Omega-3 fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are thought to reduce the risk of coronary artery disease (CHD) by lowering triglyceride levels (a type of fat / lipid in the blood).
However, there was disagreement about whether fish oil supplements could raise LDL cholesterol levels, and the European Medicines Agency (EMA) no longer considers omega-3 medicines to be effective at preventing future cardiovascular problems in patients with heart attack.
The authors of the current study note that almost all studies on the cardiovascular benefits of EPA and DHA have so far ignored genetic variants and 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 at Franklin College of Arts and Sciences, therefore analyzed the effects of fish oil supplementation on blood lipids in a sample of more than 70,000 UK participants.
“We have known for several decades that higher levels of omega-3 fatty acids in the blood are linked to a lower risk of heart disease,” said Ye It depends on your genotype. If you have a certain genetic background, a fish oil supplement will help lower your triglycerides. However, if you don’t have the right genotype, taking a fish oil supplement will actually increase your triglycerides. “
The results help explain why some research has found that fish oil has no benefit in preventing cardiovascular disease.
Ye’s team studied four blood lipids (fats) – high-density lipoprotein, low-density lipoprotein, total cholesterol, and triglycerides – that are biomarkers of cardiovascular disease.
The data comes from the UK Biobank, a large-scale cohort study that collected genetic and health information from half a million participants.
The team divided the sample into two groups, those who took fish oil supplements (approximately 11,000) and those who did not. They then performed a genome-wide scan for each group and tested 8 million genetic variants for comparison.
After over 64 million tests, their results showed a significant genetic variant of the GJB2 gene. People with the AG genotype who took fish oil decreased their triglycerides. Those with the AA genotype who ingested fish oil increased their triglycerides slightly. A third possible genotype, GG, was undetectable in enough volunteer subjects to draw conclusions.
After Ye identifies a specific gene that can alter an individual’s response to fish oil supplementation, his next step will be to directly test the effects of fish oil on cardiovascular disease.
“Personalizing and optimizing fish oil supplement recommendations based on a person’s unique genetic makeup can improve our understanding of nutrition,” he said, “and result in significant improvements in human health and well-being.”
Genetic testing companies that go straight to the consumer make it a lot easier for consumers to discover their genotype, and while these testing companies may not yet report that specific genetic variant, a tech-savvy consumer could download the raw data and look at the specific location they are wants to discover the genotype according to Ye. The ID for the variant is rs112803755 (A> G).
The end of the fishy results?
The results of the current study help shed light on previous studies that found that fish oil was of no benefit in preventing cardiovascular disease.
“One possible explanation is that these clinical trials did not take into account the genotypes of the participants,” Ye said. “Some participants may benefit from it, others may not. So if you mix them up and do the analysis, you won’t see the effects.”
Gregory Curfman, MD, associate editor of JAMA, along with the recent STRENGTH study, added an editor’s note that found omega-3 supplements had no heart health benefit in statin-treated patients. He pointed out that the zero result is similar to that in the large omega-3 clinical trial (25,871 participants) VITAL (Vitamin D and Omega-3 trial). However, the results contradict the results of the REDUCE-IT study (Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Study), in which 8179 participants participated.
Curfman discusses how these studies could potentially lead to opposite conclusions and suggests a way if a beneficial effect from EPA was offset by an adverse effect from DHA, but he says it would be extremely unlikely.
A second possibility that he suggests is that icosapent ethyl in REDUCE-IT does not reduce the risk of cardiovascular events, but rather the comparison, mineral oil, increases the risk of cardiovascular events. However, a review of the results by the U.S. Food and Drug Administration (FDA) found that only a small portion of the difference in results between ikosapentem ethyl and mineral oil can be explained by a harmful effect of mineral oil.
Whatever the answer, Curfman says cardiovascular health is a large and growing health concern and the discrepancy in these results needs further investigation.
“Given the current uncertain state of knowledge, neither patients nor doctors can be certain that omega-3 fatty acids have health benefits. However, the global market for omega-3 fatty acids reached 4.1 billion US dollars in 2019 and is expected to double by 2025 .
“To address the discrepancy between STRENGTH and REDUCE-IT, the FDA should request a post-marketing clinical trial of high-dose icosapent ethyl versus corn oil in patients at risk for cardiovascular events. This is a critical next step in further solving this mystery illuminate clinical problem and research question. “
Genetics and fish oil
This isn’t the first time researchers have discussed the effects of genes on the health effects of fish oil. It is understood that our genes influence our metabolism of fatty acids and other nutrients, hence the development of genetically based personalized nutritional services.
A 2015 study compared the DNA of 191 Inuit with that of 60 Europeans and 44 Han Chinese. The researchers found that the DNA that was most diverse between these groups was the one that directs the processing of dietary fatty acids into some of the building blocks of the body.
This 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. JT and Ye.K.,
“Genome-wide association study of supplementing fish oil with lipid traits in 81,246 people reveals new gene-diet interaction sites”