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.

Cancer and cardiovascular disease (CVD) are the two leading causes of non-communicable disease mortality globally (Vos et al., 2020). Substantial epidemiologic evidence has linked the dietary or circulating levels of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) to the risk of all-cause, cancer, and CVD mortality (Supplementary file 1 Table S1). However, the results are inconsistent, especially for omega-6 PUFAs. Most large observational studies support the inverse associations between omega-3 PUFAs and mortality. In addition to total and individual omega-3 PUFAs, the omega-3 index, defined as the percentage of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in total fatty acids in red blood cells, was shown to be a validated biomarker of the dietary intake and tissue levels of long-chain omega-3 PUFAs, and was proposed to be a risk factor for CVD and related mortality (Harris, 2009; Harris and Von Schacky, 2004). While the omega-3 index has been observed to be inversely associated with all cause-mortality, its association patterns with CVD and cancer mortality are less clear (Harris et al., 2017; Harris et al., 2018; Kleber et al., 2016). Most importantly, results from clinical trials of omega-3 PUFA supplementation have been inconsistent (Bhatt et al., 2019; Nicholls et al., 2020). On the other hand, while some studies revealed inverse associations of omega-6 PUFAs with all-cause mortality (Delgado et al., 2017; Marklund et al., 2019; Wu et al., 2014), others reported null results (Harris et al., 2017; Harris et al., 2020; Miura et al., 2016; Otsuka et al., 2019; Zhuang et al., 2019). The role of omega-6 PUFAs in cancer and CVD mortality is less studied, and the patterns are similarly conflicting (Harris et al., 2017; Delgado et al., 2017; Marklund et al., 2019; Wu et al., 2014). Interpreting previous observational results is challenging due to the limitations of small sample sizes, insufficient adjustments for confounding, and unique sample characteristics. Moreover, many studies rely on self-reported dietary intake or fish oil supplementation status, which are subject to large variability and reporting bias (Shim et al., 2014). Despite the tremendous interest and research effort, the roles of omega-3 and omega-6 PUFAs in all-cause and cause-specific mortality remain uncertain.

It has been suggested that the high omega-6/omega-3 ratio in Western diets, 20:1 or even higher, as compared to an estimated 1:1 during the most time of human evolution, contributes to many chronic diseases, including CVD, cancer, and autoimmune disorders (Simopoulos, 2001; Simopoulos, 2008). However, while many previous studies have examined total or individual omega-3 and omega-6 PUFAs, fewer investigated the role of their imbalance, as measured by the omega-6/omega-3 ratio, in mortality (Harris et al., 2017; Otsuka et al., 2019; Zhuang et al., 2019; Noori et al., 2011). In a prospective cohort study of postmenopausal women, the omega-6/omega-3 ratio in red blood cells was associated with an increased risk of all-cause mortality but not with cancer or CVD mortality (Harris et al., 2017). Similar positive associations with all-cause mortality were observed in smaller cohorts investigating the ratio in serum or dietary intake (Otsuka et al., 2019; Noori et al., 2011). However, prospective studies in two independent cohorts from China and US did not find a linear positive association between the omega-6/omega-3 ratio in diet and all-cause mortality (Zhuang et al., 2019). To address these gaps in our understanding of the roles of omega-3 and omega-6 PUFAs and their imbalance in all-cause and cause-specific mortality, we perform a prospective study in a large population-based cohort (N=85,425) from UK Biobank, using objective measurements of PUFA levels in plasma.

In this prospective population-based study of UK individuals, we showed that a higher ratio of plasma omega-6/omega-3 fatty acids was positively associated with the risk of all-cause, cancer, and CVD mortality. These associations were independent of most risk factors examined, including age, sex, TDI, BMI, comorbidities, and physical activity, but they were stronger in current smokers. These relationships were linear for cancer mortality but not for all-cause and CVD mortality. For those two outcomes, the risk of mortality first decreased at lower ratios and then increased, with an inflection point around the ratio of 8. Moreover, omega-3 and omega-6 PUFAs in plasma were consistently and inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.

To date, studies that examined the relationship between the ratio of omega-6/omega-3 PUFAs and mortality in the general population are sparse (Harris et al., 2017; Otsuka et al., 2019; Zhuang et al., 2019; Noori et al., 2011). Similar to our finding, in a 2017 report from a prospective women cohort study (n=6501; 1875 all-cause deaths, 617 CVD deaths, 462 cancer deaths) (Harris et al., 2017), the adjusted HR for all-cause mortality was 1.10 (1.02–1.19) per 1-SD increase of omega-6/omega-3 ratio in red blood cells; however, the effects were not significant for cancer and CVD deaths. Another study supporting our results was conducted on elderly Japanese individuals (n=1054; 422 deaths). It found that the ratio of an omega-3 fatty acid, EPA, to an omega-6 fatty acid, arachidonic acid (ARA), is inversely associated with all-cause mortality, with an HR of 0.71 (95% 0.53–0.96) comparing the highest to the lowest tertile (Otsuka et al., 2019). Findings of previous studies based on dietary intake were null (Zhuang et al., 2019; Noori et al., 2011). A prospective cohort involving 145 hemodialysis patients enrolled in Southern California during 2001–2007 (42 all-cause deaths) showed that the estimated HR (95% CI) for all-cause mortality among those in the lowest relative to the highest quartiles of dietary omega-6/omega-3 ratio was 0.37 (0.14–1.08) (Noori et al., 2011). Although the effect was not significant, it still shows the protective trend of a lower omega-6/omega-3 ratio against premature death, when taking the sample size and study population into consideration. In a 2019 report based on two population-based prospective cohorts in China (n=14,117, 1007 all-cause deaths) and the US (n=36,032, 4826 all-cause deaths), the effect of the omega-6/omega-3 ratio intake was not significant (HR (95% CI) is 0.95 (0.80–1.14) for China and 0.99 (0.89–1.11) for US, respectively) (Zhuang et al., 2019). These discrepancies may be explained by the usage of circulating biomarkers or dietary intakes for calculating the omega-6/omega-3 ratio. Indeed, we performed the same association analyses for dietary PUFAs and found that their associations with mortality have smaller effect sizes and are less statistically significant, although maintaining the same effect directions as plasma PUFAs. The estimated dietary intakes may be inaccurate due to recall bias or outdated food databases (Shim et al., 2014). The circulating level is a more objective measurement of PUFA status and thus provides a more reliable picture of the effects of omega-3 and omega-6 PUFAs on mortality. Additionally, we observed that the omega-6/omega-3 ratio tends to have stronger effects on mortality outcomes in current smokers. This is consistent with a previous observation that the association between habitual fish oil supplementation and a lower risk of all-cause mortality is stronger in current smokers (Li et al., 2020). Moreover, we found that current smokers in UK Biobank tend to have higher omega-6/omega-3 ratios. Similarly, prior studies reported that current smokers have lower circulating omega-3 PUFAs than non-smokers but similar circulating levels of omega-6 PUFAs (Murff et al., 2016; Scaglia et al., 2016). It is likely that omega-3 PUFAs play more important roles in current smokers, resulting in a stronger effect of the omega-6/omega-3 ratio on mortality. However, the underlying mechanism awaits future investigations.

A large number of existing observational studies documented the inverse association of circulating levels and intake of omega-3 PUFAs with mortality (Harris et al., 2018; Kleber et al., 2016; Zhang et al., 2018; Chen et al., 2016; Eide et al., 2016; Harris et al., 2021; Lee et al., 2009; Lindberg et al., 2008; Pertiwi et al., 2021), which is in line with our finding that individuals in the highest quintile of the plasma omega-3% had approximately 30% lower risk for all-cause and CVD mortality and 25% lower risk for cancer mortality, when compared to those in the lowest quintile. Our analysis of dietary omega-3% also revealed inverse associations with all-cause and cancer mortality, with 9% and 18% lower risk, respectively. Few previous studies have examined the association in generally healthy populations (Harris et al., 2018; Zhang et al., 2018; Chen et al., 2016; Harris et al., 2021). In a 2016 meta-analysis (Chen et al., 2016) of seven epidemiologic studies for dietary omega-3 PUFAs intake and four studies for circulating levels, the estimated relative risk for all-cause mortality was 0.91 (95% CI: 0.84–0.98) when comparing the highest to the lowest categories of omega-3 PUFA intake. In two 2018 reports of population-based studies in the US, the circulating level and dietary intake of omega-3 PUFAs were significantly associated with lower total mortality (Harris et al., 2018; Zhang et al., 2018). In a 2021 meta-analysis of 17 epidemiologic studies, comparing the highest to the lowest quintiles of circulating EPA and DHA, the estimated HRs for all-cause, CVD, and cancer mortality were 0.84 (0.79–0.89), 0.80 (0.73–0.88), and 0.87 (0.78–0.96), respectively (Harris et al., 2021). Moreover, inverse associations of omega-3 PUFAs biomarkers with total mortality were found in patients with myocardial infarction (Lee et al., 2009; Pertiwi et al., 2021), type 2 diabetes (Harris et al., 2020), and other diseases (Kleber et al., 2016; Eide et al., 2016; Lindberg et al., 2008; Pottala et al., 2010); inverse associations of omega-3 PUFAs with CVD mortality were also reported in these patient groups (Kleber et al., 2016; Harris et al., 2020; Pertiwi et al., 2021). However, there are also reports of a null relationship between omega-3 PUFAs and mortality (Miura et al., 2016; Otsuka et al., 2019; Miura et al., 2018). One possible explanation for the discrepancies could be the limited statistical power due to the small sample size and the small number of events. Moreover, the inconsistency may be due to unique sample characteristics; one study only involved elder patients (Otsuka et al., 2019), and one only involved women (Miura et al., 2018).

A smaller number of studies have evaluated the associations of omega-6 PUFAs with mortality. Our findings in the large UK prospective cohort are in accordance with the results of several previous studies that increased circulating levels of omega-6 PUFAs were associated with decreased all-cause mortality (Delgado et al., 2017; Wu et al., 2014; Zhuang et al., 2019; Warensjö et al., 2008). Moreover, a 2019 meta-analysis involving 18 cohort studies and 12 case-control studies showed that an omega-6 PUFA, linoleic acid, was inversely associated with CVD mortality; the HR per interquintile range was 0.78 (95% CI, 0.70–0.85) (Marklund et al., 2019). Other studies, however, did not support such inverse associations (Harris et al., 2017; Harris et al., 2020; Miura et al., 2016; Otsuka et al., 2019; Miura et al., 2018). Although the findings were inconsistent, no previous studies reported harmful effects of omega-6 PUFAs on mortality (Harris et al., 2017; Wu et al., 2014; Harris et al., 2020; Miura et al., 2016; Otsuka et al., 2019; Zhuang et al., 2019; Miura et al., 2018; Warensjö et al., 2008; de Lorgeril et al., 1994; Petrone et al., 2013). Our studies support the inverse associations between omega-6 PUFAs and all-cause and cause-specific mortality. Further research is needed to investigate the health impacts of omega-6 PUFAs in laboratory studies, epidemiological investigations, and clinical trials.

We observed that the omega-6/omega-3 ratio is positively, while both of its numerator and denominator, omega-6% and omega-3%, are negatively associated with mortality. Our findings support that both omega-6 and omega-3 PUFAs are protective against death and that the positive associations of the omega-6/omega-3 ratio with mortality outcomes are likely due to the stronger effects of omega-3 than omega-6 PUFAs. Our mediation analysis with clinical biomarkers for CVD and cancer revealed that CRP and SHBG partially medicated the effects of the omega-6/omega-3 ratio on all-cause mortality. However, the proportions mediated are relatively small (~5%), suggesting the presence of direct effects or unexamined factors. Our findings call for future studies that evaluate the utility and investigate the mechanisms of the omega-6/omega-3 ratio.

Strengths of our current study include the use of objective PUFA biomarkers in plasma instead of the estimated intakes from dietary questionnaires, which increases the accuracy of exposure assessment. Moreover, the prospective population-based study design, large sample size, long duration of follow-up, and detailed information on potential confounding variables, substantially mitigate the possible complications from reverse causality and confounding bias. In several sensitivity analyses, most of the documented associations remain materially unchanged, indicating the robustness of our results.

Several potential limitations deserve attention. First, plasma omega-3 and omega-6 PUFAs were measured only once at baseline. Their levels may vary with diet or other lifestyle factors, which could cause misclassification over follow-up. However, some studies demonstrated that multiple measurements of omega-3 PUFAs have been consistent for a 6-month period (Kobayashi et al., 2001). Moreover, the 13 year within-person correlation for circulating omega-6 PUFAs was comparable to such correlations for other major CVD risk factors (Clarke et al., 1999) Thus, the single measurement of PUFAs at baseline, although not perfect, provides us with adequate information to investigate the relative long-term effects. Second, although we adjusted for many potential confounders in the model, we cannot rule out the imprecisely measured and unmeasured factors. Third, we acknowledged that the cohort did not mirror the broader UK demographic in terms of socioeconomic and health profiles. Participants in the UK Biobank generally exhibited better health and higher socioeconomic status than the average UK resident, potentially influencing the disease prevalence and incidence rates. Nonetheless, the UK Biobank’s extensive sample size and comprehensive exposure data enable the generation of valuable estimates for exposure-disease associations. These estimates have been corroborated by findings from more demographically representative cohorts (Batty et al., 2020; Fry et al., 2017). Last, although we included individuals of different ancestries in the analysis, over 90% of the participants were of European ancestry. The generalizability of our findings across ancestries requires future verification.

The datasets analyzed during the current study are available from the UK Biobank through an application process (http://www.ukbiobank.ac.uk/). R scripts were deposited on GitHub (copy archived at Zhang, 2024).

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Author details

1. Yuchen Zhang

   Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia, United States

   Contribution

   Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8992-5258

2. Yitang Sun

   Department of Genetics, University of Georgia, Athens, Georgia, United States

   Contribution

   Data curation, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6564-8815

3. Qi Yu

   Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, United States

   Contribution

   Formal analysis, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0007-7585-1183

4. Suhang Song

   Department of Health Policy and Management, College of Public Health, University of Georgia, Athens, Georgia, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1934-632X

5. J Thomas Brenna

   1. Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
   2. Dell Pediatric Research Institute and the Depts of Pediatrics, of Nutrition, and of Chemistry, University of Texas at Austin, Austin, Texas, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9494-4245

6. Ye Shen

   Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia, United States

   Contribution

   Conceptualization, Supervision, Investigation, Project administration, Writing – review and editing

   For correspondence

   yeshen@uga.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6662-0048

7. Kaixiong Ye

   1. Department of Genetics, University of Georgia, Athens, Georgia, United States
   2. Institute of Bioinformatics, University of Georgia, Athens, Georgia, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Project administration, Writing – review and editing

   For correspondence

   kaixiong.ye@uga.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4658-7292

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