MOL/200251; Total nos of Pages: 6;
How relevant is the ratio of dietary n-6 to n-3 polyunsaturated
fatty acids to cardiovascular disease risk? Evidence from the
Bruce A. Griffin
The totality of evidence for the positive effects of long
fish and fish oil products on various outcomes of cardio-
vascular disease is almost incontrovertible [1–4], but still
lacks evidence from a definitive trial [5?]. The evidence
base has been strengthened still further by a recent
systematic review of 46 randomly controlled and prospec-
tive cohort trials selected from a total of 842 studies [6?].
The inclusion criteria in this review were rigorous in
selecting studies that measured the intake of fish and n-3
polyunsaturated fatty acids (PUFAs) on a range of car-
diovascular disease (CVD) endpoints. It showed compre-
hensively, that eicosapentaenoic acid (EPA)/docosahex-
aenoic acid (DHA) from fish and or fish oil supplements
reduce all-cause mortality, sudden cardiac death and
possibly stroke, and produce only minor adverse effects.
Unfortunately, the study found no high-quality evidence
reducing CVD risk, but did acknowledge that in addition
to the data for ALA being generally poor, there were no
direct comparisons of ALA with LC n-3 PUFA or studies
on the ratio of n-6/n-3 PUFA. The overall findings of this
review support the existing recommendations in the US
and UK to increase the consumption of EPA/DHA to
1g/day and 0.5g/day EPA/DHA for those with and with-
out existing CVD respectively [7,8]. Much of the evi-
dence upon which these guidelines are based, however,
comes from supplemented intakes of preformed EPA/
DHA at levels in excess of 1g/day, which, for many, is
unattainable through diet. Efforts to increase the con-
sumption of EPA/DHA within populations will be hin-
dered by a mass resistance to the consumption of oily fish
and in the longer term, diminishing fish stocks. This
leaves the developing area of fortified foods, and fish
Faculty of Health & Medical Sciences, University of
Surrey, Guildford, Surrey, UK
Correspondence to Dr Bruce A. Griffin, Faculty of
Health & Medical Sciences, University of Surrey,
Guildford, Surrey, GU2 7XH UK
Tel: +44 (0)1483 879724;
fax: +44 (0)1483 686401;
Current Opinion in Lipidology 2008, 19:000–000
Purpose of review
There has been much debate over the practical utility of the dietary ratio of n-6 to n-3
on cardiovascular health. This review examines the supporting evidence from the
OPTILIP study within the context of the emerging consensus on the value of this dietary
The question of whether the ratio of n-6/n-3 polyunsaturated fatty acid or total amounts
of dietary polyunsaturated fatty acids is of more importance to cardiovascular health has
been addressed recently in a randomly controlled trial (OPTILIP), and stable isotope
tracer study. These two studies were independently unanimous in concluding that the
ratio of n-6/n-3 polyunsaturated fatty acid is of no value in modifying cardiovascular
disease risk. The latter study also showed that the absolute amounts of dietary linoleic
acid and a-linolenic acid are of relevance to the efficiency of conversion of a-linolenic
acid to eicosapentaenoic acid and docosahexaenoic acid.
This review should help to settle any outstanding controversy over the dietary ratio of n-
6/n-3 polyunsaturated fatty acid. It reinforces current recommendations to increase the
consumption of preformed eicosapentaenoic acid/docosahexaenoic acid in fish, and
acid respectively, to promote the endogenous synthesis of these longer chain n-3
polyunsaturated fatty acids.
a-linolenic acid, cardiovascular disease, dietary ratio n-6/n-3 PUFA, fish-oil, linoleic
acid, long chain n-3 polyunsaturated fatty acids
Curr Opin Lipidol 19:000–000
? 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0957-9672 ? 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
MOL/200251; Total nos of Pages: 6;
oil supplements, which though efficacious, are viewed by
many as a nutritional last resort. These hurdles to the
acquisition of health benefits from LC n-3 PUFAs have
sustained interest in the role of dietary ALA as an endo-
genous and naturally sustainable source of LC n-3 PUFA,
and the value of the dietary ratio of n-6/n-3 PUFA.
Biological relevance of the dietary ratio of
In the absence of preformed EPA and DHA from fish oil
or supplements, the dietary ratio of n-6:n-3 PUFA in a
western diet is determined, for the most part, by the
relative proportion of linoleic acid (?95%) to ALA
(?90%) . While linoleic acid and ALA exert physio-
logical effects in their own right, the essentiality of these
fats and the relevance of the ratio of n-6/n-3 PUFA to
cardiovascularhealth, lies intheircompetitive conversion
to longer chain PUFAs via a series of stepwise desatura-
tions and elongations. Both fatty acids compete for the
activity of a rate-limiting D6-desaturase and although this
enzyme shows greater substrate specificity for ALA, the
over abundance of dietary linoleic acid gives it a quan-
titative advantage that limits the conversion of ALA to
EPA in vivo . Even so, the relationship between the
dietary intake of ALA and change in membrane EPA is
positive and linear over intakes of ALA between 2–10g
but strongly influenced by factors such as age, sex, and
the n-6 PUFA (linoleic acid) content of the background
diet [10,11]. The ratio of n-6/n-3 PUFA therefore has
utility in providing information on the physiological
effects of linoleic acid and ALA, and the metabolic
conversion of the latter to EPA.
Problems with the dietary ratio of n-6/n-3
The ratio of n-6/n-3 PUFA does have a number of
inherent problems that were concisely reviewed by
William Harris at a recent workshop at the UK Food
Standards Agency . Firstly, the ratio makes no distinc-
tion between ALA and the metabolically more active
EPA/DHA. Secondly, all ratios suffer from the fact that
the components can change in different directions or not
at all to produce a higher or lower ratio. In terms of n-6
and n-3 PUFA, this has produced considerable variation
in the physiological response to a decrease in the ratio
that has confounded the interpretation of intervention
studies. Finally, there is an underlying premise that the
ratio balances bad and good elements of n-3/n-6 PUFA,
primarily because eicosanoids derived from the principal
membrane n-6 PUFA, arachidonic acid, are metabolically
more potent in promoting inflammation, platelet aggre-
gation, and immune and vascular reactivity than those
derived from LC n-3 PUFA [12,13]. It follows from this
idea that high or increased intakes of dietary linoleic acid
as the dietary precursor of arachidonic acid, should
increase membrane arachidonic acid and exert adverse
effects on CVD when there is epidemiological evidence
to suggest that the opposite is true, and that both linoleic
acid and ALA exert favourable effects on CVD risk
[14–16]. Moreover, not only do patients with CVD have
low tissue arachidonic acid status, but there is also no
relationship between dietary linoleic acid and tissue
membrane arachidonic acid in humans [17?,18]. This
evidence conflicts with the widely held view, and recent
cross-cultural evidence [19?], that dietary n-6 PUFA,
chiefly linoleic acid, exerts adverse effects on cardio-
vascular health, mediated through tissue arachidonic
Two recent studies that have attempted to resolve the
controversy surrounding the dietary n-6/n-3 ratio, include
a large, randomly controlled intervention, the Quantifi-
cation of the Optimal n-6/n-3 Ratio in the UK Diet
(OPTILIP) study [20??,21?], and a smaller stable isotope
tracer study, in which the conversion rate of ALA was
measured in vivo at different dietary ratios of n-6/n-3
The OPTLIP study design
The OPTILIP study was a collaborative trial between
Kings College London and the University of Surrey. Its
aim was to determine the effects of lowering the dietary
ratio of n-6:n-3 PUFA on CVD risk factors, and primarily
insulin sensitivity, lipoprotein size, postprandial lipemia,
and fibrinogen and clotting factors in older people, aged
45–70 years. The study was unique in using a 6-month,
food-based intervention rather than dietary supplements
or a single item of food, in a relatively large cohort
compared with other studies [23–26]. OPTILIP was a
randomized, parallel, controlled study with four dietary
treatments versus a control. The treatments were
designed to provide dietary ratios of n-6 : n-3 PUFA of
between 3:1 to 5:1 versus a control (10:1), with n-3
PUFA being provided in the form of either ALA or LC
n-3 PUFA (EPA and DHA) or both. Specially prepared
yellow fat spreads and cooking oils, and tinned fish
were supplied to help achieve these target intakes. An
additional aim of the study was to maintain a constant
intake of saturated and monounsaturated fats and to
provide approximately 6% energy from total PUFAs.
Outcome measures included insulin sensitivity, using
the homeostatic model assessment of insulin resistance
(HOMA-IR) and revised quantitative insulin sensitivity
test (RQUICKI), serum lipids, LDL and HDL particle
size, postheparinlipase activities(lipoprotein and hepatic
lipase), postprandial lipaemia, fibrinogen and clotting
factors VII and XII.
Nutrition and Metabolism
MOL/200251; Total nos of Pages: 6;
Summary of the resultsfrom the OPTILIP study
Dietary intakes are shown in Table 1. Total energy and
the whole cohort or between treatments after 6 months.
Total fat,monounsaturated fattyacidandcarbohydrateall
increased slightly (?3%), while saturated fat decreased
(?0.7%) in the whole cohort but these were not different
between groups on follow-up. Body weight increased in
the whole cohort (0.8kg P<0.0001) but no differences
were observed between treatments at 6 months. The
postintervention dietary ratios of n-6 : n-3 PUFA were
remarkably close to the study target ratios for the treat-
additionalLCn-3PUFA (an additional0.5gover baseline
delivering ?1g/day of EPAþDHA) but not ALA, pro-
duced significant increases in erythrocyte membrane
phospholipid EPA and DHA [21?]. The biochemical
results revealed there to be no treatment effects, and thus
no effect of the dietary ratio of n-6 : n-3 PUFA on markers
of insulin sensitivity, or hemostatic function, plasma
postheparin lipase activities or serum lipids. Serum
HDL cholesterol increased significantly on follow-up
(P¼0.0001), as did the proportion of the larger HDL2
subclass between the control and group receiving a com-
bination of LC n-3 PUFA and ALA (n-6 : n-3 ratio 3:1)
both total and LDL cholesterol in women provided with
additional LC n-3 PUFA, who were not receiving HRT
(interactions between treatments x follow-up x sex). An
a consistent finding in several other studies [24–27]. It is
of VLDL, and increase in LDL particle size . Any
be offset by the host of other favourable effects of
EPA/DHA on serum triglycerides, small, dense LDL,
platelet reactivity and vascular function [28,29]. Further
analysis oftheOPTILIP dataset involving stratification of
the serumlipidsandratio of n-6 : n-3PUFA into quartiles,
revealed predictable and significant associations between
the dietary ratio and the tissue n-3 index (% EPAþDHA
in erythrocyte membranes), an emerging risk factor for
CVD [17?,18], but no relationship between the ratio and
serum lipids. In contrast to the general lack of effects
produced across different ratios of n-6 : n-3 PUFA,
changes in serum lipids became much more apparent
when groups were combined into those that received
additional LC n-3 PUFA and those that did not. Serum
triglyceride, small, dense LDL and the extent of post-
prandial lipemia all decreased significantly in the group
EPAþDHA, Table 2). Interestingly, these older men
and women were consuming approximately 0.5g/day of
LC n-3 PUFA and thus levels recommended for the
Evidence from the OPTILIP study Griffin3
Table 1 Dietary intakes on OPTLIP at baseline and following 6 months dietary intervention
Control (n6/n3 10:1) (n¼38)
LC n-3 (3:1) (n¼58)
ALA (3:1) (n¼51)
LC n-3þALA (3:1) (n¼47)
Moderate ALA (5:1) (n¼40)
Energy (E) MJ/day
Fat % Ea
SFA % Ea
MUFA % Ea
LA % Eb
ALA % Eb
LC n-3 P % Eb
Mean?SD adjusted for sex; data were analyzed by analysis of covariance. There were no significant diet–sex interactions. ALA, a-linolenic acid; LA, linoleic acid; LC, long chain; MUFA,
monounsaturated fatty acid; SFA, saturated fatty acid.
aOverall effect of follow-up versus baseline P¼0.0001.
bFollow-up?treatment interaction P¼0.00001. Mean values for follow-up values with unlike superscript letters are significantly different P<0.05.
Modified with permission [20??].
MOL/200251; Total nos of Pages: 6;
months of intervention they had achieved significant
changes in serum lipids with an increased intake of
EPA/DHA recommended for secondary prevention,
through dietary advice alone.
Limitations of the OPTILIP study
Since only small changes in n-6 PUFA were observed in
the observed biological effects was achieved by the
addition of LC n-3 PUFA and not ALA. It has been
repeatedly shown that dietary ALA is not equivalent to
LC n-3 PUFA with in respect to its biological effects
[30,31], and most importantly at levels that can be
attained through diet (?1–7g/day). Nonetheless, dietary
ALA has been shown in one study to be as effective as
dietary linoleic acid in lowering LDL cholesterol in ,
and also more favourable than EPA and DHA in this
respect [22??]. OPTILIP provided important evidence to
show that the ratio of n-6/n-3 PUFA, at least when n-6
PUFA intake is held constant, is of no practical value in
predicting changes in CVD risk factors such as serum
lipids. Instead, it identified dietary LC n-3 PUFA, at an
intake of approximately 1g/day and chiefly consumed in
fish, as the critical determinant of its outcome measures.
OPTILIP was not designed to establish if this effect
could be enhanced further by altering the intake of n-6
PUFA. As mentioned earlier, there is recent evidence to
suggest that further improvements in cardiovascular
health can be gained by lowering the dietary intake n-
6 PUFA as n-3 PUFA is increased, at least from a global
comparison of dietary intakes of PUFA across several
countries [19?]. OPTILIP was also not designed to
determine how variation in the ratio of n-6/n-3 PUFA
influenced the conversion of ALA to LC n-3 PUFA.
Insights into these important questions have been pro-
vided by a recent stable isotope tracer study [22??].
Importance of the absolute amounts of
dietary linoleic acid and a-linolenic acid
Variation in the design and techniques used in stable
isotope studies has made it difficult to reach any
consensus on the relative influence of the ratio of n-6/
n-3 PUFA or absolute amounts of linoleic acid and ALA
on the conversion of dietary ALA to LC n-3 PUFA .
Nevertheless, these studies have provided the most
definitive evidence to date to show that conversion does
occur in vivo but only to a limited extent (conversion of
ALA to EPA ranging from 0.2 to 8% with further con-
version to DHA being very low under 0.01%) [32–34].
The idea that the dietary ratio of n-6/n-3 PUFA may be a
more important determinant of the conversion of ALA
into EPA than the absolute amounts of linoleic acid and
ALA , has been recently examined by Goyens et al.
[22??]. This study reported findings from a double-blind
intervention trial that tested three parallel diets varying
in linoleic acid and ALA composition. After 4 weeks on a
run-in control diet (n¼9; 7% energy, linoleic acid, 0.4%
energy ALA, linoleic acid : ALA ratio 19:1), young male
and female subjects were assigned to one of three treat-
ments: either the control diet, or a low linoleic acid diet
(n¼10; 3% energy linoleic acid, 0.4% energy ALA,
linoleic acid : ALA ratio 7:1) or high ALA diet (n¼10;
7% energy linoleic acid, 1.1% energy ALA, linoleic acid :
ALA ratio 7:1) for a further 6 weeks. The composition of
the diets was similar in every other respect and not
dissimilar to the levels of intake achieved in OPTILIP.
ALA oxidation was measured and the conversion rates
plasma phospholipids respectively, after administration
of a bolus dose of [U-13C] ALA 10 days before the end of
each dietary intervention . The results were conclus-
ive by showing that lowering the absolute amount of
linoleic acid increased the conversion of ALA into EPA,
whereas increasing the intake of ALA actually reduced
the percentage conversion but increased the conversion
through to DHA. The plasma phospholipid pool of ALA
was almost completely (99%) converted to EPA on each
diet. Since both the low linoleic acid and high ALA diets
were of the same ratio of n-6/n-3 PUFA (7:1) but
produced different rates of conversion, the study could
conclude that the different absolute amounts of linoleic
acid and ALA were responsible for the differences in
conversion rates and not the relative proportions of these
fatty acids in the n-6/n-3 ratio. It also provided kinetic
data to show that lowering dietary linoleic acid may be a
13C enrichment of breath samples and
Nutrition and Metabolism
Table 2 Fasting and postprandial serum triglyceride concentrations, and proportions of small, dense LDL and HDL2on OPTILIP after
6 months of diets with and without additional long chain n-3 polyunsaturated fatty acid
?LC n-3 Percentage difference (95% CI)
Fasting serum TG (mmol/l)
Postprandial TG (IAUC)
?14.6 (?23.8 to ?5.4)
?10.2 (?18.4 to ?2)
4.2 (?.9 2 to 0.7)
?12.7 (?22.9 to 2.4)
chain; sdLDL, small dense LDL; TG, triglyceride.
aTwofactor analysis of covariance with level of LC n-3 PUFA (2) and level of ALA (3) without interaction, adjusted for age and BMI.
Table modified from reference [20??].
MOL/200251; Total nos of Pages: 6;
more effective means of synthesizing EPA from ALA
than increasing ALA. Whereas increasing dietary ALA
promotes the throughput of EPA to DHA.
The OPTILIP study set out to determine the optimal
ratio of n-6/n-3 PUFA in the UK diet but inadvertently
succeeded in establishing the irrelevance of this dietary
ratio and reaffirming the benefits of LC n-3 PUFA. The
stable isotope tracer study by Goyens et al. arrived at the
same conclusion on the value of the ratio of n-6/n-3
PUFA, and also produced evidence to suggest that the
conversion of ALA to LC n-3 PUFA could be enhanced
by decreasing and increasing the absolute amounts sof
dietary linoleic acid and ALA respectively. The ratio of
n-6/n-3 PUFA might be dead, but the question of how
linoleic acid and ALA influence the conversion of ALA,
especially under pathophysiological conditions, is still
very much alive.
The OPTILIP Study team: Dr Fiona Lewis, Dr Susanne Slaughter and
Professor Tom Sanders at Kings College London; Dr Margaret Griffin,
Dr Ian Davies and Professor Joe Millward at The University of Surrey.
The study was supported by a grant from The UK Food
References and recommended reading
Papers of particular interest, published within the annual period of review, have
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Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 000–000).
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of these fatty acids. The study tested the effects of a low linoleic acid and high ALA
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Nutrition and Metabolism
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Current opinion in Lipidology
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