American Journal of Epidemiology
Copyright © 2004 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved
Vol. 160, No. 2
Printed in U.S.A.
DOI: 10.1093/aje/kwh193
Dietary Fat and Risk of Coronary Heart Disease: Possible Effect Modification by
Gender and Age
Marianne U. Jakobsen1,2, Kim Overvad3,4,5, Jørn Dyerberg6, Marianne Schroll1,2, and Berit L.
Heitmann1
1 Research Unit for Dietary Studies and Danish Epidemiology Science Centre, Institute of Preventive Medicine, Copenhagen
University Hospital, Copenhagen, Denmark.
2 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.
3 Department of Clinical Epidemiology, Aalborg Hospital, Aalborg, Denmark.
4 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
5 Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus, Denmark.
6 Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark.
Received for publication September 30, 2003; accepted for publication February 23, 2004.
In a 16-year follow-up study (ending in 1998) of 3,686 Danish men and women aged 30–71 years at
recruitment, the association between energy intake from dietary fat and the risk of coronary heart disease was
evaluated while assessing the possible modifying role of gender and age. In the models used, total energy and
protein intake were fixed. Differences in intake of energy from fat thus reflected complementary differences in
intake of energy from carbohydrates. A 5% higher level of energy from saturated fat intake was associated with
a 36% greater risk of coronary heart disease among women (hazard ratio (HR) = 1.36, 95% confidence interval
(CI): 0.98, 1.88). No overall association between saturated fat and coronary heart disease was found among men.
However, age-dependent analyses showed that saturated fat was positively associated with coronary heart
disease among the younger men (HR = 1.29, 95% CI: 0.87, 1.91) and the younger women (HR = 2.68, 95% CI:
1.40, 5.12) but not among the older men (HR = 0.94, 95% CI: 0.70, 1.28) and the older women (HR = 1.22, 95%
CI: 0.86, 1.71). Polyunsaturated fat was inversely associated with coronary heart disease among women and
men, although not significantly. In conclusion, the present study suggests that coronary heart disease risk relates
to both the quantity and the quality of dietary fats.
carbohydrates; coronary disease; fatty acids
Abbreviations: CI, confidence interval; HR, hazard ratio.
The association between dietary fat and risk of coronary
heart disease is a subject of debate, especially whether coronary heart disease risk relates to both the quantity and the
quality of dietary fats. Prospective cohort studies have investigated the associations between the intake of total dietary fat
and the major types of dietary fat and the risk of coronary
heart disease with inconsistent results. Total fat intake was
positively associated with risk of coronary heart disease in
four studies (1–4), whereas six studies found no association
(5–10). A positive association between saturated fat intake
and risk of coronary heart disease was found in some studies
(1–4, 11, 12), whereas others found no association (6, 8–10,
13, 14). An inverse association between monounsaturated fat
intake and risk of coronary heart disease was found in one
study (9), whereas two other studies found a positive association (2, 3). Three studies found that monounsaturated fat
intake was not associated with coronary heart disease risk (6,
10, 14). Polyunsaturated fat intake was inversely associated
with risk of coronary heart disease in three studies (9, 12,
13), whereas eight studies found no association (1–3, 6, 8,
10, 11, 14). One factor potentially contributing to the
discrepancies observed across the studies may be the differences in the way of expressing fat intake and incomplete
adjustment for intake of total energy and other types of fat,
Correspondence to Marianne Uhre Jakobsen, Research Unit for Dietary Studies, Institute of Preventive Medicine, Kommunehospitalet, 1399
Copenhagen, Denmark (e-mail: [email protected]).
141
Am J Epidemiol 2004;160:141–149
142 Jakobsen et al.
FIGURE 1. Year of examination/reexamination (•) and number of participants with information on diet in four population studies conducted at
the Research Centre for Prevention and Health, Glostrup, Denmark, 1974–1993. The Danish MONICA-I and MONICA-III (Monitoring of Trends
and Determinants in Cardiovascular Disease) projects are a part of the multinational studies conducted under the auspices of the World Health
Organization.
leading to potential confounding and differences in the interpretations of the risk estimates. Moreover, effect modification by gender may contribute to the inconsistent findings,
potentially because fat intake induces postprandial hypertriglyceridemia (15), which seems to be a stronger risk factor
for death from coronary heart disease among women than
among men (16). Finally, the age of the participants may
contribute to the discrepancies. Older participants may be a
selected group who may be less vulnerable to environmental
factors.
The aims of the present study were to describe the associations between the energy intake from total dietary fat and
the major types of dietary fat and the risk of coronary heart
disease, while assessing the potential effect-modifying role
of gender and age. The results from the models used may be
interpreted as substituting a specific amount of energy from
fat for the same amount of energy from carbohydrates, thus
contributing to the understanding of the role of dietary fat
intake in the prevention of heart disease. In other words, this
study may contribute to clarifying whether dietary prevention of heart disease should focus on both the quantity and
the quality of dietary fats or on only the quantity.
300,000 inhabitants from the western suburbs of Copenhagen, Denmark (17). The four cohorts (figure 1) met the
following two criteria: 1) usual dietary intake was determined using a 7-day weighed food record or a dietary history
interview, and 2) information on intake of total fat and on
intakes of saturated, monounsaturated, and polyunsaturated
fat (major types of fat) was available. The participants were
recruited and examined between 1964 and 1991, with a
participation of from 70 percent to 88 percent. The examinations included self-administered questionnaires containing
detailed questions regarding sociodemographic factors, lifestyle, and health, as well as a general health examination.
Some of the participants have been reinvited and examined
several times, and new participants were added to the 1914
cohort (figure 1). At the examination/reexamination, all or
random subsets of the participants from the different cohorts
were requested to provide further information regarding
their habitual diet. In total, information on diet was obtained
from 3,959 participants (figure 1).
MATERIALS AND METHODS
Five persons for whom the recorded sum of saturated,
monounsaturated, and polyunsaturated fat intake in grams
was greater than the total fat intake in grams were excluded.
Persons with a previous diagnosis of coronary heart disease
(80 persons) and persons reporting diabetes mellitus (77
persons) were also excluded. The final population consisted
of 3,797 persons examined between 1974 and 1993.
Study population
The present study is based on data from four population
studies conducted at the Research Centre for Prevention and
Health, which, since 1964, has followed different cohorts
from the same background population of approximately
Exclusions
Am J Epidemiol 2004;160:141–149
Dietary Fat and Coronary Heart Disease 143
Dietary variables
Identification of events
A total of 3,553 participants were given comprehensive
verbal and written instructions on how to complete a 7-day
weighed food record and requested to complete it within 3
weeks. The remaining 244 participants underwent a dietary
history interview by the same trained dietician. The interviews were conducted by asking nonleading, open-ended
questions concerning dietary intake during the previous
month. Quantities were explored by means of food models,
photo series, and household measures. The dietary assessment methods have been described in detail previously, and
it has been shown that the methods yield comparable data on
habitual diet intake (18).
The reproducibility and validity of the 7-day weighed food
record method, as used in the population studies at the
Research Centre for Prevention and Health, have been documented previously, demonstrating that this method provides
a reproducible description of dietary habits regarding macronutrients and that the validity of the method, as assessed
using nitrogen excretions, is good (19).
Nutrient calculation into daily averages was done using
the Micro Camp and DANKOST 1 computer programs
(Danish Catering Center A/S, Herlev, Denmark) based on
Danish food composition tables (20, 21).
Fatal and nonfatal coronary heart disease events were
defined according to International Classification of
Diseases, Eighth Revision, diagnosis codes 410–414 until
December 31, 1994, and subsequently by International
Classification of Diseases, Tenth Revision, codes I20–I25.
Cases were identified by record linkage to the National
Patient Registry, including all hospitalizations since 1977
(22), and the Cause of Death Registry (23), including all
deaths since 1943. Events ascertainment was made by
review of medical files for the participants from the 1914
cohort who were included before 1977 (24).
Documentation of the validity of the diagnosis of myocardial infarction (International Classification of Diseases,
Eighth Revision, code 410) in the National Patient Registry
and the Cause of Death Registry has been published earlier
(25). The combination of the national registries was found to
be a valid and powerful tool for monitoring the population
incidence of myocardial infarction.
Nondietary covariates
Information on family history of myocardial infarction,
smoking habits, physical activity in leisure time, and education was obtained by a self-administered questionnaire.
“Family history of myocardial infarction” was defined as
persons reporting myocardial infarction in parents or
siblings. Questions on smoking concerned current and
previous habits and the kinds and average daily quantities of
tobacco consumed. Smoking habits were classified into five
categories: never smokers; former smokers; and current
smokers of from 1 to less than 15 g of tobacco per day, from
15 to less than 25 g of tobacco per day, and 25 g of tobacco
or more per day. Data on leisure-time physical activity were
based on the participants’ marking of one of four alternatives: mostly sedentary; walking, bicycling, or otherwise
active at a corresponding level at least 4 hours per week;
doing jogging or demanding sports or doing heavy activity
during leisure for at least 3 hours per week; and longdistance running or competitive sports several times per
week. We defined people in group 1 as being sedentary and
with the rest as being active. Education was assessed with
questions about the highest grade or year of regular
schooling and the highest degree earned, with classification
in three categories: 0–7 years; 8–11 years; and 12 years or
more.
Systolic blood pressure, height, and weight were measured
at the clinical examination. Systolic blood pressure was
measured after at least 5 minutes’ rest. Body mass index was
calculated as weight (kg)/height (m)2.
Am J Epidemiol 2004;160:141–149
Statistical analysis
Analyses were carried out separately for women and men.
Hazard ratios with 95 percent confidence intervals for fatal
and nonfatal coronary heart disease were calculated using
Cox’s proportional hazard regression models with age as the
underlying time variable and delayed entrance accordingly.
The observation time for each participant was the period
from the date of examination (participants from the 1936
cohort who underwent the examination in 1976 were
followed from 1977) until the incidence of or mortality from
coronary heart disease, death of another cause, date of
emigration, or December 31, 1998, whichever came first.
The analyses included the 3,686 persons (1,849 women and
1,837 men) who provided information on all potential
confounding variables.
Three models were used for investigation of the associations between intake of total fat and major types of fatty
acids and risk of coronary heart disease. Model 1 included
fat intake expressed as the percentage of total energy intake,
in other words, as a nutrient density term, and total energy
intake as a separate term. This approach, referred to as the
“nutrient density model” (26), eliminates the effect of energy
intake when assessing the association between fat intake and
coronary heart disease. This model also included cohort
identification as a covariate. Model 2a included the variables
of model 1 plus the percentage of energy derived from
protein and the percentages of energy derived from the other
major types of fatty acids (in analyses where the major types
of fatty acids were the variables of interest). Model 2b
included the variables of model 2a plus nondietary and
dietary coronary heart disease risk factors: familial history of
myocardial infarction (yes, no, do not know); smoking
(never smokers, former smokers, and current smokers of 1–
<15 g of tobacco per day and ≥15 g of tobacco per day);
leisure-time physical activity (sedentary, active); educational attainment (0–7 years, 8 years or more); alcohol
(grams per day) (nondrinkers, drinkers by tertiles); dietary
fiber (grams per megajoule per day) (as a continuous vari-
144 Jakobsen et al.
TABLE 1. Baseline characteristics and risk factors for coronary heart disease among 3,686
Danish women and men aged 30–71 years who participated in a 16-year prospective study
ending in 1998
Women by percentiles
Men by percentiles
10
50
90
10
50
90
Age (years)
31
50
61
31
51
61
Body mass index (kg/m2)
19.7
23.1
28.8
21.4
25.0
29.6
Systolic blood pressure (mmHg)
104
120
148
108
126
152
Serum total cholesterol (mmol/liter)
4.7
6.1
7.8
4.8
6.2
7.9
Serum triglyceride (mmol/liter)
0.6
1.0
1.8
0.7
1.2
2.4
Alcohol (g/day)
0
6.8
24.9
2.4
19.0
56.0
Cholesterol (mg/MJ*)
30.5
46.4
71.3
29.5
44.6
66.1
Fiber (g/MJ)
1.5
2.1
3.1
1.4
2.0
2.8
Total energy (MJ)
5.0
7.3
10.2
6.6
10.0
13.6
Total protein
11.2
14.6
19.2
11.2
14.1
17.9
Total carbohydrate
31.1
38.9
47.4
31.1
38.9
48.0
Total fat
36.6
46.0
54.4
37.4
46.9
55.1
Saturated fatty acids
14.1
19.5
24.8
14.5
19.7
24.8
Monounsaturated fatty acids
11.3
15.2
18.6
12.1
15.8
19.4
Polyunsaturated fatty acids
4.5
6.5
9.5
4.4
6.5
9.3
Daily nutrient intake
% of energy from
* MJ, megajoule.
able); and dietary cholesterol (mg per megajoule per day) (as
a continuous variable). Adjustments of systolic blood pressure and body mass index were expanded beyond simple
linear approaches to include flexible curves via spline regression (27) that make use of intracategory information. The
knots were defined using equal events in each line segment.
The actual values of systolic blood pressure knots were 122,
134, and 152 mmHg among women and 120, 132, and 150
mmHg among men. The actual values of body mass index
knots were 22, 24, and 28 kg/m2 among women and 24, 26,
and 28 kg/m2 among men.
A covariate (cohort identification and covariates in models
2a and 2b) was included if it changed the beta coefficient for
the dietary variable of interest 10 percent or more. This
strategy was chosen because of the limited number of cases.
For every Cox model, we checked the proportional hazard
assumption with a smoothed plot of scaled Schoenfeld residuals versus time. Statistical interaction between gender and
fat intake was tested using the likelihood ratio test in a model
stratified by gender.
The estimated hazard ratios for total fat and the major
types of fatty acids in model 1 may be interpreted as the estimated differences in risk for a 5 percent higher level of
energy from fat where, for a fixed total energy intake, the
complementary 5 percent lower intake of energy comes from
other nonspecified sources of energy. In contrast, the results
of models 2a and 2b may be interpreted as the estimated
differences in risk for a 5 percent higher level of energy from
fat, where the lower intake of energy is due to a lower intake
of energy from carbohydrates. In other words, the results
may be interpreted as substituting 5 percent of energy from
fat for the same amount of energy from carbohydrates.
Further, when studying the risk associated with 5 percent
higher intake of polyunsaturated fatty acids, we added the
percentage of energy from carbohydrates to model 2a and
model 2b, and we removed the percentage of energy from
saturated fatty acids from the models. The results of models
2a and 2b may in this case be interpreted as the estimated
differences in risk for a 5 percent higher level of energy from
polyunsaturated fat, where the lower intake of energy is due
to a lower intake of energy from saturated fat.
To evaluate the age-related differences in coronary heart
disease, we added a time (age)-dependent variable to the
models that allows for different associations between fat
intake and risk of coronary heart disease for the two age
bands of less than 60 years and 60 years or more. This variable was added because previous studies have shown an agerelated difference (2, 3), and because the plot of scaled
Schoenfeld residuals versus time suggested an age-related
difference. Statistical interaction between age band and fat
intake was tested using the likelihood ratio test.
Data analyses were performed using Stata statistical software, release 7.0 (Stata Corporation, College Station,
Texas).
RESULTS
Characteristics of the participants are given in table 1.
During the 7–22 years (median, 16 years) of follow-up from
1974 to 1998, 326 participants (98 women and 228 men)
Am J Epidemiol 2004;160:141–149
Dietary Fat and Coronary Heart Disease 145
TABLE 2. Risk of coronary heart disease according to intake of 5% higher level of
energy from dietary fat in a 16-year prospective study (ending in 1998) of 3,686
Danish women and men aged 30–71 years
Women (98 CHD* events)
Men (228 CHD events)
HR*
95% CI*
HR
95% CI
1.10
0.95, 1.28
1.00
0.91, 1.10
Model 2a‡
1.12
0.96, 1.30
0.99
0.90, 1.10
Model 2b§
1.12
0.93, 1.36
0.98
0.87, 1.10
1.24
0.98, 1.57
1.04
0.88, 1.23
Model 2a
1.24
0.91, 1.70
0.93
0.72, 1.21
Model 2b
1.36
0.98, 1.88
1.03
0.78, 1.37
1.25
0.85, 1.84
1.05
0.83, 1.33
Model 2a
1.14
0.65, 2.00
1.15
0.80, 1.66
Model 2b
1.01
0.56, 1.83
0.95
0.65, 1.40
0.83
0.51, 1.33
0.86
0.62, 1.20
Model 2a
0.83
0.47, 1.45
0.84
0.59, 1.18
Model 2b
0.89
0.50, 1.57
0.80
0.55, 1.15
Model 2a
0.72
0.44, 1.19
0.84
0.59, 1.18
Model 2b
0.71
0.42, 1.18
0.80
0.55, 1.15
Total fat
Model 1†
Total fat for carbohydrates
Saturated fatty acids
Model 1
Saturated fat for carbohydrates
Monounsaturated fatty acids
Model 1
Monounsaturated fat for
carbohydrates
Polyunsaturated fatty acids
Model 1
Polyunsaturated fat for
carbohydrates
Polyunsaturated fat for
saturated fat
* CHD, coronary heart disease; HR, hazard ratio; CI, confidence interval.
† Model 1 included the variable of interest as the percentage of total energy intake (5%
unit), total energy intake (megajoule), and cohort identification.
‡ Model 2a included the variables of model 1 plus the percentage of energy derived
from protein and the percentages of energy derived from the other major types of fatty
acids (in analyses where the major types of fatty acids were the variables of interest).
When we studied the difference in risk associated with a higher level of polyunsaturated
fat, where the lower intake of energy is due to a lower intake of energy from saturated fat,
the percentage of energy from carbohydrates was added to model 2a, and the percentage
of energy from saturated fatty acids was removed from the model.
§ Model 2b included the variables of model 2a and the other nondietary and dietary
coronary heart disease risk factors.
with fatal or nonfatal events of coronary heart disease were
identified (table 2).
The following results are the estimated differences in risk
for a 5 percent higher level of energy from fat, where the
lower intake of energy is due to a lower intake of energy
from carbohydrates. All the hazard ratios are multivariate
adjusted.
Among women, the percentage of energy derived from
saturated fat was borderline significantly positively associated with the risk of coronary heart disease (hazard ratio
Am J Epidemiol 2004;160:141–149
(HR) = 1.36, 95 percent confidence interval (CI): 0.98, 1.88)
(table 2). The hazard ratio for percentage of energy from
monounsaturated fat was 1.01 (95 percent CI: 0.56, 1.83)
(table 2). In age-dependent analyses (table 3), energy from
total fat was associated with a 74 percent greater risk of coronary heart disease among the younger women (HR = 1.74,
95 percent CI: 1.15, 2.64), whereas there was no association
between total fat and risk of coronary heart disease among
the older women (HR = 1.05, 95 percent CI: 0.86, 1.28). The
p value for effect modification by age was 0.02. Energy from
146 Jakobsen et al.
TABLE 3. Age-related risk of coronary heart disease according to intake of 5% higher level of energy from dietary fat
in a 16-year prospective study (ending in 1998) of 3,686 Danish women and men aged 30–71 years
Women
Men
≥60 years
<60 years
≥60 years
<60 years
HR*
95% CI*
HR
95% CI
HR
95% CI
HR
95% CI
1.66
1.12, 2.47
1.03
0.88, 1.21
1.17
0.96, 1.42
0.96
0.86, 1.07
Model 2a‡
1.77
1.15, 2.55
1.05
0.89, 1.23
1.16
0.95, 1.41
0.95
0.85, 1.06
Model 2b§
1.74
1.15, 2.64
1.05
0.86, 1.28
1.15
0.93, 1.41
0.93
0.81, 1.06
2.48
1.33, 4.65
1.12
0.87, 1.44
1.29
0.92, 1.80
0.96
0.79, 1.17
Model 2a
2.49
1.30, 4.77
1.11
0.80, 1.54
1.16
0.79, 1.61
0.86
0.65, 1.14
Model 2b
2.68
1.40, 5.12
1.22
0.86, 1.71
1.29
0.87, 1.91
0.94
0.70, 1.28
2.98
1.38, 6.44
1.03
0.68, 1.57
1.47
0.91, 2.37
0.95
0.73, 1.24
Model 2a
2.85
1.22, 6.69
0.89
0.49, 1.61
1.61
0.93, 2.78
1.04
0.71, 1.53
Model 2b
2.56
1.15, 5.73
0.75
0.40, 1.41
1.37
0.78, 2.40
0.85
0.57, 1.28
0.68
0.20, 2.34
0.86
0.51, 1.44
1.12
0.60, 2.09
0.79
0.53, 1.16
Model 2a
0.67
0.19, 2.44
0.86
0.48, 1.56
1.09
0.58, 2.05
0.76
0.51, 1.14
Model 2b
0.66
0.19, 2.35
0.94
0.51, 1.74
1.06
0.56, 1.99
0.72
0.47, 1.10
Model 2a
0.60
0.17, 2.12
0.75
0.44, 1.28
1.09
0.58, 2.05
0.76
0.51, 1.14
Model 2b
0.54
0.15, 1.95
0.75
0.43, 1.30
1.06
0.56, 1.99
0.72
0.47, 1.10
Total fat
Model 1†
Total fat for carbohydrates
Saturated fatty acids
Model 1
Saturated fat for
carbohydrates
Monounsaturated fatty acids
Model 1
Monounsaturated fat for
carbohydrates
Polyunsaturated fatty acids
Model 1
Polyunsaturated fat for
carbohydrates
Polyunsaturated fat for
saturated fat
* HR, hazard ratio; CI, confidence interval.
† Model 1 included the variable of interest as the percentage of total energy intake (5% unit), total energy intake (megajoule),
and cohort identification.
‡ Model 2a included the variables of model 1 plus the percentage of energy derived from protein and the percentages of
energy derived from the other major types of fatty acids (in analyses where the major types of fatty acids were the variables of
interest). When we studied the difference in risk associated with a higher level of polyunsaturated fat, where the lower intake of
energy is due to a lower intake of energy from saturated fat, the percentage of energy from carbohydrates was added to model
2a, and the percentage of energy from saturated fatty acids was removed from the model.
§ Model 2b included the variables of model 2a and the other nondietary and dietary coronary heart disease risk factors.
saturated fat was strongly positively associated with risk of
coronary heart disease among the younger (HR = 2.68, 95
percent CI: 1.40, 5.12), but not among the older (HR = 1.22,
95 percent CI: 0.86, 1.71), women (table 3). The p value for
effect modification by age was 0.02. The percentage of
energy derived from monounsaturated fat was positively
associated with risk of coronary heart disease among the
younger (HR = 2.56, 95 percent CI: 1.15, 5.73), but not
among the older (HR = 0.75, 95% CI: 0.40, 1.41), women
(table 3). The p value for effect modification by age was
0.01. There was an inverse trend between the percentage of
energy derived from polyunsaturated fat and risk of coronary
heart disease among women (table 2). This trend was
stronger when the lower intake of energy was due to a lower
intake of energy from saturated fat (HR = 0.71, 95 percent
CI: 0.42, 1.18) than when the lower intake of energy was due
to a lower intake of energy from carbohydrates (HR = 0.89,
95 percent CI: 0.42, 1.18) (table 2).
Among men, there were no associations between total fat
and the major types of fat and risk of coronary heart disease
(table 2). However, there was a positive trend between the
percentage of energy derived from saturated fat and risk of
Am J Epidemiol 2004;160:141–149
Dietary Fat and Coronary Heart Disease 147
coronary heart disease among the younger men (HR = 1.29,
95 percent CI: 0.87, 1.91) but not among the older men
(HR = 0.94, 95 percent CI: 0.70, 1.28) (table 3). The p value
for effect modification by age was 0.12. The same pattern
was seen for total fat (among the younger men: HR = 1.15,
95 percent CI: 0.93, 1.41; among the older men: HR = 0.93,
95 percent CI: 0.81, 1.06; p value for effect modification by
age = 0.05) and for monounsaturated fat (among the younger
men: HR = 1.37, 95 percent CI: 0.78, 2.40; among the older
men: HR = 0.85, 95 percent CI: 0.57, 1.28; p value for effect
modification by age = 0.09) (table 3). There was an inverse
trend between the percentage of energy derived from polyunsaturated fat and risk of coronary heart disease among the
older men (table 3). This trend was the same, whether the
lower intake of energy was due to a lower intake of energy
from saturated fat or from carbohydrates (HR = 0.72, 95
percent CI: 0.47, 1.10) (table 3).
There was no effect modification by gender in the whole
sample (p values not shown). However, in age-dependent
analyses, the association between total fat and risk of coronary heart disease was modified by gender among the
younger (p = 0.12) and among the older (p = 0.17) participants; for saturated fat, the p values were 0.10 among the
younger and 0.19 among the older participants; for monounsaturated fat, the p values were 0.15 among the younger and
0.19 among the older participants.
DISCUSSION
In the present study, a 5 percent higher level of energy
intake from saturated fat was associated with a 36 percent
greater risk of coronary heart disease among women,
whereas no overall association was found among men.
However, age-dependent analyses among men showed a
positive trend between saturated fat and risk of coronary
heart disease among the younger but not among the older
men. The same pattern, and even stronger, was seen among
women. There was an inverse trend between polyunsaturated
fat intake and risk of coronary heart disease among women
and among the older men. Among women, the trend was
stronger when the lower intake of energy was due to a lower
intake of energy from saturated fat than when the lower
intake of energy was due to a lower intake of energy from
carbohydrates, highlighting the importance of the quality of
dietary fats.
A number of limitations should be noted. First, the small
number of cases caused wide confidence intervals and
limited the possibility to further assess possible effect modification. Second, a potential source of random error arises
from the assessment of dietary intake. Seven days may be
too short a period to give information on the habitual food
intake. However, with regard to nutrients that are consumed
in a relatively large amount daily (e.g., protein, fats, carbohydrates, and fiber), a 7-day weighed food record classifies
about 80 percent in the top and bottom thirds of the distribution correctly (28). Finally, in the present study only baseline
information regarding dietary habits was available. The
effect of changes in dietary habits could therefore not be
assessed.
Am J Epidemiol 2004;160:141–149
Information bias is not likely to have affected the study, as
cases were identified by record linkage to the National
Patient Registry (22) and the Cause of Death Registry (23),
and diagnoses were established independently of the dietary
habits of the participants. Only 11.5 percent were lost to
follow-up, and selection bias is therefore unlikely to have
affected the study. Control for confounding did not change
the estimates for total fat and the major types of fats considerably. Residual confounding is therefore unlikely.
However, in observational studies, diets differing in fat
content—both quantitatively and qualitatively—inevitably
differ in other dietary constituents that may influence coronary heart disease risk. We decided to respect the observational nature of this study and not to try to control for these
potential confounders.
The gender-related difference in the association between
saturated fat intake and risk of coronary heart disease found
in the present study is to some extent supported by findings
from a recent prospective cohort study among women and
men (4) and from some prospective cohort studies examining women (9) or men (6, 8, 10, 13, 14) separately.
However, in the study by Hu et al. (9), the positive association between saturated fat intake and risk of coronary heart
disease among women was weak and not statistically significant. In contrast to the present findings, some others have
found a positive association between saturated fat intake and
coronary heart disease among men (1, 11, 12). Several explanations may account for the effect modification by gender.
One explanation may be differences in baseline risk.
Because the magnitude of the relative effect depends on the
magnitude of the baseline risk, the same absolute effect in
two populations can correspond to greatly differing relative
associations (29). Another possibility is that intakes of
complementary carbohydrates were qualitatively different
between the genders. In the present study, only types of fat,
but not types of carbohydrates, were considered. Finally,
there may be a biologic interaction. Fats produce postprandial hypertriglyceridemia (15), and a raised nonfasting
concentration of triglycerides seems to be a stronger risk
factor for death from coronary heart disease among women
than among men (16). However, the increased risk of coronary heart disease associated with high-fat diet’s causing
postprandial hypertriglyceridemia may, in part, be counterbalanced by the cis-monounsaturated and n-6 polyunsaturated fatty acids’ positive effect on serum low-density
lipoprotein cholesterol (30) and n-3 fatty acids’ positive
effect on other risk factors for coronary heart disease (31,
32).
Epidemiologic studies on age-related differences in the
association between fat intake and risk of coronary heart
disease are sparse. Only two prospective studies have been
published (2, 3). In agreement with the present study, these
studies found that risk of coronary heart disease increased
with higher intakes of total, saturated, and monounsaturated
fat among the younger, but not among the older, participants.
Differences in baseline risk may be an explanation. It is also
possible that older participants may be a selected group (a
large number of the study base has already died or has been
excluded because of coronary heart disease) and may be less
vulnerable to environmental factors.
148 Jakobsen et al.
A potentially important factor contributing to the discrepancies across the prospective studies is differences in the
ways of expressing fat intake (as relative or absolute) and
whether intake of total energy and other types of fat has been
controlled for. The strategy used for the analyses in the
present study has been used in only one previous study (9).
We expressed fat intake as energy percentage and included
total energy intake and percentages of energy from saturated,
monounsaturated, and polyunsaturated fat in the models
because of extraneous variation and potential confounding.
This also allowed us to estimate the difference in risk for a
higher level of energy from the major types of fat, where the
lower intake of energy was due to a lower intake of energy
from carbohydrates. As pointed out by Kipnis et al. (33) and
Willett et al. (26), the beta coefficient of the macronutrient of
interest in the energy-adjusted model has a substitution interpretation (in its continuous version): It represents the change
in disease incidence associated with substitution of one unit
of that macronutrient for an equivalent amount of energy
from other macronutrients. Consequently, adjusting for total
energy excludes the possibility of addressing hypotheses on
the effects of increased intake of selected nutrients (34). The
effect of one nutrient can be assessed only in relation to
another. The present study showed that we may be able to
provide evidence that saturated fat increases risk more than
carbohydrates do, but we cannot, as also emphasized by
Freedman et al. (34), predict whether fat promotes disease or
whether carbohydrates prevent disease.
In the present study, monounsaturated fat intake seems to
be associated with increased coronary heart disease risk
among the younger participants. This relation is unclear.
However, it may, in part, be due to intake of trans fatty acids,
which is included in the sum of monounsaturated fatty acids.
Trans fatty acids have a negative effect on the serum total:
high density lipoprotein cholesterol ratio when dietary
carbohydrates are replaced by trans fatty acids under isoenergetic conditions, whereas monounsaturated fatty acids
have a positive effect on the total:high density lipoprotein
cholesterol ratio when carbohydrates are replaced by
monounsaturated fatty acids (30). Further, intake of trans fat
has been shown to be positively associated with risk of coronary heart disease (35), whereas intake of monounsaturated
fat has been shown to be inversely associated with risk of
coronary heart disease (9). However, Rudel et al. (36)
demonstrated that primates on a monounsaturated diet developed more atherosclerosis than those on a polyunsaturated
diet (corresponding to those fed the saturated diet) despite a
more favorable lipid profile.
That the estimated differences in risk for a 5 percent higher
level of energy from polyunsaturated fat were the same,
whether the lower intake of energy was from carbohydrates
or saturated fat among men, may be due to the weak association between saturated fat and coronary heart disease found
among men.
We estimated the difference in risk for a higher level of
energy from fat, where the lower intake of energy was due to
a lower intake of energy from carbohydrates. The usual mix
of carbohydrates in the Western diet contains many highglycemic foods, such as potatoes and baked goods. The
possibility remains that the positive association between
saturated fat intake and risk of coronary heart disease would
have been even stronger if compared with a mix of carbohydrates from low-glycemic foods, such as whole grain cereals
and vegetables. Future studies need to address this.
In conclusion, our data suggest that coronary heart disease
risk relates to both the quantity and the quality of dietary fats
rather than only the quantity of fat. In future studies, it is
recommended that the study populations be subdivided
according to gender and age to account for possible effect
modification.
ACKNOWLEDGMENTS
This study was financed by the Danish Heart Foundation
(grants 02-1-9F-7-22961 and 02-2-9-8-22010) and the
Female Researchers in Joint Action (FREJA) program from
the Danish Medical Research Council. The establishment of
the Research Unit for Dietary Studies was also financed by
the FREJA program.
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