Higher ratio of plasma omega-6/omega-3 fatty acids is associated with greater risk of all-cause, cancer, and cardiovascular mortality: A population-based cohort study in UK Biobank

Background: Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been
associated with various chronic diseases and mortality, but results are conflicting. Few studies examined
the role of omega-6/omega-3 ratio in mortality. Methods: We investigated plasma omega-3 and omega-
6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort,
the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died
during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD).
Associations were estimated by multivariable Cox proportional hazards regression with adjustment for
relevant risk factors. Results: Risk for all three mortality outcomes increased as the ratio of omega-
6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals
had 26% (95% CI, 15-38%) higher total mortality, 14% (95% CI, 0-31%) higher cancer mortality, and 31%
(95% CI, 10-55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all
inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.
Conclusions: Using a population-based cohort in UK Biobank, our study revealed a strong association
between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD
mortality.
Key Points
Fatty acids play an essential role in health. Studies have shown that diets high in omega-3 fatty
acids found in foods like fish, fish oil, flaxseed and walnuts may be beneficial. Yet some studies
have raised concern that too many omega-6 fatty acids in Western diets rich in vegetable oils
may be harmful. Some scientists have proposed that the balance of omega-3 and omega-6 in
diets is vital to health. They hypothesize that a higher omega-6 to omega-3 fatty acids ratio is
detrimental. But, proving that a higher ratio of omega-6 to omega-3 fatty acids is harmful has
been difficult. Many studies have found conflicting results. Scientists have struggled to
accurately measure fatty acid intake as tracking an individual’s dietary intake is challenging and
self-reported dietary intake may be incorrect. Additionally, scientists must follow individuals for
many years to determine if a high ratio of omega-6 to omega-3 is linked with cancer, heart
disease, or death. But, measuring circulating fatty acids in an individual’s blood may offer an
easier and more reliable approach to studying the health impacts of these vital nutrients. Zhang
et al. show that people with higher ratios of omega-6 to omega-3 fatty acids in their blood are at
greater risk of dying from cancer, heart disease, or any cause than those with lower ratios. The
experiments measured omega-6 and omega-3 fatty acid levels in more than 85,000 participants
in the UK Biobank who scientists followed for an average of about 13 years. Participants with
the highest ratios of omega-6 to omega-3 fatty acids were 26% more likely to die of any cause,
14% more likely to die of cancer, and 31% more likely to die of heart disease than individuals with the lowest ratios. Individually, high levels of omega-6 fatty acids and high levels of omega-3
fatty acids were both associated with a lower risk of dying. But the protective effects of omega-3
were greater. For example, individuals with the highest levels of omega-6 fatty acids were 23%
less likely to die of any cause. By comparison, those with the highest levels of omega-3s were
31% less likely to die. The stronger protection offered by high levels of omega-3s likely explains
why having a high ratio of omega-6s to omega-3s was linked to harm. Both are protective. But
the protection provided by omega-3s is more robust. The experiments support dietary
interventions to raise omega-3 fatty acid levels and maintain a low omega-6 to omega-3 fatty
acid ratio to prevent early deaths from cancer, heart disease or other causes. More research is
needed to understand the impact of dietary fatty acid intake on other diseases and how genetics
may influence the health impact of fatty acids.