Nutrition 28 (2012) 856–863

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Nutrition
journal homepage: www.nutritionjrnl.com

Applied nutritional investigation

Association between interaction and ratio of u-3 and u-6 polyunsaturated

fatty acid and the metabolic syndrome in adults
Parvin Mirmiran Ph.D. a, Somayeh Hosseinpour-Niazi M.Sc. b, Zahra Naderi M.Sc. b,
Zahra Bahadoran M.Sc. b, Mahbobeh Sadeghi M.Sc. b, Fereidoun Azizi M.D. c, *
a
Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti
University of Medical Sciences, Tehran, Iran
b
Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
c
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To investigate the association of the intakes of u-3 (including a-linolenic acid [ALA],
Received 15 June 2011 eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA]) and u-6 polyunsaturated fatty acids
Accepted 27 November 2011 (PUFAs), the interaction, and the ratio of these PUFAs with the metabolic syndrome (MetS) in adults.
Methods: This cross-sectional study was conducted in a random sample of participants (n ¼ 2451,
Keywords: 19–84 y old) in the Tehran Lipid Glucose Study. Dietary intake was assessed using a validated
Metabolic syndrome
semiquantitative food-frequency questionnaire. Anthropometric characteristics, blood pressure,
Polyunsaturated fatty acid
and fasting plasma concentrations of glucose and lipids were measured. The MetS was defined
u-6/u-3 Ratio
a-Linolenic acid according to the Adult Treatment Panel III guidelines.
Eicosapentaenoic acid Results: Among the PUFAs, the ALA and u-6 PUFA intakes were inversely associated with the MetS.
Docosahexaenoic acid Subjects in the highest quartile of ALA and u-6 fatty acid intakes had a 38% (odds ratio 0.62, 95%
confidence interval 0.41–0.95) and a 0.47% (odds ratio 0.53, 95% confidence interval 0.31–0.89)
lower prevalence of MetS, respectively, compared with those in the lowest quartile. The dietary
ratio of u-6 to u-3 fatty acids was not associated with the MetS. When the interaction between ALA
and u-6 fatty acid was assessed, the ALA intake was associated with a lower prevalence of the
MetS, without modification by the u-6 PUFA intake. Subjects with at least the median ALA intake
(1084 mg/d) had a lower prevalence of the MetS, irrespective of an u-6 PUFA intake lower or
higher than the median compared with subjects with intakes below the median for both.
Conclusion: The ALA intake was inversely associated with the MetS, irrespective of the background
intake of u-6 PUFAs, in adults.
Ó 2012 Elsevier Inc. All rights reserved.

Introduction decrease the MetS risk as a result of the beneficial effect on

The metabolic syndrome (MetS) refers to the constellation of
metabolic abnormalities including glucose intolerance, abdom-
inal obesity, dyslipidemia, and hypertension [1] and is associated
with an increased risk of cardiovascular disease and diabetes [2].
The intake of polyunsaturated fatty acids (PUFAs) may influence
the MetS risk. Two types of PUFAs, u-6 and u-3, have received
attention with regard to health and disease. The u-3 PUFAs may
This study was funded by a grant from the research Institute of Endocrine
Sciences, Shadid Beheshti University of Medical Sciences, Tehran, Iran.
* Corresponding author. Tel.: þ98-21-223-57-484; fax: þ98-21-224-16-264/
224-02-463.
E-mail address: azizi@endocrine.ac.ir (F. Azizi).
0899-9007/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2011.11.031
insulin resistance, blood pressure, and dyslipidemia [3,4].
Conversely, u-6 PUFAs, which competes with u-3 for several
physiologic processes, can increase inflammatory eicosanoids [3,
5], possibly increasing the risk of chronic disease [6]. However,
the results from epidemiologic studies have not confirmed these
findings [7–11].
Recent evidence has suggested that a balanced ratio of u-6 to
u-3 PUFAs may be more relevant for optimal health and the
prevention of chronic disease than absolute intakes of these fatty
acids [6,12]. However, some studies have shown no association
between ratio of these fatty acids and insulin resistance [13,14].
Also, a few studies have evaluated the effects of a background
dietary intake of u-6 PUFAs on the relation between u-3 PUFAs
and chronic disease [9,10]. Considering the limited data available
 P. Mirmiran et al. / Nutrition 28 (2012) 856–863
on the association between the ratio of u-6 to u-3 PUFA intakes
and the MetS, this study was conducted to assess the association
between of u-6 and u-3 PUFAs (a-linolenic acid [ALA], eicosa-
pentaenoic acid [EPA], and docosahexaenoic acid [DHA]) intakes
and the MetS. The present study also aimed at determining
whether the background dietary intake of u-6 PUFAs modulates
the effects of dietary u-3 PUFAs on the MetS and its components
in 19- to 84-y-old subjects.
Materials and methods
This cross-sectional study was conducted within the framework of the Teh-
ran Lipid and Glucose Study (TLGS), which is an ongoing community-based
prospective investigation, aimed at preventing non-communicable disease by
the development of a program to promote healthy lifestyles and decrease non-
communicable disease risk factors. This study is being conducted in a sample
of residents under the coverage of three medical health centers in District No. 13
of Tehran, the capital city of Iran. These health centers were considered together
for analysis because of the similar characteristics of the participants, including
the prevalence of MetS risk factors. The design of the study has been described
previously [15,16]. Briefly, using multistage cluster random sampling methods,
15 005 people at least 3 y old were selected and followed up every 3 y. During the
third examination survey of the TLGS (2006–2008), of 12 523 participants who
had data on their medical histories and underwent a physical examination,
a representative sample of 2979 participants 19 to 84 y old was randomly
selected for a dietary assessment using a valid food-frequency questionnaire
(FFQ). Participants were excluded if they had a medical history of myocardial
infarction (n ¼ 22), stroke (n ¼ 19), and cancer (n ¼ 7), because of the possible
changes in diet associated with these conditions, a reported daily energy intake
outside the range of 800 to 4200 kcal/d (n ¼ 167), and for missing data on
physical activity or any anthropometrical measurement and biochemical variable
(n ¼ 103). Also excluded were participants with hyperlipidemia, hyperglycemia,
and hypertension because of the consequent changes in their dietary intake (n ¼
204). Data for 2457 individuals (1327 male and 1130 female subjects) were
analyzed. The design of the study was approved by the ethical committee of the
Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical
Sciences, and informed written consent was obtained from all participants.
Dietary assessment
The usual dietary intake was assessed using a 168-item validated semi-
quantitative FFQ. The validity and reliability of the FFQ have been described in
detail elsewhere [17]. The FFQ consisted of a list of foods with standard serving
sizes commonly consumed by Iranians. Trained dietitians with at least 5 y of
experience in the TLGS survey completed the FFQ during face-to-face interviews,
asking participants to report their frequency of consumption of a given serving of
each food item during the previous year on a daily (e.g., bread), weekly (e.g.,
meat), or monthly (e.g., fish) basis. Detailed questions on dietary fat intake such
as type of foods consumed (e.g., full fat versus fat free) were asked. The reported
frequency for each food item was converted to a daily intake. The portion sizes of
the consumed food were then converted to grams using household measure-
ments [18]. The intakes of u-3 (ALA, EPA, and DHA) and u-6 PUFAs were calcu-
lated by multiplying the gram of consumption of each food by the content of u-3
and u-6 PUFAs per 100 g. The composition values for u-3 (ALA, EPA, and DHA)
and u-6 PUFAs were obtained from the U.S. Department of Agriculture’s (USDA)
food composition table (FCT), because the Iranian FCT is incomplete (limited to
only raw materials and a few nutrients). The Iranian FCT was used only for food
items such as kashk, which are not listed in the USDA FCT [19]. However, the
energy and macronutrients of breads and fruits are almost similar to the alter-
native food items in the USDA FCT (correlation >0.9) [17].
The validity and reliability of the FFQ were assessed in a random sample of
132 subjects at least 20 y old by comparing the data from the two FFQs that were
completed 1 y apart and comparing the data from the FFQs and 12 dietary recalls,
respectively. The validity and reliability of the FFQ for total dietary fat were
acceptable; the correlation coefficients between the FFQ and multiple 24 recalls
were 0.59 and 0.38 and those between the two FFQs were 0.43 and 0.42 in male
and female subjects, respectively [17].
Biochemical assessment
After 12 to 14 h of overnight fasting, blood samples were drawn into Vacu-
tainer tubes from all participants while in a seated position. All blood analyses
were done at the TLGS research laboratory on the day of blood collection, and
analyses were conducted using a Selectra 2 autoanalyzer (Vita; Scientific, Span-
keren, the Netherlands). Serum triacylglycerol concentrations were measured
using triacylglycerol kits (Pars Azmoon, Inc., Tehran, Iran) using the enzymatic
857
calorimetric test with glycerol phosphate oxidase. High-density lipoprotein
(HDL) cholesterol was measured after precipitation of the apolipoprotein
B-containing lipoproteins with phosphotungstic acid. The serum fasting glucose
concentration was assayed using an enzymatic colorimetric method with the
glucose oxidase technique. Inter- and intra-assay coefficients of variations were
2.2% for serum glucose, 2% and 0.5% for HDL cholesterol, and 1.6% and 0.6% for
triacylglycerol, respectively.
Assessment of other variables
At the beginning of the study, trained physicians undertook the collection of
demographic data. Using digital scales (Seca, Hamburg, Germany), a subject’s
weight was measured while the subject was minimally clothed and not wearing
shoes and was recorded to the nearest 100 g. Height was measured while the
subjects were standing, without shoes, with their shoulders in a normal position,
using a tape fixed to the wall, and was recorded to the nearest 0.5 cm. Body mass
index was calculated as weight (kilograms) divided by the square of height
(meters). Waist circumference was measured at the level of the umbilicus site,
using an outstretched tape meter, without pressure to body surfaces, and was
recorded to the nearest 0.5 cm. Systolic and diastolic blood pressures were
measured twice at a subject’s right arm while the subject was in a seated position
and after a 15-min rest, and the mean of the two measurements was considered the
subject’s blood pressure. Physical activity was assessed using an oral questionnaire,
including a list of common activities of daily life; the frequency and amount of time
spent on activities per week over the previous 12 mo were documented [20]. Levels
of physical activity were expressed as metabolic equivalent hours per week [21].
Cigarette smoking status was dichotomized as current smoker, non-smoker, and
ex-smoker. Additional covariate information, including age, medical history, and
current use of medications, was obtained using an oral questionnaire.
Definition of MetS
The MetS was defined as the presence of at least three of the following five
components as recommended by the Adult Treatment Panel III [1]: low serum
HDL cholesterol (<40 mg/dL in men and <50 mg/dL in women), high serum
triacylglycerol concentrations (150 mg/dL), increased blood pressure (130/85
mmHg), impaired fasting glucose (fasting plasma glucose concentrations 110
mg/dL), and enlarged waist circumference. The cutoff for the waist circumference
was adopted from the new description of abdominal obesity for Iranian adults,
which is 95 cm for men and women [22].
Statistical analysis
The SPSS 15.0 (SPSS, Inc., Chicago, IL, USA) was used for all statistical analyses.
Significant differences in general characteristics across quartiles of the u-6/u-3
ratio were evaluated using one-way analysis of variance. The chi-square test was
used to detect any significant differences in the distribution of participants across
quartile categories with regard to qualitative variables. We determined age-,
gender-, and energy-adjusted means for the dietary variables across quartiles of
the u-6/u-3 ratio using a general linear model analysis of covariance.
Odd ratios (ORs) and their 95% confidence intervals (CIs) for the MetS and its
components were estimated using multivariable logistic regression models
across quartiles of u-6 PUFA, u-3 PUFA, ALA, EPA þ DHA, and the u-6/u-3 ratio
and adjusted for gender, age, smoking status (smoker, non-smoker, ex-smoker),
physical activity (light, moderate, or heavy), total energy intake (kilocalories per
day), percentage of energy from carbohydrate, percentage of energy from
protein, percentage of energy from saturated fatty acid, and percentage of energy
from monounsaturated fatty acid, oleic acid, and total fiber. In all multivariate
models, the first quartile was considered the reference. To determine the P value
for trends across quartile categories, we assigned the median intake of each
quartile category to individuals’ variables in the logistic regression for MetS and
its components. P < 0.05 was considered statistically significant.
We also estimated the ORs and their 95% CIs for the MetS and its components
according to u-3 (ALA and EPA þ DHA) and u-6 PUFA intakes using joint cate-
gories of higher (at least the median) versus lower (below the median) intakes [9]
by multivariable logistic regression models, adjusted for gender, age, smoking
status (smoker, non-smoker, ex-smoker), physical activity (light, moderate, or
heavy), total energy intake (kilocalories per day), percentage of energy from
carbohydrate, percentage of energy from protein, percentage of energy from
saturated fatty acid, and percentage of energy from monounsaturated fatty acid,
oleic acid, and total fiber. In all multivariate models, subjects with lower intakes
of dietary u-3 and u-6 PUFAs were considered a reference.
Results
Of 2457 study participants, 54.0% were female and 46% were
male, with a mean age of 38.0  12.8 and 40.7  14.4 y,
858 P. Mirmiran et al. / Nutrition 28 (2012) 856–863

respectively. The reported mean daily intakes  standard devia-
tion were u-6 PUFA 15.2  7.4 g/d, u-3 PUFA 1.3  0.9 g/d,
ALA 1176  645 mg/d, and EPA þ DHA 122  205 mg/d, and the u-
6/u-3 ratio was 12.6  4.5. The characteristics and dietary intakes
of the participants by quartiles of categories of the u-6/u-3 ratio
are presented in Table 1. Compared with participants in the lowest
quartile, those in the highest quartile were slightly younger.
There were no significant differences in the body mass index,
physical activity, smoking status, educational levels, occupational
status, and obesity across quartiles of the u-6/u-3 ratio. Those
subjects in the upper categories consumed less protein, saturated
fatty acid, linolenic acid, and cholesterol and more carbohydrate,
linoleic acid, dietary fiber, vegetable oil, and fish.
The characteristics and dietary intakes of the participants
according to EPA þ DHA and u-6 PUFA intake are presented in
Table 2. There were no differences in age, body mass index,
physical activity, smoking status, educational levels, and occu-
pational status among the different patterns of EPA þ DHA and
u-6 PUFA intake. The prevalence of obesity was lower in the
pattern of a high intake of EPA þ DHA and u-6 PUFA compared
with other intake patterns. Intakes of fish and vegetable oil were
higher in the pattern of high EPA þ DHA and u-6 PUFA,
respectively.
Multivariate-adjusted ORs for the MetS and its components
across quartiles of the u-6/u-3 ratio, u-6 and u-3 intakes, EPA þ
DHA, and ALA are presented in Table 3. After an adjustment for
potential confounding variables and dietary factors, the intake of
u-6 fatty acid was not significantly associated with the compo-
nents of MetS except for high serum triacylglycerol concentra-
tions, with a trend toward a lower prevalence (P < 0.061). Intakes
of u-3 PUFA and ALA were inversely associated with an enlarged
waist circumference and high serum triacylglycerol concentra-
tions, whereas the intake of EPA þ DHA was inversely associated
only with high serum triacylglycerol concentrations. A higher
dietary ratio of u-6 to u-3 PUFAs was associated with an
enlarged waist circumference. Among PUFAs, only intakes of ALA
and u-6 PUFA were inversely associated with the MetS. Subjects
in the highest quartile of ALA and u-6 fatty acid intakes had
a 38% (OR 0.62, 95% CI 0.41–0.95) and a 0.47% (OR 0.53, 95% CI
0.31–0.89) lower risk for developing MetS, respectively,
compared with those in the lowest quartile, after an adjustment
for confounders.

Table 1
Characteristics and dietary intakes of participants of the Tehran Lipid and Glucose Study across u-6/u-3 ratio quartiles

u-6/u-3 Ratio quartile categories P*

1 2 3 4
Participants (n) 614 612 613 612
Range of intake 10.3 10.4–12.3 12.4–14.3 14.4
Median intake 8.7 11.1 13.2 16.4
Characteristics
Women (%) 53.9 53.9 54.0 54.1 0.947
Age (y) 40.6  14.1y 38.9  13.5 38.4  13.5 37.3  12.6 0.013
BMI (kg/m2) 26.7  4.5y 26.6  4.6 26.6  5.1 27.2  5.2 0.07
Physical activity (%)
Light 64.0 64.5 65.3 68.8 0.312
Moderate 16.9 19.3 17.0 14.5
Heavy 19.1 16.2 17.8 16.7
Current smoker (%) 8.0 10.3 9.0 10.9 0.508
Educational levels (%)
Primary and secondary 15.6 15.2 17.6 14.2 0.101
High school 63.1 67.8 66.9 68.6
University 21.3 17.0 15.5 17.2
Occupational status (%)
Unemployed 45.8 46.4 45.2 47.9 0.950
Worker 16.9 15.5 17.3 15.7
Housework 37.3 38.1 37.5 36.4
Obese (%)z 37.6 39.2 39.5 35.0 0.341
Dietary intakex
Total energy intake (kcal/d) 2239  43 2248  42 2304  43 2166  43 0.155
Carbohydrate (% energy intake) 57.0  0.3 56.9  0.3 57.2  0.3 59.3  0.3 <0.005
Protein (% energy intake) 15.3  0.2 14.1  0.2 13.6  0.2 13.8  0.2 0.025
Total fat (% energy intake) 32.5  0.6 33.5  0.5 33.2  0.4 31.0  0.5 <0.005
SFA (% energy intake) 11.9  0.2 10.8  0.2 10.2  0.2 9.2  0.2 <0.005
MUFA (% energy intake) 10.2  0.1 11.0  0.1 11.4  0.1 10.9  0.1 0.005
PUFA (% energy intake) 5.7  0.1 6.5  0.1 6.7  0.1 7.0  0.1 0.015
Oleic acid (g/d) 23.5  0.4 25.5  0.4 25.9  0.4 24.4  0.4 <0.005
Linoleic acid (g/d) 12.2  0.3 14.6  0.3 15.5  0.3 14.9  0.3 <0.005
Linolenic acid (mg/d) 1373  22 1278  22 1172  22 878  22 <0.005
EPA þ DHA (g/d) 236  7.8 109  7.8 77  7.8 64  7.8 <0.005
Cholesterol (mg) 261  5.3 235  5.3 214  5.3 188  5.3 <0.005
Total fiber (g/d) 34.8  0.8 38.0  0.8 39.4  0.8 39.2  0.8 <0.005
Vegetable oil (g/d) 14.4  0.6 21.1  0.7 24.5  0.8 20.2  0.6 <0.005
Fish (g/d) 18.1  0.9 10.9  0.8 8.1  0.7 7.2  0.9 <0.005

BMI, body mass index; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; SFA, saturated
fatty acid
* The P value compared the characteristics across quartiles of u-6/u-3 ratio using analysis of variance (for age and BMI) and chi-square test (for categorized variables).
y
Values are presented as mean  SD.
z
BMI 25 kg/m2.
x
The dietary intake was adjusted for age, gender, and total energy intake using analysis of covariance, except for total energy intake (adjusted for age and gender); the
dietary variables are presented as mean  SEM.
 P. Mirmiran et al. / Nutrition 28 (2012) 856–863 859

Table 2
Characteristics and dietary intakes of participants of the Tehran Lipid and Glucose Study according to EPA plus DHA and u-6 PUFA intakes

Low EPA þ DHA High EPA þ DHA

Low u-6 PUFA High u-6 PUFA Low u-6 PUFA High u-6 PUFA
Participants (n) 651 559 572 669
Women (%) 57.5 59.9 51.4 47.8
Age (y) 41.2  14.0* 37.7  12.8 39.8  13.7 37.5  13.0
BMI (kg/m2) 26.9  4.9* 26.9  5.0 26.9  4.8 26.7  4.6
Physical activity (%)
Light 68.2 64.0 65.7 64.4
Moderate 16.1 18.4 25.1 15.4
Heavy 15.7 17.5 16.1 20.2
Educational levels (%)
Primary and secondary 20.0 15.9 12.9 13.6
High school 62.2 70.5 66.5 67.7
University 17.8 13.6 20.6 18.7
Occupational status (%)
Unemployed 43.9 41.2 48.4 51.1
Worker 17.1 15.9 16.8 15.7
Housework 39.0 42.9 34.8 33.2
Current smoker (%) 8.9 7.0 10.7 11.4
Obese (%)y 62.2 62.6 64.9 59.9
Dietary intakez
Total energy intake (kcal/d) 1803  39 2539  42 1978  41 2636  38
Carbohydrate (% energy intake) 60.3  0.3 55.3  0.3 59.8  0.3 54.6  0.3
Protein (% energy intake) 13.4  0.2 13.4  0.2 14.8  0.2 15.1  0.2
Total fat (% energy intake) 27.7  0.4 36.9  0.4 27.7  0.4 37.7  0.4
SFA (% energy intake) 10.2  0.2 10.7  0.2 10.5  0.2 10.7  0.2
MUFA (% energy intake) 9.6  0.1 12.3  0.1 9.4  0.1 12.1  0.1
PUFA (% energy intake) 5.3  0.1 7.1  0.1 5.1  0.1 7.6  0.1
Oleic acid (g/d) 18.2  0.3 30.5  0.3 18.6  0.3 31.7  0.3
Linoleic acid (g/d) 9.6  0.2 19.1  0.2 9.3  0.2 19.0  0.2
Linolenic acid (mg/d) 803  19.8 1502  21.1 830  20.7 1561  19.5
Cholesterol (mg) 177  5.1 215  5.5 218  5.4 285  5.0
Total fiber (g/d) 33.6  0.8 42.7  0.8 33.7  0.8 41.4  0.8
Vegetable oil (g/d) 11.6  0.5 30.2  0.6 9.9  0.6 28.5  0.5
Seafood (g/d) 4.0  0.8 4.5  0.9 16.28  0.9 19.0  0.8

BMI, body mass index; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; SFA, saturated
fatty acid
* Values are presented as mean  SD.
y
BMI 25 kg/m2.
z
The dietary intake was adjusted for age, gender, and total energy intake using analysis of covariance, except for total energy intake (adjusted for age and gender); the
dietary values are presented as mean  SEM.

Table 4 presents the ORs of the MetS and its components
according to the intakes of EPA þ DHA and u-6 PUFA. After an
adjustment for lifestyle and dietary confounders, a higher EPA þ
DHA intake (66 mg/d) was associated with a 34% lower high
serum triacylglycerol concentration in subjects with a lower u-6
PUFA intake (OR 0.66, 95% CI 0.51–0.85) and a 28% lower
concentration in subjects with a higher u-6 PUFA intake (OR
0.72, 95% CI 0.52–0.98) compared with subjects with lower
intakes of both. The different patterns of EPA þ DHA and u-6
PUFA intake were not significantly associated with the preva-
lence of MetS, enlarged waist circumference, high fasting blood
glucose, increased blood pressure, or low HDL cholesterol
concentrations.
Table 5 presents the ORs of the MetS and its components
according to ALA and u-6 PUFA intakes. A higher ALA intake
(1084 mg/d) was associated with a lower prevalence of an
enlarged waist circumference whether the u-6 PUFA intake was
lower (OR 0.67, 95% CI 0.46–0.97) or higher (OR 0.75, 95% CI
0.56–1.02). Also, the combination of a higher ALA intake and
a lower u-6 PUFA intake was associated with lower serum tri-
acylglycerol concentrations. After an adjustment for lifestyle and
dietary confounders, a higher ALA intake was associated with
a 28% lower risk of the MetS in subjects with lower (OR 0.72, 95%
CI 0.48–1.08) and higher (OR 0.73, 95% CI 0.53–1.01) u-6 PUFA
intakes.
Discussion
The purpose of the present study was to determine whether
the background dietary intake of u-6 PUFAs modulates the effects
of EPA þ DHA and ALA on the risk of the MetS and its components.
Our findings showed that intakes of EPA þ DHA were associated
with a lower risk of high serum triacylglycerol concentrations,
regardless of the background intake of u-6 PUFAs. In addition, the
ALA intake with a high or low u-6 PUFA intake decreased the risk
of an enlarged waist circumference and the MetS. Also, the
dietary intake of u-6 PUFA decreased the risk for the MetS.
Our results showed no association between u-3 PUFA intake and
the u-6/u-3 ratio and the MetS in Tehranian adults.
Imbalances in the dietary ratio of u-6/u-3 PUFAs have been
suggested as an important risk factor for coronary heart disease,
insulin resistance, and blood lipid abnormalities of the MetS [6,
12]. Also, a high u-6/u-3 PUFA ratio in the skeletal muscle
membrane has been adversely associated with insulin sensitivity
[23] and glucose intolerance [24]. Therefore, lower intakes of u-6
fatty acids have been suggested to decrease the ratio of u-6/u-3
and thus decrease the risk of cardiovascular disease and diabetes
[6]. In contrast, recent studies on the u-6/u-3 ratio have sug-
gested that it does not play a major role in the development of
insulin resistance, diabetes, and cardiovascular disease [13,
25–27]. In an animal study, Zhang et al. [28] found that a high
860 P. Mirmiran et al. / Nutrition 28 (2012) 856–863

Table 3
Multivariate-adjusted odds ratios* (95% confidence intervals) for metabolic syndrome and its components across quartiles of PUFA intakes

Quartiles of PUFA intake P for trendy

1 2 3 4
u-6 PUFA (g/d)
Range of intake 10.0 10.1–14.0 14.1–18.5 18.6
Median intake 7.7 12.1 16.0 22.9
Enlarged waist circumference 1 0.78 (0.59–1.04) 0.74 (0.53–1.03) 0.89 (0.56–1.43) 0.682
High serum triacylglycerol concentrationsz 1 0.64 (0.48–0.85) 0.73 (0.52–1.01) 0.58 (0.36–0.93) 0.061
Low serum HDL cholesterolz 1 0.81 (0.62–1.05) 0.91 (0.67–1.24) 0.95 (0.61–1.47) 0.989
Abnormal glucose homeostasisz 1 0.83 (0.55–1.23) 0.90 (0.56–1.43) 0.83 (0.42–1.62) 0.676
Increased blood pressurez 1 1.03 (0.74–1.45) 0.91 (0.61–1.36) 1.15 (0.66–2.00) 0.680
Metabolic syndromex 1 0.62 (0.45–0.84) 0.59 (0.41–0.84) 0.53 (0.31–0.89) 0.024
u-3 PUFA (g/d)
Range of intake 0.8 0.9–1.2 13–1.6 1.7
Median intake 0.62 0.99 1.4 2.0
Enlarged waist circumference 1 0.53 (0.41–0.69) 0.57 (0.42–0.77) 0.52 (0.35–0.75) 0.014
High serum triacylglycerol concentrations 1 0.76 (0.59–1.01) 0.78 (0.58–1.05) 0.63 (0.43–0.92) 0.042
Low serum HDL cholesterol 1 1.04 (0.81–1.34) 0.95 (0.72–1.26) 1.01 (0.71–1.44) 0.952
Abnormal glucose homeostasis 1 1.19 (0.81–1.73) 1.08 (0.70–1.67) 1.55 (0.90–2.66) 0.142
Increased blood pressure 1 1.10 (0.79–1.51) 1.04 (0.72–1.49) 1.22 (0.77–1.92) 0.447
Metabolic syndrome 1 0.72 (0.54–0.95) 0.68 (0.49–0.94) 0.72 (0.47–1.08) 0.253
ALA (mg/d)
Range of intake 729 730–1084 1085–1467 1468
Median intake 520 905 1252 1858
Enlarged waist circumference 1 0.67 (0.51–0.88) 0.59 (0.43–0.80) 0.54 (0.37–0.80) 0.003
High serum triacylglycerol concentrations 1 0.77 (0.59–1.01) 0.64 (0.47–0.87) 0.61 (0.41–0.91) 0.013
Low serum HDL cholesterol 1 1.06 (0.82–1.37) 0.90 (0.67–1.19) 0.92 (0.64–1.33) 0.557
Abnormal glucose homeostasis 1 1.08 (0.75–1.57) 0.88 (0.56–1.35) 1.09 (0.62–1.90) 0.878
Increased blood pressure 1 1.09 (0.78–1.51) 1.10 (0.76–1.58) 1.25 (0.78–1.99) 0.364
Metabolic syndrome 1 0.78 (0.58–1.04) 0.62 (0.45–0.86) 0.62 (0.41–0.95) 0.026
EPA þ DHA (mg/d)
Range of intake 29 30–66 67–135 136
Median intake 14 53 92 240
Enlarged waist circumference 1 1.09 (0.84–1.41) 0.96 (0.74–1.25) 1.07 (0.81–1.41) 0.70
High serum triacylglycerol concentrations 1 0.69 (0.54–0.89) 0.59 (0.46–0.77) 0.51 (0.38–0.66) <0.005
Low serum HDL cholesterol 1 0.91 (0.71–1.16) 0.91 (0.71–1.16) 0.84 (0.65–1.08) 0.217
Abnormal glucose homeostasis 1 0.94 (0.67–1.39) 1.04 (0.72–1.50) 1.20 (0.82–1.75) 0.252
Increased blood pressure 1 0.84 (0.62–1.13) 0.80 (0.59–1.09) 0.75 (0.54–1.04) 0.860
Metabolic syndrome 1 1.09 (0.82–1.44) 0.94 (0.71–1.25) 0.92 (0.68–1.23) 0.386
u-6/u-3 ratio
Range of intake 10.3 10.4–12.3 12.4–14.3 14.4
Median intake 8.7 11.1 13.2 16.4
Enlarged waist circumference 1 1.03 (0.79–1.34) 0.99 (0.75–1.31) 1.51 (1.14–2.00) 0.003
High serum triacylglycerol concentrations 1 1.08 (0.83–1.41) 1.12 (0.86–1.48) 1.29 (0.98–1.71) 0.062
Low serum HDL cholesterol 1 1.00 (0.78–1.28) 1.15 (0.89–1.48) 0.98 (0.75–1.27) 0.987
Abnormal glucose homeostasis 1 0.75 (0.52–1.08) 0.66 (0.45–0.97) 0.76 (0.51–1.11) 0.143
Increased blood pressure 1 1.01 (0.74–1.36) 0.87 (0.63–1.21) 0.98 (0.71–1.37) 0.826
Metabolic syndrome 1 0.91 (0.68–1.21) 0.78 (0.58–1.06) 1.18 (0.87–1.60) 0.248

ALA, a-linolenic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDL, high-density lipoprotein; PUFA, polyunsaturated fatty acid
* The odds ratios were adjusted for gender, age, smoking status, physical activity, total energy intake, percentage of energy from carbohydrate, percentage of energy
from protein, percentage of energy from saturated fatty acid, percentage of energy from monounsaturated fatty acid, oleic acid, and total fiber.
y
The median intake of each quartile category was assigned and then these quartile median variables were included as a continuous variable in the logistic regression.
z
Further adjusted for body mass index.
x
Defined as the presence of at least three of the following components: 1) enlarged waist circumference (95 cm in men and women), 2) high serum triacylglycerol
concentrations (150 mg/dL), 3) low serum HDL cholesterol (<40 mg/dL in men and <50 mg/dL in women), 4) abnormal glucose homeostasis, and 5) increased blood
pressure (130/85 mmHg).

dietary u-6/u-3 ratio increases HDL cholesterol concentrations.
In the present study, no association was found between the
u-6/u-3 ratio and the MetS. Our findings are in accordance with
clinical trial studies reporting no clinically significant effects of
dietary patterns with different u-6/u-3 PUFAs ratio on insulin
sensitivity [13,25]. Furthermore, in the 10-y follow-up of the
Nurses’ Health Study, no association was found between the ratio
of a-linolenic to linoleic acid and the risk of fatal ischemic heart
disease [29]. In the present study, no association was observed
between the u-6/u-3 fatty acid ratio intake and the MetS, which
may be due to the inverse association between u-6 PUFA
(mainly) and u-3 PUFA (marginally) and the MetS.
It has been argued that u-6 PUFAs may have detrimental
effects on human health, and u-6 PUFAs are believed to be
precursors of proinflammatory eicosanoids [3,5], thus increasing
the risk of chronic disease through inflammatory processes [6].
In contrast, others have found that dietary u-6 PUFA has
a protective effect on health by its anti-inflammatory properties
[30–33]. In the present study, we found that an intake of u-6
PUFAs was inversely associated with the MetS independent of
the other dietary confounders. Consistent with our findings,
previous intervention studies have reported the beneficial effects
of u-6 PUFAs on insulin resistance [34,35]. In a randomized
controlled trial by Summers et al. [35], a diet rich in u-6 PUFAs
improved insulin sensitivity and decreased visceral fat compared
with a diet rich in saturated fatty acids after a 5-wk intervention
[35]. In a prospective study, lowering the intake of linoleic acid
was associated with the development of MetS over 20 y [7]. In
 P. Mirmiran et al. / Nutrition 28 (2012) 856–863 861

Table 4
Multivariate-adjusted odds ratios (95% confidence intervals) for metabolic syndrome and its components according to EPA plus DHA and u-6 PUFA intakes*

Low EPA þ DHA High EPA þ DHA

Low u-6 PUFA High u-6 PUFA Low u-6 PUFA High u-6 PUFA
Enlarged waist circumference 1 1.07 (0.78–1.47)y 1.17 (0.90–1.52) 0.91 (0.66–1.25)
High serum triacylglycerol concentrationsz 1 0.97 (0.71–1.32) 0.66 (0.51–0.85) 0.72 (0.52–0.98)
Low serum HDL cholesterolz 1 1.25 (0.93–1.69) 1.04 (0.82–1.33) 1.01 (0.75–1.34)
Abnormal glucose homeostasisz 1 1.02 (0.65–1.58) 1.10 (0.77–1.57) 1.20 (0.76–1.88)
Increased blood pressurez 1 1.03 (0.71–1.48) 0.93 (0.68–1.25) 0.81 (0.55–1.18)
Metabolic syndromex 1 1.01 (0.71–1.42) 1.04 (0.78–1.37) 0.78 (0.54–1.11)

DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDL, high-density lipoprotein; PUFA, polyunsaturated fatty acid
* Grouped according to below or at or above the median of u-6 fatty acids (14.0 g/d) and EPA plus DHA (66 mg/d), with the reference group consuming below the
median intake of the two fatty acid groups.
y
The odds ratios were adjusted for gender, age, smoking status, physical activity, total energy intake, percentage of energy from carbohydrate, percentage of energy
from protein, percentage of energy from saturated fatty acid, percentage of energy from monounsaturated fatty acid, oleic acid, total fiber, body mass index and a-
linolenic acid.
z
Further adjusted for body mass index.
x
Defined as the presence of at least three of the following components: 1) enlarged waist circumference (95 cm in men and women), 2) high serum triacylglycerol
concentrations (150 mg/dL), 3) low serum HDL cholesterol (<40 mg/dL in men and <50 mg/dL in women), 4) abnormal glucose homeostasis (100 mg/dL), and 5)
increased blood pressure (130/85 mmHg).

a cross-sectional study, the intake of dietary linoleic acid was
inversely associated with the MetS [8].
There is increasing interest in the beneficial effects of dietary
u-3 PUFAs on the MetS and its associated cardiovascular
complications. Results from animal studies have indicated that
u-3 PUFAs have beneficial effects on insulin sensitivity and
prevent insulin resistance [36,37]; however, it should be noted
that in animal model studies, intakes of u-3 PUFAs were higher
than those of a typical human diet. Data from human studies are
controversial; some have reported beneficial effects [38–41],
whereas others have reported no effects of u-3 PUFAs [10,42], on
insulin sensitivity and the MetS. Our findings showed no
significant association between u-3 PUFAs and EPA þ DHA with
the MetS; however, a tendency toward a lower prevalence of
MetS was observed with increasing the intakes of both. EPA and
DHA are derived primary from fish and seafood. In the present
study, one possible reason for the lack of associations between
EPA and DHA and the MetS was the lower intake of these fatty
acids (median 66 mg/d) and their sources including fish (mean
intake12 g/d) compared with other studies that showed fish and
EPA þ DHA intake have a protective effect against the MetS and
coronary heart disease [9,43]. Also, the type of study population
may influence this association. In diabetic patients and those
with impaired glucose tolerance, supplementation with u-3
PUFAs has been reported to improve insulin sensitivity [40,41],
but its effects on healthy and normoglycemic patients are not
consistent [10,39,42].
In the present study, an inverse association between ALA
intake and the MetS was consistent with other observational
prospective cohort studies that showed a beneficial effect of ALA
on diabetes and cardiovascular disease [9,29,44]. In the present
study, the intake of ALA was 1.2 g/d (median 1084 mg/d), which
was similar to the median daily intake of the Health Professional
study (1080 mg/d) and the mean intake of the Nurses’ Health
study (1.1 g/d) [9,29]. The recommended dietary allowance for
ALA intake was 1.6 and 1.1 mg/d for men and women, respec-
tively. These estimates suggest that the ALA intake in Tehranian
adults was adequate. Our finding was in accordance with that of
the Health Professional Follow-up Study that showed that ALA
decreases the risk for coronary heart disease when the intake of
u-3 PUFA intake is low [9].
There is limited evidence from epidemiologic studies inves-
tigating whether the effect of u-3 PUFAs on the risk of chronic
disease is modified by the dietary u-6 PUFA intake. We found an
inverse association between ALA intake and the MetS, and this
association was not modulated by the intake of u-6 PUFAs.
Consistent with our finding, Mozaffarian et al. [9] showed that u-
6 PUFA intake does not counteract the effect of ALA or EPA þ DHA

Table 5
Multivariate-adjusted odds ratios (95% confidence intervals) for the metabolic syndrome and its components according to ALA and u-6 PUFA intakes*

Low ALA High ALA

Low u-6 PUFA High u-6 PUFA Low u-6 PUFA High u-6 PUFA
Enlarged waist circumference 1 1.06 (0.73–1.52)y 0.67 (0.46–0.97) 0.75 (0.56–1.02)
High serum triacylglycerol concentrationsz 1 1.22 (0.85–1.75) 0.74 (0.52–1.07) 0.86 (0.64–1.15)
Low serum HDL cholesterolz 1 1.20 (0.84–1.72) 0.82 (0.59–1.14) 0.98 (0.74–1.29)
Abnormal glucose homeostasisz 1 1.22 (0.74–2.02) 0.82 (0.48–1.37) 0.92 (0.61–1.39)
Increased blood pressurez 1 0.85 (0.51–1.36) 1.05 (0.69–1.58) 1.01 (0.71–1.43)
Metabolic syndromex 1 1.02 (0.68–1.51) 0.72 (0.48–1.08) 0.73 (0.53–1.01)

ALA, a-linolenic acid; HDL, high-density lipoprotein; PUFA, polyunsaturated fatty acid
* Grouped according to below or at or above the median of u-6 fatty acids (14.0 g/d) and ALA (1084 mg/d), with the reference group consuming below the median
intake for both.
y
The odds ratios were adjusted for gender, age, smoking status, physical activity, total energy intake, percentage of energy from carbohydrate, percentage of energy
from protein, percentage of energy from saturated fatty acid, percentage of energy from monounsaturated fatty acid, oleic acid, total fiber, body mass index, and
eicosapentaenoic acid plus docosahexaenoic acid.
z
Further adjusted for body mass index.
x
Defined as the presence of at least three of the following components: 1) enlarged waist circumference (95 cm in men and women), 2) high serum triacylglycerol
concentrations (150 mg/dL), 3) low serum HDL cholesterol (<40 mg/dL in men and <50 mg/dL in women), 4) abnormal glucose homeostasis (100 mg/dL), and 5)
increased blood pressure (130/85 mmHg).
862 P. Mirmiran et al. / Nutrition 28 (2012) 856–863
PUFA intake on the risk of coronary heart disease events [9]. In
the Nurses’ Health study, the inverse association between u-3
PUFA intake and coronary heart disease risk was independent of
the u-6/u-3 PUFA intake [45]. In a prospective cohort study, ALA,
but not the ratio of ALA to linoleic acid, lowered the risk of fatal
ischemic heart disease [29]. Results from a clinical study have
shown that high or low dietary intakes of u-6 PUFAs do not
attenuate the beneficial effects of fish oil supplementation on
plasma triacylglycerol concentrations [10]. The mechanism of
the interaction between u-6 and u-3 PUFAs and its effect on
chronic disease have not been elucidated. One explanation is that
these fatty acids can be desaturated and elongated through the
Δ-6 desaturase enzyme. Through this enzyme, linoleic acid
converts to arachidonic acid and ALA converts to EPA [9]. ALA
and its metabolite, EPA, can decrease the generation of inflam-
matory markers through an inhibitory action of the conversion
linoleic acid to arachidonic acid [46]. However it seems that the
amount of ALA intake may affect this metabolism pathway of the
u-6 PUFAs. Pischon et al. [46] found that, at a low intake of u-3
PUFAs, u-6 PUFAs are associated with high levels of inflamma-
tory factors, whereas at a high intake of u-3 PUFAs, the combi-
nation of u-6 and u-3 PUFAs is related to the lowest levels of
inflammation. This inhibitory effect of ALA on the conversion of
linoleic acid to arachidonic acid, which may lead to a participa-
tion of linoleic acid in other pathways that may decrease the risk
of chronic disease, including suppressing the atherogenic acti-
vation of vascular endothelial cells, inhibiting the production of
chemokines and interleukins by the endothelial cells of adhesion
molecules, and inhibiting the activation of nuclear factor-kB in
endothelial cells, a transcription factor for proinflammatory
genes [32], and improving blood lipid profiles, blood pressure,
a thrombotic tendency, insulin resistance, oxidative stress, and
endothelial function [27]. Therefore, it seems that the amount of
ALA intake may determine whether u-6 PUFAs are positively or
negatively associated with the risk of chronic disease. We found
that the ALA intake was inversely associated with the risk of
MetS independent of the PUFA intake, indicating that the inverse
association between the intake of u-6 PUFA and the Mets may be
modulated by an adequate intake of ALA, an association that
needs to be studied further.
Although previous studies have focused mostly on the rela-
tion between general obesity and u-3 PUFAs [47,48], the present
study showed an inverse association between u-3 PUFAs and
ALA intake with waist circumference at higher and lower u-6
PUFA intakes. A previous observational study reported an inverse
association between fish consumption and central obesity [49].
Also, in obese adults, waist circumference was inversely associ-
ated with the plasma u-3 PUFAs EPA and DHA [50]. However, in
the present study, no association was found between the EPA þ
DHA intake and waist circumference, possibly because of the
lower intakes.
In the present study, EPA þ DHA intakes were associated with
a lower prevalence of high serum triacylglycerol concentrations,
regardless of the background of u-6 PUFA intake. Consistent with
our findings, Brady et al. [10] found no significant differences in
fasting and postprandial plasma triacylglycerols and decreased
apolipoprotein B concentrations between the moderate and high
u-6 PUFA dietary intervention groups after fish oil supplemen-
tation. In another clinical trial study, the supplementation of u-3
PUFAs lowered triacylglycerol concentrations in normolipidemic
subjects with higher or lower u-6 PUFA intakes [51]. The u-3
PUFAs lower triacylglycerol concentrations by a modified gene
expression of the protein involved in the fatty acid oxidation and
triacylglycerol secretion by the liver [52].
Some limitations should be considered, one being the use of
the FFQ to determine the intake of u-3 and u-6 PUFAs. Although
the validity of the FFQ for total fat was acceptable in this pop-
ulation [17], the validity was not determined for u-3 and u-6
PUFAs. Using the USDA FCT rather than a complete Iranian FCT is
another limitation. In addition, given the cross-sectional design,
we could not determine the causality between PUFA intake and
the risk of MetS and its components. Future studies using
longitudinal data are needed to determine these effects. In
addition, the concentrations of free fatty acids that have a strong
association with insulin resistance and the MetS were not
measured. Also, conclusions from the association between die-
tary observational studies and the MetS are always difficult
because of the potential factors that affect the ingestive behavior,
that is, appetite and food intake; these factors include some
important biochemical factors such as total plasma ghrelin and
its circulated forms (acylated and desacylated ghrelin) that have
been associated with the MetS [53,54]. In addition, this study
included only healthy adults, and our findings cannot be
extrapolated to other populations.
Conclusions
The present findings suggest that an ALA intake decreases the
prevalence of the MetS in adults but is not affected by u-6 PUFA
intakes. Although the intake of u-6 PUFAs decreased the preva-
lence of the MetS, the u-6/u-3 PUFA ratio was not associated
with a decrease in the prevalence of the MetS.
Acknowledgments
The authors express their appreciation to the participants in
the Tehran Lipid and Glucose Study for their enthusiastic support
and the staff of the Research Institute for Endocrine Sciences,
Tehran Lipid and Glucose Study Unit, for their valuable help. They
acknowledge Ms. N. Shiva for language editing of the manuscript.
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