Nutritional Epidemiology—Research Communication
Dietary ?-Linolenic Acid Is
Associated with Reduced Risk of
Fatal Coronary Heart Disease, but
Increased Prostate Cancer Risk:
(Manuscript received 25 November 2003. Initial review completed
30 December 2003. Revision accepted 28 January 2004.)
Ingeborg A. Brouwer,3Martijn B. Katan, and Peter L. Zock
Wageningen Centre for Food Sciences, Wageningen, the
Netherlands and Division of Human Nutrition and Epidemiology,
Wageningen University, Wageningen, the Netherlands
timate quantitatively the associations between intake of ?-lin-
olenic acid [ALA, the (n-3) fatty acid in vegetable oils], mor-
tality from heart disease, and the occurrence of prostate
cancer in observational studies. We identified 5 prospective
cohort studies that reported intake of ALA and mortality from
heart disease. We also reviewed data from 3 clinical trials on
ALA intake and heart disease. In addition, we identified 9
cohort and case-control studies that reported on the associ-
ation between ALA intake or blood levels and incidence or
prevalence of prostate cancer. We combined risk estimates
across studies using a random-effects model. High ALA in-
prospective cohort studies (combined relative risk 0.79, 95%
CI 0.60–1.04). Three open-label trials also indicated that ALA
may protect against heart disease. However, epidemiologic
studies also showed an increased risk of prostate cancer in
men with a high intake or blood level of ALA (combined rela-
tive risk 1.70; 95% CI 1.12–2.58). This meta-analysis shows
that consumption of ALA might reduce heart disease mortal-
ity. However, the association between high intake of ALA and
prostate cancer is of concern and warrants further study.
Nutr. 134: 919–922, 2004.
The objective of this meta-analysis was to es-
● linolenic acid
(n-3) fatty acids
A high intake of very long-chain (n-3) fatty acids from fish
decreases the risk of death from coronary heart disease (1–6).
However, much less is known about the effects of ?-linolenic
acid [18:3 (n-3); ALA], the parent compound of all (n-3) fatty
acids. Dietary ALA occurs mainly in plants and vegetable oils;
its intake in affluent countries is 5–10 times higher than that
of (n-3) fatty acids from fish. In the Netherlands, the major
sources of ALA include margarine (25% of daily intake), meat
(11%), bread (10%), and vegetables (8%) (7). In the United
States, important sources of ALA are mayonnaise, creamy
salad dressings, margarine, butter, beef, pork, lamb, and oil-
and-vinegar–based dressings (8). An advantage of ALA over
the very long-chain (n-3) fatty acids from fish is that it is easier
to incorporate into food products because it does not have the
pronounced smell and taste of fish oil. Furthermore, replacing
very long-chain (n-3) fatty acids from fish by ALA from
vegetable sources would prevent further depletion of the al-
ready low stocks of edible fish in the ocean (9). Here, we
present quantitative estimates of the associations between
ALA intake, mortality from heart disease, and occurrence of
prostate cancer in observational studies.
MATERIALS AND METHODS
Sources and search criteria. Studies on the relationship between
ALA intake and disease were identified in the MEDLINE databases
by using the keywords, linolenic acid and human, and by checking
citations in identified publications. For our meta-analysis of the
magnitude of the association between dietary intake of ALA and fatal
heart disease risk, we selected only prospective cohort studies. We
used only prospective studies because these are regarded as having the
strongest design of all observational studies, and also because case-
control studies do not provide reliable information on diet and fatal
heart disease. Because the cases in these studies have died, it is very
hard to obtain reliable dietary intake data retrospectively. In addition
to the meta-analysis, we reviewed the results of 3 randomized clinical
trials investigating effects of ALA intake on heart disease.
For a meta-analysis on the relationship between ALA intake or
status and risk of prostate cancer we selected all observational studies
that related either ALA intake or ALA concentrations in blood with
incidence or prevalence of prostate cancer. In this meta-analysis, we
did include case-control studies because prospective studies on a
possible association are scarce and a possible association has never
been systematically addressed. Furthermore, retrospective assessment
of the diet is feasible because prostate cancer is not immediately fatal.
Meta-analyses. For inclusion in the meta-analyses, studies had
to provide a quantitative estimate of relative risk (RR) and its
standard error. We extracted from individual studies the risk estimate
that referred to the largest difference in intake. Combined risk esti-
mates were calculated by using the crude estimates of the individual
studies (unadjusted RR) and by using the risk estimates that reflected
the greatest degree of control for other environmental and dietary risk
factors (RR adjusted for confounding factors). Risk estimates were
combined using the random-effects model of DerSimonian and Laird
Five prospective epidemiologic studies (11–15) reported
intake of ALA in relation to the incidence of fatal heart
1Presented in poster form at the meeting of the American Heart Association,
43rd Annual Conference on Cardiovascular Disease Epidemiology and Prevention
(in association with the Council on Nutrition, Physical Activity and Metabolism),
March 5–8, 2003, Miami, FL [Zock, P. L. & Brouwer, I. A.
acid and heart disease: a meta-analysis of prospective cohort studies] and at the
EGEA first international conference on health benefits of the Mediterranean diet,
June 5–8, 2003, Crete, Greece [Brouwer, I. A., Katan, M. B. & Zock, P. L.
Dietary alpha-linolenic acid intake, heart disease and prostate cancer].
2Supported by Wageningen Centre for Food Sciences (WCFS). WCFS is an
alliance of major Dutch food industries, TNO Nutrition and Food Research, Zeist,
the Netherlands, and Wageningen University and Research Centre, Wageningen,
the Netherlands, with financial support from the Dutch Government.
3To whom correspondence and reprint requests should be addressed.
0022-3166/04 $8.00 © 2004 American Society for Nutritional Sciences.
by guest on March 11, 2011
disease (Fig. 1). Four of these cohort studies consisted of men
(11–13,15) and one of women (14). All cohorts consisted of
people who were free of diagnosed cardiovascular disease at
baseline. The 12,866 participants of the MRFIT study were
between 35 and 57 y old at baseline and were determined to be
at high risk of coronary heart disease (11). The 43,757 health
professionals were between 40 and 75 y of age at baseline (12).
The 21,930 men in the Finnish ATBC study were all smokers
and aged between 50 and 69 y (13). The 667 men in the
Zutphen study were between 64 and 84 y old at the start of the
study (15). The 76,283 female nurses in the Nurses’ Health
Study were 30–55 y old (14). The combined risk estimates of
fatal heart disease for a high vs. low intake of ALA were 0.88
(95% CI: 0.66–1.17) when using unadjusted RR of the indi-
vidual studies, and 0.79 (95% CI: 0.60–1.04) when using RR
adjusted for confounding factors (Fig. 1). The mean ALA
intake in the highest categories in the individual studies was
2.0 vs. 0.8 g/d in the lowest categories; thus the RR referred to
a mean difference of 1.2 g/d.
Three clinical trials investigated the effect of increasing
ALA intake on the incidence of fatal coronary heart dis-
ease(3,16,17). In the Lyon Diet Heart Study, 192 patients in
the experimental group consumed 1.1 g ALA/d more than the
219 patients in the control group. The experimental group had
a significantly lower incidence of fatal coronary heart disease
(adjusted RR 0.24; 95% CI 0.07–0.85) than the control group
(3). In a trial in India, 120 patients received 20 g/d mustard oil
(similar to canola oil) containing 2.9 of ALA daily and 118
patients received placebo treatment, which contained no
ALA, for 1 y. All patients had experienced an acute myocar-
dial infarction shortly before they entered the study. Patients
using mustard oil had a lower risk of cardiac death (RR 0.60;
95% CI 0.23–1.40) than patients who received placebo treat-
ment (16). In another recent Indian trial, 499 patients in the
experimental group were advised to consume an Indo-Medi-
terranean diet and 501 patients in the control group were
advised to consume the step I National Cholesterol Education
Program diet. The experimental diet contained on average
1.0 g ALA more than the control diet. Patients in the exper-
imental group experienced significantly fewer total cardiac
events (RR 0.48; 0.33–0.71) and sudden deaths (RR 0.33;
0.13–0.86) than those in the control group. In all three trials,
the investigators were aware of the treatment. Another short-
coming of the large Indian trial and the Lyon Diet Heart trial
is that changes in the diet involved more than ALA intake
alone (3,17). Moreover, the small Indian trial lacked power,
and the number of cardiac events in this population was
extremely high (30% in 1 y), making it difficult to extrapolate
from this specific patient population to other populations.
Thus, the above three trials did not have the ideal double-
blind structure and had other limitations in design. Therefore,
they cannot firmly establish a causal relationship between
intake of ALA and reduced risk of fatal heart disease. Never-
theless, the findings from these trials are in line with the
associations found in the prospective observational studies.
Furthermore, animal experiments indicate that ALA may pre-
vent fatal heart disease by inhibiting life-threatening arrhyth-
mias (18,19). Taken together, the prospective studies and the
trials provide strong indications for a role of ALA in prevent-
ing fatal heart disease; they suggest that increasing intake of
ALA by 1.2 g/d decreases the risk of fatal coronary heart
disease by at least 20%.
Any favorable effects of ALA should be weighed against
possible adverse effects. There have been reports suggesting
that subjects with high ALA intake may be at increased risk of
prostate cancer. We found a total of 9 observational studies
(8,20–27) that investigated the relationship between prostate
cancer incidence or prevalence and intake of ALA or blood
levels of ALA (Fig. 2). Blood levels of ALA reflect intake of
ALA (28). A cohort study from the Netherlands consisting of
58,279 men aged 55–69 y at baseline was the only prospective
study showing a slight protective effect of ALA intake on
prostate cancer incidence (RR 0.76; 95% CI 0.66–1.04) (22).
The U.S. Health Professionals’ follow-up study, which in-
volved 51,529 men age 40–75 y at baseline, showed a slightly
increased risk with increasing dietary ALA intake (RR 1.25;
95% CI 0.82–1.92) (8). Two nested case-control studies, one
from the United States (20) and one from Norway (21)
showed an increased risk of prostate cancer for men in the
highest quartile of blood ALA. In these four prospective
studies (8,20–22), the combined estimate of adjusted RR for
prostate cancer incidence was 1.32 (95% CI 0.80–2.18) for
men with high vs. low intake or blood levels of ALA. When
we combined these data with those from five nonprospective
studies (23–27), the risk estimate increased to 1.70 (95% CI
1.12–2.58). It should be noted that the results from these
studies were quite heterogeneous (Fig. 2).
intake of ALA in prospective cohort studies. Values are mean RR and
95% CI. The density of the points represents the weighting factor used
for calculating the combined RR.
Relative risk of fatal heart disease for high vs. low
ALA intake or blood concentrations in prospective (8,20–22) and case-
control studies (23–27). Values are mean RR and 95% CI. The density
of the points represents the weighting factor used for calculating the
Relative risk of prostate cancer with high versus low
BROUWER ET AL.
by guest on March 11, 2011
The outcome of our meta-analysis of prospective studies
taken together with the results of the clinical trials (3,16,17)
suggests that an increased intake of ALA can lower the risk of
fatal coronary heart disease.
The most likely mechanism by which ALA may prevent
fatal heart disease is by reducing cardiac arrhythmia. In the
Western world, ?50% of all deaths from cardiovascular dis-
ease can be ascribed to sudden cardiac death (29). The ma-
jority of sudden deaths are directly caused by acute ventricular
arrhythmia (30). In vitro and animal studies have suggested
antiarrhythmic effects of ALA (18,19).
The data reviewed here suggest that ALA protects against
heart disease, but there are also indications for an increased
risk of prostate cancer in men with a high intake of ALA
compared with those with a low intake. It is quite uncertain at
present whether the effect on prostate cancer is real. Even if it
were real, the protective effect on fatal coronary heart disease
would probably outweigh these possible negative effects, espe-
cially for men with an increased risk of heart disease. In the
United Sates, 6 times more men are diagnosed with coronary
heart disease than with prostate cancer, and almost 8 times
more men die of coronary heart disease than of prostate cancer
(CDC/NCHS, www.cdc.gov). Furthermore, prostate cancer
occurs at an older age: ?40% of coronary heart disease pa-
tients are ?65 y old when diagnosed, whereas ?50% of
prostate cancer patients are ?75 y old when diagnosed.
A possible explanation for the heterogeneity in results
between the observational studies might be that ALA can
come from different dietary sources. This might lead to differ-
ent types of confounding for different studies. For example, in
some countries, such as Uruguay (24), meat and not vegetable
oil is the major source of ALA, and the apparently deleterious
effect of ALA could therefore be caused by high meat intake
instead of high ALA intake. This would lead to an increased
risk of prostate cancer in those studies in which meat was the
major source of ALA and not in those studies in which
vegetable oils were the major source of ALA. In the Nether-
lands, where the study of Schuurman et al. (22) showed a
protective effect of linolenic acid intake on prostate cancer,
vegetable oils in margarines are indeed the main source of
ALA (7). Unfortunately, only 3 studies of ALA intake and
prostate cancer provided additional information about the
source of ALA. These studies do not show a clear association
with intake of either vegetable oils or meat (8,23,24). In the
Health Professionals Follow-Up Study (8), red meat was an
important source of ALA, but not the main source. Further-
more, the relation between ALA intake and prostate cancer
was still present after adjustment for meat intake in the Health
Professionals Follow-Up Study (8) and after adjustment for
animal fat in the study of Ramon et al. (23). Moreover, in the
study in Uruguay, both ALA from animal sources and ALA
from vegetable sources were associated with an increased risk
of prostate cancer (24). Thus, it is unlikely that the differences
in results between populations are caused by either meat or
vegetable oil as the major source of ALA in a particular
population. Other reasons for the heterogeneity of the results
might include the differences in the design of the studies,
differences in the background diets of the populations, random
error, and publication bias.
Intake of very-long chain (n-3) PUFA as present in fish is
not related to an increased risk of prostate cancer in epidemi-
ologic or animal studies. There are even indications that high
intakes of very-long chain (n-3) PUFA from fish may protect
against prostate cancer (31). Data from clinical trials and
prospective studies showed that moderate-to-high intake of
(n-3) fatty acids from fish reduces the risk of total mortality by
at least 20% (1,2,16). Therefore, fish should be the first rec-
ommended source of (n-3) fatty acids. However, ALA could
provide an alternative for those subjects who are at high risk
of cardiovascular disease and who, for various reasons, do not
want to consume fish. Another advantage of increased use of
ALA instead of (n-3) fatty acids from fish would be the lower
burden on the environment. Use of ALA instead of fish fatty
acids could help to prevent depletion of the oceans from
certain fish species.
ALA consumption might have a substantial effect on heart
disease mortality, but the positive association between intake
of ALA and prostate cancer is of concern and requires further
study. Double-blind, randomized clinical trials are required to
provide definitive answers on ALA intake and heart disease.
Such trials will lack the power to detect effects of ALA intake
on prostate cancer, but studies of prostate-specific antigen may
provide a surrogate marker. In the meantime, very long-chain
(n-3) fatty acids from fish should remain the recommended
source of (n-3) fatty acids in the prevention of heart disease.
Note added in proof:
smokers [Ma ¨nnisto, S., Pietinen, P., Virtanen, M. J., Salminen, I.,
Albanes, D., Giovannucci, E. & Virtamo, J.
and risk of prostate cancer in a nested case-control study in male
smokers. Cancer Epidemiol. Biomarkers Prev. 12: 1422–1428] the
relative risk (RR) for prostate cancer in the fourth versus the first
quartile of ALA intake was 1.16 (95% CI 0.64–2.13). Inclusion of
this study changes the combined RR for prospective studies from 1.32
to 1.28 (95% CI 0.84–1.94). The combined RR for all studies on
ALA and prostate cancer changes from 1.70 to 1.62 (95% CI 1.11–
In a recent prospective study in male
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