24-h), 14-day Alcohol
(grams/day), Cholesterol (mg/1,000 kJ), Total SFA and Total PFA (% kJ)
Model 5a-5e, Main Analyses: Controlled for Model 4 variables + each stipulated nutrient (expressed per 1,000 kJ)
Sensitivity Analyses: controlled for Model 4 variables + each stipulated variable, or variables in Model 5b - Mg + each stipulated variable
Month of field survey: mid-point between first and fourth clinic visit. Season of field survey: Winter = December/January/February; Spring =
March/April/May; Summer = June/July/August; Fall = September/October/November
Z-value=regression coefficient/standard error; Z-value ≥1.96: uncorrected p ≤0.05; ≥2.58: uncorrected p ≤0.01; ≥3.29: uncorrected p ≤0.001
2 s.d. higher proline intake for % Total Protein – 2.54%; for grams/day – 3.34; for % Total Kilocalories – 0.40%
*Test for cross-country heterogeneity significant, p <0.05.
28
Table S.7. Estimated Mean Difference in Blood Pressure, Phenylalanine Intake (% Total Protein) from Foods Higher by 2 s.d., Multiple
Regression Analyses
Model
Systolic BP
Diastolic BP
Difference, mm Hg
(Z- value)
Difference, mm Hg
(Z- value)
4
-1.49
(-3.35)
-1.03
(-3.40)
5a - P
-1.13
(-2.46)
-0.81
(-2.59)
5b - Mg
-1.31
(-2.89)
-0.98
(-3.16)
5c - Ca
-0.90
(-1.89)
-0.70
(-2.17)
5d - Fe
-1.33
(-2.97)
-0.96
(-3.14)
5e - Fiber
-1.28
(-2.83)
-0.94
(-3.05)
Main Analyses – All 4,680 Participants
continued on next page
29
Table S.7. continued, page 2
Sensitivity Analyses
Adjusted also for Education (years), and
Current Smoking (yes/no) – N=4,680
4
-1.47
(-3.29)
-1.07
(-3.52)
5b - Mg
-1.30
(-2.85)
-1.03
(-3.31)
4
-1.47
(-3.27)
-1.04
(-3.40)
5b - Mg
-1.28
(-2.80)
-0.98
(-3.15)
4
-1.47
(-3.30)
-1.04
(-3.41)
5b - Mg
-1.30
(-2.84)
-0.98
(-3.17)
Adjusted also for Month of Field Survey –
N=4,680
Adjusted also for Season of Field Survey –
N=4,680
continued on next page
30
Table S.7. continued, page 3
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
4
-1.57
(-3.52)
-1.04
(-3.42)
5b - Mg
-1.37
(-3.00)
-0.98
(-3.14)
4
-1.44
(-3.23)
-1.00
(-3.30)
5b - Mg
-1.34
(-2.94)
-0.98
(-3.16)
-1.36*
(-2.85)
-1.09
(-3.36)
-0.88
(-1.79)
-0.92
(-2.74)
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) instead of
Urinary Na and Urinary K (mmol/24-h) –
(N=4,680)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
4
5b - Mg
continued on next page
31
Table S.7. continued, page 4
Adjusted also for Starch (% kJ) – (N=4,680)
4
-1.36
(-2.80)
-0.87
(-2.62)
5b - Mg
-1.18
(-2.40)
-0.79
(-2.36)
4
-2.01*
(-3.98)
-1.41
(-4.13)
5b - Mg
-1.80
(-3.49)
-1.33
(-3.81)
4
-0.58*
(-1.55)
-0.63
(-2.25)
5b - Mg
-0.48*
(-1.24)
-0.61
(-2.13)
4
-1.38
(-2.59)
-0.88
(-2.42)
5b - Mg
-1.21
(-2.22)
-0.85
(-2.29)
Censored normal regression adjusting for
antihypertensive treatment – (N=4,680)
Nonhypertensive Persons – (N=3,671)
Excluding Persons with High Day-to-day
Variability in Nutrient Intake and/or BP –
(N=3,473)
continued on next page
32
Table S.7. continued, page 5
Phenylalanine Expressed as grams/day
(instead of % Total Protein) – (N=4,680)
4 + Total Energy (kJ/day)
-0.97
(-1.17)
-0.61
(-1.08)
0.95
(1.03)
0.34
(0.54)
4 + Total Energy + Height + Weight
-1.49
(-1.88)
-0.97
(-1.77)
5b - Mg + Total Energy + Height + Weight
-0.75
(-0.85)
-0.73
(-1.20)
-0.80
(-1.68)
-0.53
(-1.62)
0.38
(0.71)
-0.0004
(-0.01)
4 + Height + Weight
-0.99
(-2.17)
-0.64
(-2.05)
5b - Mg + Height + Weight
-0.56
(-1.08)
-0.58
(-1.62)
5b - Mg + Total Energy (kJ/day)
Phenylalanine Expressed as % kJ (instead
of % Total Protein) – (N=4,680)
4
5b - Mg
continued on next page
33
Table S.7. continued, page 6
Model 4: Controlled for Sample, Age, Gender, Diet (Yes/No), Supplement Intake (Yes/No), CVD-DM Diagnosis (Yes/No), Physical Activity
(Medium + Heavy, hours/day), Family History of High BP (Yes, No or Unknown), Urinary Na and Urinary K (mmol/24-h), 14-day Alcohol
(grams/day), Cholesterol (mg/1,000 kJ), Total SFA and Total PFA (% kJ)
Model 5a-5e, Main Analyses: Controlled for Model 4 variables + each stipulated nutrient (expressed per 1,000 kJ)
Sensitivity Analyses: controlled for Model 4 variables + each stipulated variable, or variables in Model 5b - Mg + each stipulated variable
Month of field survey: mid-point between first and fourth clinic visit. Season of field survey: Winter = December/January/February; Spring =
March/April/May; Summer = June/July/August; Fall = September/October/November
Z-value=regression coefficient/standard error; Z-value=regression coefficient/standard error; Z-value ≥1.96: uncorrected p ≤0.05; ≥2.58:
uncorrected p ≤0.01; ≥3.29: uncorrected p ≤0.001
2 s.d. higher phenylalanine intake for % Total Protein – 0.35%; for grams/day – 2.16; for % Total Kilocalories – 0.24%
*Test for cross-country heterogeneity significant, p <0.05.
34
Table S.8. Estimated Mean Difference in Blood Pressure, Serine Intake (% Total Protein) from Foods Higher by 2 s.d., Multiple Regression
Analyses
Model
Systolic BP
Diastolic BP
Difference, mm Hg
(Z- value)
Difference, mm Hg
(Z- value)
4
-1.29
(-2.95)
-0.85
(-2.87)
5a - P
-0.99
(-2.20)
-0.66
(-2.18)
5b - Mg
-1.18
(-2.67)
-0.84
(-2.80)
5c - Ca
-0.55
(-1.15)
-0.44
(-1.33)
5d - Fe
-1.21
(-2.75)
-0.82
(-2.73)
5e - Fiber
-1.10
(-2.51)
-0.77
(-2.56)
Main Analyses – All 4,680 Participants
continued on next page
35
Table S.8. continued, page 2
Sensitivity Analyses
Adjusted also for Education (years), and
Current Smoking (yes/no) – N=4,680
4
-1.28
(-2.94)
-0.88
(-2.97)
5b - Mg
-1.18
(-2.67)
-0.88
(-2.92)
4
-1.30
(-2.97)
-0.86
(-2.90)
5b - Mg
-1.19
(-2.68)
-0.85
(-2.81)
4
-1.29
(-2.95)
-0.86
(-2.89)
5b - Mg
-1.18
(-2.66)
-0.84
(-2.81)
Adjusted also for Month of Field Survey –
N=4,680
Adjusted also for Season of Field Survey –
N=4,680
continued on next page
36
Table S.8. continued, page 3
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
4
-1.39*
(-3.18)
-0.87
(-2.91)
-1.26
(-2.81)
-0.85
(-2.78)
4
-1.13
(-2.58)
-0.75
(-2.53)
5b - Mg
-1.08
(-2.45)
-0.76
(-2.54)
4
-1.14*
(-2.39)
-0.93
(-2.86)
5b - Mg
-0.69
(-1.42)
-0.80
(-2.39)
5b - Mg
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) instead of
Urinary Na and Urinary K (mmol/24-h) –
(N=4,680)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
continued on next page
37
Table S.8. continued, page 4
Adjusted also for Starch (% kJ) – (N=4,680)
4
-1.14
(-2.52)
-0.70
(-2.27)
5b - Mg
-1.05
(-2.29)
-0.69
(-2.22)
4
-2.01*
(-4.03)
-1.37
(-4.10)
5b - Mg
-1.87*
(-3.70)
-1.34
(-3.93)
-0.50*
(-1.35)
-0.51
(-1.86)
-0.44
(-1.17)
-0.53
(-1.89)
4
-1.18
(-2.29)
-0.71
(-2.04)
5b - Mg
-1.06
(-2.04)
-0.72
(-2.04)
Censored normal regression adjusting for
antihypertensive treatment – (N=4,680)
Nonhypertensive Persons – (N=3,671)
4
5b - Mg
Excluding Persons with High Day-to-day
Variability in Nutrient Intake and/or BP –
(N=3,473)
continued on next page
38
Table S.8. continued, page 5
Serine Expressed as grams/day (instead of %
Total Protein) – (N=4,680)
4 + Total Energy (kJ/day)
-1.15
(-1.33)
-0.69
(-1.18)
0.90
(0.94)
0.30
(0.46)
4 + Total Energy + Height + Weight
-1.46
(-1.79)
-0.92
(-1.63)
5b - Mg + Total Energy + Height + Weight
-0.68
(-0.74)
-0.69
(-1.08)
-0.91
(-1.83)
-0.60
(-1.76)
0.36
(0.63)
-0.05
(-0.14)
4 + Height + Weight
-1.00
(-2.11)
-0.65
(-1.98)
5b - Mg + Height + Weight
-0.54
(-0.99)
-0.60
(-1.60)
5b - Mg + Total Energy (kJ/day)
Serine Expressed as % kJ (instead of % Total
Protein) – (N=4,680)
4
5b - Mg
continued on next page
39
Table S.8. continued, page 6
Model 4: Controlled for Sample, Age, Gender, Diet (Yes/No), Supplement Intake (Yes/No), CVD-DM Diagnosis (Yes/No), Physical Activity
(Medium + Heavy, hours/day), Family History of High BP (Yes, No or Unknown), Urinary Na and Urinary K (mmol/24-h), 14-day Alcohol
(grams/day), Cholesterol (mg/1,000 kJ), Total SFA and Total PFA (% kJ)
Model 5a-5e, Main Analyses: Controlled for Model 4 variables + each stipulated nutrient (expressed per 1,000 kJ)
Sensitivity Analyses: controlled for Model 4 variables + each stipulated variable, or variables in Model 5b - Mg + each stipulated variable
Month of field survey: mid-point between first and fourth clinic visit. Season of field survey: Winter = December/January/February; Spring =
March/April/May; Summer = June/July/August; Fall = September/October/November
Z-value=regression coefficient/standard error; Z-value=regression coefficient/standard error; Z-value ≥1.96: uncorrected p ≤0.05; ≥2.58:
uncorrected p ≤0.01; ≥3.29: uncorrected p ≤0.001
2 s.d. higher serine intake for % Total Protein – 0.45%; for grams/day – 2.20; for % Total Kilocalories – 0.24%
*Test for cross-country heterogeneity significant, p <0.05.
40
Table S.9. Sensitivity Analyses: Two Amino Acids Regressed Simultaneously, Model 5b - Mg
Amino Acids, Analysis
Systolic BP
Diastolic BP
Difference, mm Hg
(Z- value)
Difference, mm Hg
(Z- value)
-2.70
(-2.50)
-2.01
(-2.83)
0.27
(0.23)
0.55*
(0.72)
-3.18
(-2.94)
-2.20
(-3.11)
0.91
(0.78)
0.92
(1.20)
-2.71
(-2.51)
-1.98
(-2.79)
0.26
(0.22)
0.54
(0.70)
-2.81
(-2.54)
-1.87
(-2.58)
0.30
(0.26)
0.46
(0.59)
Glutamic Acid (% Total Protein)
-0.97
(-1.08)
-1.51
(-2.29)
Proline (% Total Protein)
-1.11
(-1.18)
0.51
(0.75)
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
Glutamic Acid (% Total Protein)
Proline (% Total Protein)
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) – (N=4,680)
Glutamic Acid (% Total Protein)
Proline (% Total Protein)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
Glutamic Acid (% Total Protein)
Proline (% Total Protein)
Adjusted also for Starch (% kJ) – (N=4,680)
Glutamic Acid (% Total Protein)
Proline (% Total Protein)
Nonhypertensive Persons – (N=3,671)
continued on next page
41
Table S.9. continued, page 2
Excluding Persons with High Day-to-day
Variability in Nutrient Intake/BP – (N=3,473)
Glutamic Acid (% Total Protein)
-2.82
(-2.11)
-1.43
(-1.63)
0.03
(0.02)
-0.32
(-0.34)
2.01
(1.01)
0.31
(0.23)
Proline + Total Energy (kJ/day)
-2.20
(-1.18)
-0.51
(-0.41)
Glutamic Acid + Energy + Height + Weight
-0.24
(-0.13)
-1.09
(-0.84)
Proline + Energy + Height + Weight
-1.20
(-0.67)
0.12
(0.10)
0.39
(0.36)
0.03
(0.04)
Proline
-0.63
(-0.53)
-0.20*
(-0.25)
Glutamic Acid + Height + Weight
-0.61
(-0.58)
-0.59
(-0.85)
Proline + Height + Weight
-0.14
(-0.13)
0.13*
Glutamic Acid (% Total Protein)
-1.96
(-2.43)
-1.25
(-2.34)
Phenylalanine (% Total Protein)
-0.78
(-1.42)
-0.63
(-1.69)
Glutamic Acid (% Total Protein)
-2.03
(-2.52)
-1.21
(-2.26)
Phenylalanine (% Total Protein)
-0.73
(-1.35)
-0.64
(-1.74)
Proline (% Total Protein)
Amino Acids as g/day – (N=4,680)
Glutamic Acid + Energy (kJ/day)
Amino Acids as % kJ – (N=4,680)
Glutamic Acid
(0.17)
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) – (N=4,680)
continued on next page
42
Table S.9. continued, page 3
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
Glutamic Acid (% Total Protein)
-2.01
(-2.50)
-1.25
(-2.33)
Phenylalanine (% Total Protein)
-0.72
(-1.30)
-0.60
(-1.60)
Glutamic Acid (% Total Protein)
-2.09
(-2.57)
-1.23
(-2.28)
Phenylalanine (% Total Protein)
-0.74
(-1.33)
-0.55
(-1.46)
Glutamic Acid (% Total Protein)
-1.40
(-2.09)
-0.81
(-1.64)
Phenylalanine (% Total Protein)
0.18
(0.39)
-0.24
(-0.71)
Glutamic Acid (% Total Protein)
-2.56
(-2.62)
-1.29
(-1.98)
Phenylalanine (% Total Protein)
-0.34
(-0.52)
-0.39
(-0.89)
-5.53
(-2.57)
-3.83
(-2.68)
5.78
(2.56)
4.04
(2.66)
Glutamic Acid + Energy + Height + Weight
-4.38
(-2.12)
-3.04
(-2.28)
Phenylalanine + Energy + Height + Weight
2.92
(1.35)
2.14
(1.46)
Adjusted also for Starch (% kJ) – (N=4,680)
Nonhypertensive Persons – (N=3,671)
Excluding Persons with High Day-to-day
Variability in Nutrient Intake/BP – (N=3,473)
Amino Acids as g/day – (N=4,680)
Glutamic Acid + Energy (kJ/day)
Phenylalanine + Total Energy (kJ/day)
continued on next page
43
Table S.9. continued, page 4
Amino Acids as % kJ – (N=4,680)
Glutamic Acid
-2.89
(-2.42)
-1.70
(-2.14)
Phenylalanine
3.22
(2.47)
1.84
(2.08)
Glutamic Acid + Height + Weight
-2.02
(-1.76)
-1.11
(-1.45)
Phenylalanine + Height + Weight
1.39
(1.11)
0.64
(0.75)
Glutamic Acid (% Total Protein)
-2.22
(-2.77)
-1.38
(-2.59)
Serine (% Total Protein)
-0.59
(-1.09)
-0.40
(-1.10)
Glutamic Acid (% Total Protein)
-2.43
(-3.04)
-1.41
(-2.67)
Serine (% Total Protein)
-0.35
(-0.66)
-0.31
(-0.85)
Glutamic Acid (% Total Protein)
-2.28
(-2.85)
-1.37
(-2.59)
Serine (% Total Protein)
-0.53
(-0.98)
-0.38
(-1.03)
Glutamic Acid (% Total Protein)
-2.37
(-2.93)
-1.33
(-2.48)
Serine (% Total Protein)
-0.50
(-0.94)
-0.35
(-0.96)
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) – (N=4,680)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
Adjusted also for Starch (% kJ) – (N=4,680)
continued on next page
44
Table S.9. continued, page 5
Nonhypertensive Persons – (N=3,671)
Glutamic Acid (% Total Protein)
-1.65
(-2.48)
-0.93
(-1.90)
0.26
(0.57)
-0.07
(-0.22)
Glutamic Acid (% Total Protein)
-2.78
(-2.86)
-1.40
(-2.16)
Serine (% Total Protein)
-0.13
(-0.21)
-0.19
(-0.45)
-4.95
(-2.28)
-3.66
(-2.54)
5.53
(2.33)
4.03
(2.50)
-4.71
(-2.27)
-3.43
(-2.48)
3.67
(1.62)
2.76
(1.78)
-2.58
(-2.15)
-1.51
(-1.88)
3.14
(2.28)
1.70
(1.81)
-2.11
(-1.84)
-1.18
(-1.52)
1.73
(1.31)
0.77
(0.85)
Proline (% Total Protein)
-1.00
(-1.13)
-0.44
(-0.72)
Phenylalanine (% Total Protein)
-0.85
(-1.48)
-0.69
(-1.76)
Serine (% Total Protein)
Excluding Persons with High Day-to-day
Variability in Nutrient Intake/BP – (N=3,473)
Amino Acids as g/day – (N=4,680)
Glutamic Acid + Energy (kJ/day)
Serine + Total Energy (kJ/day)
Glutamic Acid + Energy + Height + Weight
Serine + Energy + Height + Weight
Amino Acids as % kJ – (N=4,680)
Glutamic Acid
Serine
Glutamic Acid + Height + Weight
Serine + Height + Weight
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
continued on next page
45
Table S.9. continued, page 6
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) – (N=4,680)
Proline (% Total Protein)
-0.73
(-0.83)
-0.21
(-0.35)
Phenylalanine (% Total Protein)
-0.94
(-1.67)
-0.77
(-2.00)
Proline (% Total Protein)
-1.06
(-1.19)
-0.43
(-0.72)
Phenylalanine (% Total Protein)
-0.77
(-1.34)
-0.64
(-1.64)
Proline (% Total Protein)
-1.07
(-1.20)
-0.47
(-0.77)
Phenylalanine (% Total Protein)
-0.78
(-1.33)
-0.55
(-1.38)
Proline (% Total Protein)
-1.24
(-1.71)
-0.08
(-0.14)
Phenylalanine (% Total Protein)
-0.17
(-0.36)
-0.46
(-1.30)
Proline (% Total Protein)
-1.82
(-1.71)
-0.98
(-1.36)
Phenylalanine (% Total Protein)
-0.31
(-0.46)
-0.35
(-0.76)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
Adjusted also for Starch (% kJ) – (N=4,680)
Nonhypertensive Persons – (N=3,671)
Excluding Persons with High Day-to-day
Variability in Nutrient Intake/BP – (N=3,473)
continued on next page
46
Table S.9. continued, page 7
Amino Acids as g/day – (N=4,680)
Proline + Energy (kJ/day)
-3.00
(-2.24)
-1.55*
(-1.72)
3.72
(2.51)
2.25
(2.22)
-2.27
(-1.77)
-1.08*
(-1.25)
1.28
(0.90)
0.67
(0.68)
-1.47
(-1.68)
-0.73*
(-1.24)
1.86
(2.15)
1.09
(1.84)
-0.96
(-1.14)
-0.38*
(-0.67)
0.47
(0.56)
0.19
(0.34)
Proline (% Total Protein)
-1.38
(-1.51)
-0.59
(-0.95)
Serine (% Total Protein)
-0.60
(-1.02)
-0.42
(-1.04)
Proline (% Total Protein)
-1.28
(-1.40)
-0.46
(-0.75)
Serine (% Total Protein)
-0.51
(-0.87)
-0.39
(-0.99)
Proline (% Total Protein)
-1.44
(-1.57)
-0.58
(-0.94)
Serine (% Total Protein)
-0.53
(-0.88)
-0.38
(-0.93)
Phenylalanine + Total Energy (kJ/day)
Proline + Energy + Height + Weight
Phenylalanine + Energy + Height + Weight
Amino Acids as % kJ – (N=4,680)
Proline
Phenylalanine
Proline + Height + Weight
Phenylalanine + Height + Weight
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) – (N=4,680)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
continued on next page
47
Table S.9. continued, page 8
Adjusted also for Starch (% kJ) – (N=4,680)
Proline (% Total Protein)
-1.50
(-1.63)
-0.61
(-0.98)
Serine (% Total Protein)
-0.48
(-0.81)
-0.30
(-0.75)
Proline (% Total Protein)
-1.55
(-2.09)
-0.15
(-0.28)
Serine (% Total Protein)
-0.02
(-0.04)
-0.28
(-0.76)
Proline (% Total Protein)
-2.09
(-1.90)
-1.00
(-1.34)
Serine (% Total Protein)
0.06
(0.08)
-0.05
(-0.10)
-3.06
(-2.17)
-1.59*
(-1.68)
4.20
(2.54)
2.63
(2.33)
Proline + Energy + Height + Weight
-2.54
(-1.88)
-1.25*
(-1.38)
Serine + Energy + Height + Weight
1.95
(1.23)
1.16
(1.07)
Proline
-1.45
(-1.59)
-0.66*
(-1.07)
Serine
2.14
(2.21)
1.25
(1.88)
Proline + Height + Weight
-1.03
(-1.17)
-0.36*
(-0.62)
Serine + Height + Weight
0.79
(0.85)
0.38
(0.59)
Nonhypertensive Persons – (N=3,671)
Excluding Persons with High Day-to-day
Variability in Nutrient Intake/BP – (N=3,473)
Amino Acids as g/day – (N=4,680)
Proline + Energy (kJ/day)
Serine + Total Energy (kJ/day)
Amino Acids as % kJ – (N=4,680)
continued on next page
48
Table S.9. continued, page 9
Adjusted also for Total Energy (kJ/day) –
(N=4,680)
Phenylalanine (% Total Protein)
-1.29
(-1.52)
-0.90
(-1.58)
Serine (% Total Protein)
-0.25
(-0.30)
-0.09
(-0.17)
-1.65
(-1.94)
-1.12
(-1.96)
0.23
(0.27)
0.17
(0.30)
Phenylalanine (% Total Protein)
-1.28
(-1.50)
-0.89
(-1.56)
Serine (% Total Protein)
-0.24
(-0.28)
-0.09
(-0.15)
Phenylalanine (% Total Protein)
-1.33
(-1.53)
-0.79
(-1.35)
Serine (% Total Protein)
-0.15
(-0.19)
-0.10
(-0.18)
-0.54
(-0.75)
-0.58
(-1.08)
0.16
(0.23)
0.08
(0.16)
-1.245
(-1.21)
-0.75
(-1.08)
-0.17
(-0.17)
-0.08
(-0.12)
Adjusted for Urinary Na/Creatinine and
K/Creatinine Ratio (mmol/mmol) – (N=4,680)
Phenylalanine (% Total Protein)
Serine (% Total Protein)
Adjusted also for Total Carbohydrate (% kJ) –
(N=4,680)
Adjusted also for Starch (% kJ) – (N=4,680)
Nonhypertensive Persons – (N=3,671)
Phenylalanine (% Total Protein)
Serine (% Total Protein)
Excluding Persons with High Day-to-day
Variability in Nutrient Intake/BP – (N=3,473)
Phenylalanine (% Total Protein)
Serine (% Total Protein)
continued on next page
49
Table S.9. continued, page 10
Amino Acids as g/day – (N=4,680)
Phenylalanine + Energy (kJ/day)
2.91
(0.61)
1.33
(0.41)
Serine + Total Energy (kJ/day)
-2.41
(-0.48)
-1.19
(-0.35)
Phenylalanine + Energy + Height + Weight
-2.73
(-0.60)
-2.28
(-0.73)
1.79
(0.37)
1.50
(0.46)
1.36
(0.50)
1.03
(0.56)
Serine
-1.21
(-0.42)
-1.19
(-0.61)
Phenylalanine + Height + Weight
-1.28
(-0.49)
-0.66
(-0.37)
0.68
(0.22)
-0.01
(-0.01)
Serine + Energy + Height + Weight
Amino Acids as % kJ – (N=4,680)
Phenylalanine
Serine + Height + Weight
Model 5b: Sample, Age, Gender, Special Diet, Supplement Intake, CVD-DM Diagnosis, Physical Activity, Family History of High BP, Urinary
Na, Urinary K, 7-Alcohol, Cholesterol, Total SFA, Total PFA, Magnesium
Sensitivity Analyses: controlled for Model 5b - Mg + each stipulated variable
Z-value=regression coefficient/standard error; Z-value ≥1.96: uncorrected p ≤0.05; ≥2.58: uncorrected p ≤0.01; ≥3.29: uncorrected p ≤0.01
2 s.d. higher glutamic acid intake for % Total Protein – 4.72%; for grams/day – 9.60; for % Total Kilocalories – 1.00%
2 s.d. higher proline intake for % Total Protein – 2.54%; for grams/day – 3.34; for % Total Kilocalories – 0.40%
2 s.d. higher phenylalanine intake for % Total Protein – 0.35%; for grams/day – 2.16; for % Total Kilocalories – 0.24%
2 s.d. higher serine intake for % Total Protein – 0.45%; for grams/day – 2.20; for % Total Kilocalories – 0.24%
*Test for cross-country heterogeneity significant, p <0.05.
50
Table S.10. Estimated Mean Difference in Blood Pressure, by Gender, Glutamic Acid Intake (% Total Protein) from Foods Higher by 2 s.d.,
Multiple Regression Analyses
Systolic BP
Men (N=2,359)
Difference,
Diastolic BP
Women (N=2,321)
Difference,
(Z-value)
mm Hg
Men (N=2,359)
Difference,
(Z-value)
mm Hg
Women (N=2,321)
Difference,
(Z-value)
mm Hg
(Z-value)
mm Hg
1
-2.06*
(-2.56)
-3.98
(-4.55)
-1.10
(-1.98)
-1.83
(-3.31)
2
-2.01*
(-2.52)
-3.43
(-3.97)
-1.13
(-2.04)
-1.77
(-3.21)
3
-0.82
(-1.01)
-3.01
(-3.49)
-0.54
(-0.96)
-1.51
(-2.73)
4
-1.19
(-1.30)
-2.29
(-2.41)
-1.03
(-1.62)
-1.34
(-2.20)
5a - P
-1.82
(-1.94)
-2.50
(-2.54)
-1.39
(-2.11)
-1.51
(-2.39)
5b - Mg
-2.00
(-2.11)
-2.45
(-2.47)
-1.56
(-2.33)
-1.66
(-2.60)
5c - Ca
-0.79
(-0.85)
-1.76
(-1.81)
-0.95
(-1.45)
-0.99
(-1.58)
5d - Fe
-1.17
(-1.27)
-1.85
(-1.92)
-1.02
(-1.59)
-1.19
(-1.92)
5e - Fiber
-1.12
(-1.20)
-2.15
(-2.23)
-1.04
(-1.59)
-1.29
(-2.08)
51
Model 1: Controlled for Sample, Age
Model 2: Model 1 Variables + Special Diet (Yes/No), Supplement Intake (Yes/No), CVD-DM Diagnosis (Yes/No), Physical Activity (Medium +
Heavy, hours/day), Family History of High BP (Yes, No or Unknown)
Model 3: Model 2 Variables + Urinary Na and Urinary K (mmol/24-h), 14-day Alcohol (grams/day)
Model 4: Model 3 Variables + Cholesterol (mg/1,000 kJ), Total SFA and Total PFA (% kJ)
Model 5a-5e: Controlled for Model 4 variables + each stipulated nutrient (expressed per 1,000 kJ)
Z-value = regression coefficient/standard error; Z-value ≥1.96: uncorrected p ≤0.05; ≥2.58: uncorrected p ≤0.01; ≥3.29: uncorrected p ≤0.001
2 s.d. higher glutamic acid intake 4.72 % Total Protein
*Test for cross-country heterogeneity significant, p <0.05.
52
Table S.11. Estimated Mean Difference in Blood Pressure, by Age Group (40-49 and 50-59 years), Glutamic Acid Intake (% Total Protein) from
Foods Higher by 2 s.d., Multiple Regression Analyses
Systolic BP
40-49 years (N=2,365)
Difference,
Diastolic BP
50-59 years (N=2,315)
Difference,
(Z-value)
mm Hg
40-49 years (N=2,365)
Difference,
(Z-value)
mm Hg
50-59 years (N=2,315)
Difference,
(Z-value)
mm Hg
(Z-value)
mm Hg
1
-3.19
(-4.13)
-2.93
(-3.24)
-1.65
(-3.04)
-1.24
(-2.21)
2
-3.08
(-4.01)
-2.58
(-2.87)
-1.55
(-2.86)
-1.33
(-2.35)
3
-2.27
(-2.91)
-1.99
(-2.21)
-1.06
(-1.94)
-1.07
(-1.87)
4
-1.67
(-1.94)
-2.25
(-2.22)
-0.86
(-1.42)
-1.70
(-2.67)
5a - P
-2.00
(-2.26)
-2.88
(-2.76)
-0.99
(-1.57)
-2.17
(-3.29)
5b - Mg
-2.21
(-2.47)
-2.79
(-2.65)
-1.15
(-1.81)
-2.26
(-3.38)
5c - Ca
-1.07
(-1.22)
-2.08
(-2.01)
-0.60
(-0.96)
-1.60
(-2.44)
5d - Fe
-1.61
(-1.85)
-2.13
(-2.07)
-0.81
(-1.32)
-1.66
(-2.57)
5e - Fiber
-1.41
(-1.61)
-2.48
(-2.41)
-0.67
(-1.09)
-1.93
(-2.96)
53
Model 1: Controlled for Sample, Gender
Model 2: Model 1 Variables + Special Diet (Yes/No), Supplement Intake (Yes/No), CVD-DM Diagnosis (Yes/No), Physical Activity (Medium +
Heavy, hours/day), Family History of High BP (Yes, No or Unknown)
Model 3: Model 2 Variables + Urinary Na and Urinary K (mmol/24-h), 14-day Alcohol (grams/day)
Model 4: Model 3 Variables + Cholesterol (mg/1,000 kJ), Total SFA and Total PFA (% kJ)
Model 5a-5e: Controlled for Model 4 variables + each stipulated nutrient (expressed per 1,000 kJ)
Z-value = regression coefficient/standard error; Z-value ≥1.96: uncorrected p ≤0.05; ≥2.58: uncorrected p ≤0.01; ≥3.29: uncorrected p ≤0.001
2 s.d. higher glutamic acid intake 4.72 % Total Protein
No significant cross-country heterogeneity detected
54

Europe Commercial Amino Acids Market

Phenylalanine Market

North America Commercial amino acids market

Ch 15

Automotive Intake Manifold Market

Urinary Catheters Market Expected To Reach US$1,755.0Mn By 2021

Urinary Catheters Market

Dietary FibersInsights

Dietary Fibers Market

Dietary Fibers Market

L12 worksheet Ans