Bringing precision to the murky debate on fish oil

Omega-3 fatty acids are essential nutrients commonly found in nuts, seeds and seafood; yet, many Americans struggle to get these important fatty acids through diet alone. Healthcare professionals are frequently asked by their patients: Should I be taking fish oil supplements? But results of large-scale clinical studies on fish oil supplementation have been inconsistent at best, and at worst, seemingly downright contradictory. 

The nutritional good-for-you, bad-for-you tug-of-war on fish oil has left a lot of room for confusion, but University of Arizona precision nutrition researcher Floyd “Ski” Chilton believes there may be overlooked explanations: ancestry and related genetics.

“We're in the middle of a precision revolution. It largely started with cancer, moved to other fields of medicine, and now has found its way to nutrition,” said Chilton, Director of the U of A Center for Precision Nutrition and Wellness and professor in the School of Nutritional Sciences and Wellness. 

The rapidly expanding field of precision nutrition draws on multiple scientific disciplines including evolutionary biology, nutrition, genetics, data science and bioinformatics to provide personalized dietary guidance based on an individual's genetic makeup, environment and lifestyle.

Chilton has been an early champion in the field and has spent his career working to understand how genes and diets interact to impact everything from prostate cancer to cardiovascular health. Now, with a $3.9 million grant from the National Institutes of Health, he aims to bring precision to the fish oil saga.

Together with colleagues from the U of A, Georgetown University, and the MedStar Health Research Institute, Chilton will carry out a clinical trial investigating how ancestry and genetics shape the body’s response to omega-3 fatty acids.

Addressing knowledge gaps, health disparities among diverse ancestries

The framework for the new clinical trial will build off of Chilton and his collaborators’ reanalysis of data provided from the landmark VITAL study—a large-scale randomized, controlled clinical trial spanning five years and involving more than 25,000 participants. The study sought to investigate whether taking daily supplements of vitamin D and omega-3 fatty acids could reduce the risk of cancer and cardiovascular disease, including heart attack and stroke, in people without a history of these illnesses.

Where initial results and media coverage from the 2018 study reported no significant overall benefit from fish oil supplementation, that broad-stroke interpretation overshadowed suggestively significant benefits among the 5,100 African American participants in the study, Chilton explained.

While not the specific focus of the clinical trial, data collected through the VITAL study suggested there was a marked reduction - 77% - in risk of myocardial infarction, or heart attacks, among African American participants taking omega-3 supplements.

“The VITAL investigators should be congratulated for including more African American participants than all other omega-3 trials combined,” said Jason Umans, co-author on the reanalysis and member of the Georgetown-Howard Universities Center for Clinical and Translational Science.

“But the original analysis identified the possibility of a selective benefit to African Americans and our reanalysis suggests the likelihood that African Americans are being denied a uniquely beneficial preventive treatment, simply because it did not work in the larger number of Non-Hispanic White trial participants,” Umans said.

Open access data and artificial intelligence

Using applied mathematics and machine learning, U of A and Georgetown University researchers reanalyzed the VITAL data to focus specifically on how race impacted the effectiveness of omega-3 supplementation. Using sophisticated statistical methods, they clinically matched 3,766 African American with 3,766 non-Hispanic White participants across 13 different variables - including sex, age, medication, medical history and fish consumption.

Clinical trial conditions within these groups were then simulated using machine learning methodologies to assess risk of heart attack, stroke and cardiovascular disease mortality with omega-3 supplementation and the analysis showed an 83% risk reduction in heart attacks in African American participants.

“When you clear away all the noise that you had there before, the apparent benefit of omega-3 supplementation in African American participants is even bigger. The decrease in heart attacks was not just large, it was huge,” Umans said. “It seems inconceivable that you could have something of such huge benefit to one population group, but there it is.”

The research team’s analytical efforts set the stage for the new NIH-funded study, which aims to investigate these benefits further. The new clinical study will test the overarching hypothesis that ancestral and resulting genetic differences significantly impact how individuals respond to omega-3 fatty acids.

Beyond race, it’s a precision revolution

“This new clinical study along with our work over the past 15 years strongly suggest that there are racial and associated genetic differences that affect the levels and balance of omega-6 and omega-3 fatty acids in the human body, and this balance is critical to maintain cardiovascular health,” Chilton said.

The research will not only encompass ancestry but specific genetic variations that may alter how an individual produces pro-inflammatory, pro-blood-clotting omega-6 fatty acids versus anti-inflammatory, anti-blood clotting omega-3 fatty acids, he explained.

“When it comes down to how our bodies mediate these omega fatty acids and their impact, it’s all about balancing immune function, inflammation and blood clotting,” Chilton said. "No matter where our ancestors originated—Europe, Africa, Asia, or the Americas—each population faced unique evolutionary pressures based on their available diets. These pressures led to distinct genetic variations that enabled early humans to metabolize dietary components into crucial molecules like omega-6 and omega-3 fatty acids.”

These molecules play key roles in complex functions such as regulating innate immunity and brain development. The research underscores the limitations of a one-size-fits-all approach to nutrition, he said, and “it’s paving the way for a precision nutrition revolution, promising more effective disease prevention for everyone, tailored to each of our genetic profiles."

“By sorting out the mechanisms that may link genetic variation and omega-3 fatty acid effects, we could find a large subgroup from among other populations who would, like African Americans, also benefit from omega-3 supplementation but could not be teased out by the ‘blunt instrument’ of only identifying study participants by self-described ‘race,’” Umans said.

The $3.9M National Institutes of Health grant, “Addressing Diet-Induced Health Disparities with Precision Nutrition and Omega-3 Fatty Acids,” is a collaborative between the University of Arizona, Georgetown University, and MedStar Health Research Institute; led by principal investigators Floyd Chilton, Susan Schembre, and Cynthia Thomson, with support from Brian Hallmark, Dawn Coletta, Chiranjeev Dash, and Jason Umans.