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Dramatic Omega-3 Discovery: Genes Matter
5/7/2012
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A landmark study shows that people’ genetic profiles greatly influence the impact of the omega-3 and omega-6 fatty acids they consume.
 
The findings hold serious implications for each person’s own risk of cardiovascular disease, cancer, dementia, diabetes, depression, and other major disorders.
 
Before we review the dramatic report, it’s important to describe its context, which explains why the findings matter so much.
 
Omega 3 & 6 fatty acids: The basics
To survive and thrive, humans need to consume small amounts of two kinds of polyunsaturated fat, called omega-3 fatty acids and omega-6 fatty acids.
 
Key Points
  • Landmark study reveals the powerful health impacts and ethnic distribution of genetic variations that affect the conversion of short-chain, plant-source omega-3s and omega-6s into their long-chain, animal-source forms.
  • People who possess one gene variant may be at higher risk for cardiovascular disease, diabetes, cancer, and dementia.
  • People who possess the opposite gene variant get more benefit out of diets lacking fish and shellfish, but would be harmed more by diets high in omega-6 fatty acids from vegetable oils.
  • The authors propose genetic testing to fine-tune diet advice, and their finding highlights the value of blood testing to monitor and optimize the omega-3/omega-6 balance in people’s cells.
Both are essential to the structure and function of our cells, and regulate critical aspects of brain function, metabolism, and immune-system health.
 
We cannot make omega-3 and omega-6 fatty acids in our bodies, so we have to get them from foods or supplements.
 
Omega-3s come in two basic forms, with distinctly different health impacts:
  • Short-chain omega-3 ALA from plant foods
  • Long-chain omega-3s (EPA and DHA) from seafood and fish oil
The body only needs EPA and DHA, which it can make from plant-source ALA … but only in small amounts.
 
This conversion rate ranges from one percent to 10 percent, and varies by gender, pregnancy/nursing status, and overall diet.
 
The biggest dietary influence on this rate is your intake of short-chain omega-6 fatty acids, which compete with short-chain omega-3 ALA for the body's limited capacity to convert them into their long-chain forms.
 
On average, less than 0.5% (one half of one percent) of dietary ALA gets converted into DHA … the omega-3 most critical to human health.
 
The average American gets too many omega-6 fatty acids, primarily from the vegetable oils used in home kitchens and in almost all restaurant, take-out, prepared, and packaged foods.
 
In fact, most Americans consume omega-6 fatty acids to unhealthful excess … a subject covered in our summary, “America's Sickening Omega Imbalance.”
 
Importantly, omega-3s moderate inflammation – low levels of which underlie and drive most major diseases – while omega-6s tend to promote inflammation.
 
(Admittedly, this is an oversimplification … for a fuller picture, see our sidebar, “How do omega fatty acids affect health?”.)
 
In contrast, most Americans don’t get enough omega-3 fatty acids to enable and maintain optimal health …in part because of their overconsumption of competing omega-6 fatty acids.
 
But the new findings show that people with a particular genetic profile get much less benefit from the short-chain omega-3s found in a few plant foods and oils.
 
And they show that people with the opposite genetic profile suffer more harm than most from excess intake of short-chain omega-6 fatty acids … an eating pattern that typifies the average American diet.
 
How do omega fatty acids affect health?
Long-chain omega-3 and omega-6 fatty acids exert their most important effects in two ways:
  1. The body uses them to make ephemeral, hormone-like compounds called eicosanoids (eye-koss-uh-noyds), and it uses omega-3s to make resolvins and protectins. Among other effects, these agents are used to activate, moderate, or end inflammation.
  2. The omega fatty acids we consume influence a mechanism called cell-signaling, which in turn yields “nutrigenomic” effects on the expression of working genes in our cells.

Omega-3s are invariably used to make inflammation-moderating or inflammation-ending eicosanoids, resolvins, and protectins.
 
In contrast, omega-6s typically form the basis of pro-inflammatory eicosanoids. (The situation is not entirely black-and-white … under certain conditions, some omega-6s are used to make inflammation-moderating eicosanoids.)
 
In addition, our cells sense certain food constituents – including omega fatty acids and the carotenes and polyphenols in plant foods – as signals that affect gene “switches.”
 
These switches are proteins (e.g., transcription factors, cytokines, and kinases) that affect the expression of working genes in charge of key functions such as inflammation and food metabolism.
 
For example, omega-3 fatty acids influence two key gene transcription factors – nuclear factor kappa B (NF-kB) and peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) – in ways that moderate inflammation and enhance sugar metabolism, respectively.
International team looks for suspected gene variations
The new findings come from an international scientific team that includes researchers based at Harvard and major universities in Sweden, Germany, Holland, and Italy (Ameur A et al 2012).
 
They examined DNA profiles and omega fatty acid levels in 6,612 people in five European countries, as well as genetic data from ethnic groups worldwide, Neanderthals, chimps, and other primates.
 
As we explained, humans must either get the long-chain omega-3s they need (DHA and EPA) from fish or shellfish, or convert plant-source omega-3s (ALA) into long-chain omega-3s.
 
This conversion is a several step process that requires specific enzymes … especially certain “rate-limiting” enzymes.
 
You can think of these enzymes as “metabolic bottlenecks” that limit the amounts of long-chain omega-3 fatty acids and omega-6 fatty acids we make from the short-chain forms in our diets.
 
The body’s production of these rate-limiting enzymes is governed by genes called FADS1 and FADS2.
 
The international team knew about existing evidence for differences in people’s ability to convert short-chain omega fatty acids to long-chain ones.
 
Their suspicions led them on an exhaustive hunt for DNA variations that might affect these two critical rate-limiting genes.
 
And they struck pay dirt, in the form of a genetic discovery with dramatic implications for our understanding of diet, health, and disease.
 
Landmark findings change the omega-3/omega-6 story
The team found two variants – called haplotype A and haplotype D – in the genes that govern production of the enzymes needed to turn short-chain omega-3s and omega-6s into their long-chain forms.
 
More accurately, there are three gene variants: haplotype AA (“A” for short), haplotype DD (“D” for short), and haplotype DA.
 
Haplotype DA is much less common than A or D. Its effects on the omega-conversion process fall in between those of the other two variants, and can be considered neutral.
 
The focus falls on A and D because they are more common and produce, as the researchers put it, “dramatically” different impacts on the levels of long-chain omega-3 and omega-6 fatty acids in people’s blood and cells.
 
People who possess the haplotype D variant easily convert short-chain omega-3 ALA and omega-6 LA into their long-chain counterparts: omega-3 DHA and EPA and omega-6 AA.
 
In contrast, people who possess the haplotype A variant produce relatively small amounts of long-chain omega-3 or omega-6 fatty acids from the short-chain forms in plant foods.
 
Specifically, the average blood levels of omega-3 DHA are 24 percent higher in people possessing haplotype D, compared to people with haplotype A.
 
Likewise, the average blood levels of long-chain omega-6s are 43 percent higher in people possessing haplotype D, compared to people with haplotype A.
 
We’ve said that it’s unhealthful to have an excess of long-chain omega-6s in your blood and cells … but that’s only true if the proportion of omega-6s to omega-3s exceeds a four-to-one ratio.
 
Humans thrive on a ratio of about three parts omega-6s to one part omega-3s … but the average American diet produces an unhealthful ratio of 10-20 parts omega-6s to one part omega-3s.
 
(Remember, we need long-chain omega-3s and omega-6s to survive and thrive, and only these long-chain forms exert strong influence over inflammation and other fundamental aspects of human health.)
 
Having haplotype A or D could explain why some people are at higher risk for diseases related to the “omega balance” in cell membranes, such as cardiovascular disease, cancer, diabetes, and dementia.
 
Most obviously, people with haplotype A need to ensure ample intake of long-chain omega-3s from seafood or fish oil supplements.
 
But most people with haplotype A – especially those who eat animal foods – don’t need to worry about getting enough long-chain omega-6s in their cells.
 
This is because meats, eggs, poultry, and dairy foods contain ample amounts of long-chain omega-6s.
 
Vegans with haplotype A can ensure adequate blood levels of long-chain omega-6s, despite their genetic disadvantage, if they get plenty of short-chain omega-6s from nuts, seeds, and vegetable oils.
 
Vegans with haplotype A would need to make extra efforts to consume lots of short-chain omega-3s, from the chief commonly available sources:
Flaxseed, flaxseed oil, walnuts walnut oil, canola oil, soybeans, soybean oil*, hemp seed, hemp oil, leafy green vegetables (purslane, grape leaves, spinach, kale, chard, collards), cauliflower, radish sprouts, beans, broccoli, Brussels sprouts, seaweed, and green or yellow squash.
 
Haplotype D: A beneficial but double-edged sword
Haplotype D is highly advantageous for people eating diets low in fish and shellfish … such as prehistoric Africans living on dry savannahs, with little access to fish or other aquatic foods rich in omega-3 DHA.
 
Again, people who possess haplotype D have higher average blood levels of long-chain omega-3s (EPA and DHA), which moderate inflammation and exert myriad beneficial “nutrigenomic” effects.
 
This could make carriers of haplotype D less susceptible to coronary artery disease and other inflammation- and diet-related disorders.
 
However, people who have haplotype D could be at a disadvantage if – like the average American – their diet is high in short-chain omega-6 fatty acids from vegetable oil.
 
As we’ve noted, haplotype D maximizes the conversion of short-chain omega fatty acids to their long-chain forms … and an excess of long-chain omega-6s in your cells promotes the chronic inflammation associated with increased risk of cardiovascular disease and other major degenerative disorders.
 
The history, distribution, and health impacts of omega-conversion variants
In addition to revealing their existence, the scientists detailed the history, ethnic distribution, and potentially dramatic health impacts of these genetic variations.
 
Haplotype A – which impedes the omega-conversion process – appeared about 606,000 years ago.
 
Haplotype D – which makes the omega-conversion process highly efficient – appeared in modern humans prior to their exodus from Africa some 50,000 to 100,000 years ago.
 
The study authors noted uncertainty about the timing, and estimate that haplotype D may have appeared as recently as 255,000 years ago or as long as 433,000 years ago.
 
They hypothesized that the haplotype D variation evolved among pre-humans living in places that lack foods providing long-chain omega-3s (i.e., dry, inland places lacking fish or shellfish).
 
People of African, Asian, Oceanic, and European ancestry tend to have the haplotype D variant.
 
In contrast, almost all Native Americans – whether from North, South, or Central America – have the haplotype A variant.
 
The authors suggest that these gene variations may contribute to certain health disparities seen between populations worldwide.
 
And they proposed testing to determine people’s genotypes, to allow doctors to deliver customized dietary guidance.
 
We would add that it makes sense to test your blood levels of omega-3 and omega-6 fatty acids, so you know where you stand and can take steps to improve your status.
 
Haplotype A shown in blue, type D shown in red.
 
Source
  • Ameur A et al. Genetic Adaptation of Fatty-Acid Metabolism: A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids. The American Journal of Human Genetics (2012). doi:10.1016/j.ajhg.2012.03.014.Published online April 12, 2012.
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