Omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are believed to reduce risk of coronary heart disease (CHD) by decreasing triglyceride levels (a type of fat/lipid found in the blood).
But there has been disagreement about whether fish oil supplements may raise LDL-cholesterol levels and the European Medicines Agency (EMA) no longer considers omega-3 medicines effective at preventing future cardiovascular issues in patients who have had a heart attack.
The authors of the current study note that nearly all studies into the cardiovascular benefits of EPA and DHA to date have ignored genetic variants and have instead focused on random cross sections of the population.
Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs.
The current study, led by Kaixiong Ye, assistant professor of genetics in the Franklin College of Arts and Sciences, therefore analysed the gene-diet interaction effects of fish oil supplementation on blood lipids in a sample of more than 70,000 UK participants.
"We've known for a few decades that a higher level of omega-3 fatty acids in the blood is associated with a lower risk of heart disease," said Ye, "What we found is that fish oil supplementation is not good for everyone; it depends on your genotype. If you have a specific genetic background, then fish oil supplementation will help lower your triglycerides. But if you do not have that right genotype, taking a fish oil supplement actually increases your triglycerides."
The results help to explain why some research has found that fish oil provides no benefit in preventing cardiovascular disease.
Ye's team examined four blood lipids (fats) - high-density lipoprotein, low-density lipoprotein, total cholesterol and triglycerides - that are biomarkers for cardiovascular disease.
The data was taken from UK Biobank, a large-scale cohort study collecting genetic and health information from half a million participants.
The team divided the sample into two groups, those taking fish oil supplements (about 11,000) and those not. Then they performed a genome-wide scan for each group, testing for 8 million genetic variants to compare.
After running over 64 million tests, their results revealed a significant genetic variant at gene GJB2. Individuals with the AG genotype who took fish oil decreased their triglycerides. Individuals with the AA genotype who took fish oil slightly increased their triglycerides. A third possible genotype, GG, was not evident in enough study volunteers to draw conclusions.
Now that Ye has identified a specific gene that can modify an individual's response to fish oil supplementation, his next step will be directly testing the effects of fish oil on cardiovascular disease.
"Personalising and optimising fish oil supplementation recommendations based on a person's unique genetic composition can improve our understanding of nutrition," he said, "and lead to significant improvements in human health and well-being."
Direct-to-consumer genetic testing companies make it much easier for consumers to discover their genotype and although these testing companies may not report that specific genetic variant yet, a tech-savvy consumer could download the raw data and look at the specific position to discover the genotype, according to Ye. The ID for the variant is rs112803755 (A>G).
The end of fishy results?
The current study's findings help to shed light on previous trials which have found that fish oil provides no benefit in preventing cardiovascular disease.
"One possible explanation is that those clinical trials didn't consider the genotypes of the participants," Ye said. "Some participants may benefit, and some may not, so if you mix them together and do the analysis, you do not see the impact."
Gregory Curfman, MD, Deputy Editor for JAMA, provided an editor's note alongside the recent STRENGTH trial which found no heart health benefit from omega-3 supplements in statin-treated patients. He pointed out that the null result is similar to that in the large (25 871 participants) omega-3 clinical trial, VITAL (Vitamin D and Omega-3 Trial). Yet the results contradict the results of the REDUCE-IT trial (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) involving 8179 participants.
Discussing how these trials could possibly come to opposite conclusions, Curfman suggests one possibility is if a beneficial effect of EPA was offset by a detrimental effect of DHA, but he says that would be extremely unlikely.
A second possibility he suggests is that in REDUCE-IT, icosapent ethyl did not reduce the risk of cardiovascular events, but instead, the comparator, mineral oil, increased the risk of cardiovascular events. However, a review by the US Food and Drug Administration (FDA) of the results concluded that only a small fraction of the difference in outcomes between icosapent ethyl and mineral oil could be explained by a harmful effect of mineral oil.
Whatever the answer, Curfman says cardiovascular health is a huge and growing health concern and the discrepancy in these results needs to be further investigated.
"Given the current uncertain state of knowledge, neither patients nor physicians can be confident that omega-3 fatty acids have any health benefits, yet in 2019 the global market for omega-3 fatty acids reached $4.1 billion and is expected to double by 2025.
"To resolve the discrepancy between STRENGTH and REDUCE-IT, the FDA should require a postmarketing clinical trial of high-dose icosapent ethyl vs corn oil in patients at risk for cardiovascular events. This is a critical next step to shed further light on this perplexing clinical issue and research question."
Genetics and fish oil
This is not the first time researchers have discussed the impacts that genes have on the health effect of fish oil. It is understood that our genes impact our metabolism of fatty acids, and other nutrients, hence the development of genetics-based personalised nutrition services.
One study in 2015 compared the DNA of 191 Inuits with that of 60 Europeans and 44 Han Chinese. The researchers found the DNA that was most different between these groups were those that control the processing of dietary fatty acids into some of the body’s building blocks.
That report concludes that people lacking 'Inuit DNA' may not get the same cardiovascular benefits from dietary fatty acids.
Source: PLOS Genetics
Francis. M., Li. C., Sun. Y., Zhou. J., Li. X., Brenna. J. T., and Ye.K.,
"Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci"
