In Genomics, as in Life, the "80/20 Rule" Applies

nutrigenomicsThere’s a lot of hype around genomics these days. From a patient care perspective, it comes down to two basic questions: What types of tests give truly useful information? And, who benefits most from having the testing done?

The reality is, most patients who get their genomes done have no idea what they’re really getting into. For their part, most clinicians don’t know how to interpret the myriad of genes and turn the test results into clinical decisions.

Over the summer, Maryland University of Integrative Health (MUIH) in collaboration with the Maryland Naturopathic Association tried to tackle these questions and shed light on the issues in a three-day symposium on Nutritional Genomics in Clinical Practice.

Leaders in the field came together to share how they utilize these tools and which labs and tests they find most valuable.

Who Benefits?

I was among the speakers, and I discussed how to utilize 23andMe data with 2nd party interpretation systems to guide patient care.

23andMe has been very active in promoting their tests to the general public. People come to practitioners wanting—and expecting—help in making sense of their data. What do we really need to know?

As genetic science progresses, we are discovering ever smaller components of human physiology that are influenced by genetic variations. But gene expression is highly influenced by the food we eat.

For example, we’ve learned that lycopene and hesperidin in tomatoes, and phloretin in apples, can inhibit methylation. We now know there are foods that enhance histone deacetylation, such as anacardic acid in cashews, resveratrol in grapes, allyl mercaptan in garlic, quercetin in apples and garlic, sulphorophanes and isothiocynates in cruciferous vegetables, and ECGC in green tea.

Butyrate, synthesized in the colon when microbes eat prebiotic fibers from artichokes, plantains, and legumes, modulates a wide range of genes.

It’s all good to know. But do we really need gene testing in order to figure out what’s going on with our patients? In most cases, I think the answer is no.

Health is very much an, “as above, so below” proposition. Research indicates that the things that make us truly feel good—like meditation, yoga, singing, exercise, eating vegetables—will up- and down-regulate genes in ways that decrease inflammation and enhance immune function. We don’t need special tests to tell us that.

Much of what we can learn from genomic testing can be discovered via a thorough medical history and physical exam, listening to the person’s story, asking the right questions, and utilizing simpler functional tests, such as organic acid testing.

I think the “80/20 rule” applies. For 80% of patients, we can usually figure out what’s going on and make good therapeutic choices without genomic evaluation. But, then there are the 20% who are mysteries. They’re the ones that don’t fit the common patterns, and don’t get better when we try the obvious.

In these cases, genomic testing can have the biggest benefit.

For example, at least one-third of people with depression are not helped with medication, or anything else they’re given. In these cases, it makes sense to look at SNPs that affect methylation and detoxification. Taking just on example, the dihydrofolate reductase gene (DHFR) regulates synthesis of tetrahyrobiopterin (BH4). Ths is required for synthesis of dopamine, norepinephrine, epinephrine, serotonin, and nitric oxide.

People with certain DHFR genotypes are predisposed to synthesizing less BH4, and are therefore less able to produce these important neurotransmitters. This becomes useful information, because we can support DHFR function by giving supplemental NADH (the reduced form of nicotinamide adenine dinucleotide).

MUIHSomeone who has a compromised monoamine oxidase (MAO) gene may also benefit from increased flavin adenine dinucleotide (FAD), which is enhanced with riboflavin (vitamin B2).

Another example: In families of people with Alzheimer’s disease, knowing whether the APOE4 gene is present can help with prevention. The APOE4 gene is strongly associated with AD, conferring a four-fold risk increase if someone has one copy and a 15-fold increase for those carrying two copies. Herpes simplex, and cardiovascular disease are also associated with this gene. People with the APOE4 gene benefit from low-fat diets and increased omega 3 fatty acids.

Plentiful Options

Accuracy of gene testing depends on who put together the algorithms and what processes are utilized. There is no standardization at this point. Some companies are marketing to clinicians and consumers alike; others are accessible only through practitioners. There are comprehensive genetic panels, as well as single SNP tests that can be done by virtually any medical lab.

The number of companies doing genomic testing is mushrooming. Some that our conference participants have found useful include: Genova Diagnostics, Nutrigenomix, Pathways Genomics, Great Plains Lab, Genomic Solutions Now, Genovive, and Nordic Labs. This is by no means a comprehensive list.

In addition to the companies that provide the tests, there are other services that piggyback on existing tests. You upload the information obtained from one of the above labs, and download interpretation reports, often within minutes. These include: Livewello, Genetic Genie, MethylGenetic Nutrition Analysis, MTHFR Support, Nutrahacker, Opus23, and Promethease.

Nutrigenomics is a new and fast-moving field. It takes time, energy and commitment to learn how to utilize these tests intelligently. Your interests—and your patients’ needs—will shape how deeply you want to go. But these days, all clinicians should have at least some awareness of what’s going on.

Here are some highlights of the MUIH meeting:

Should Genes Determine What We Eat?

One of the most interesting lines of genomic research is focused on the ways that genetic predispositions influence physiological responses to specific foods.

According to Ahmed El-Sohemy, PhD, who holds a Canada Research Chair at the University of Toronto, none of the current genome tests that claim to predict disease risk actually do it well. But these tests can give important information about an individual’s ability to metabolize foods, drugs, and chemicals in the environment.

They can also enable us to move away from broad-stroke dietary generalizations to more specific—and therefore more useful—recommendations.

For example, the Costa Rica Heart Study showed that people who drank more than four cups of coffee daily had a 36% increased risk of myocardial infarction. That’s equivalent to smoking a pack of cigarettes a day (Cornelis MC, et al. JAMA. 2006; 295 (10): 1135-1141).

But it turns out that the risk increase was specifically in people who carried particular variants of the CYP1A2 gene, which regulates the ability to metabolize caffeine. People with the 163A -> C genotype are slow metabolizers of caffeine. For them, high coffee consumption could be dangerous.

Carriers of this SNP also have higher risk of hypertension and pre-diabetes. Interestingly, this SNP is not the one that makes one wakeful or jittery from caffeine.

Basically, what it means is that for people with one genotype, drinking 4 cups per day raises MI risk, while for others with a different genotype it may be cardioprotective.

Another example is the FTO gene on chromosome 16, which influences how someone is likely to respond to a high-protein diet. People who are homozygous for the AA genotype of FTO are far more likely to lose weight with high-protein diets than those with the TT or TA genotype.

Nutrigenomics 2Dr. El-Sohemy is the founder and Chief Science Officer of Nutrigenomix, a University of Toronto start-up that offers a 45-gene test panel focused on metabolism of dietary components including: saturated fat, whole grains, caffeine, omega-3 fats, sodium, B vitamins, and vitamin C. The test is saliva-based, and available only through qualified healthcare practitioners.

Like many genomics advocates, Dr. El-Sohemy believes people are much more willing to change their eating habits if recommendations are personalized and backed up by their own genetic data.

In 2014, he and co-author Daiva Nielsen looked at behavior changes in 92 people who’d received DNA-based dietary advice versus a similar cohort of 46 who got general recommendations. The nutrigenomic guidance centered around 4 genes: CYP1A2 (affecting caffeine metabolism); GSTM1 plus GSTT1 (predictive of vitamin C deficiency); TAS1R2 (predicts sugar overconsumption) and ACE (sodium sensitivity).

At one year, patients who got genome-guided advice were more likely to follow it, particularly regarding sodium intake. They were much more willing than controls to lower sodium intake to 300 mg daily (Nielsen DE, El-Sohemy A. PLOS1. Nov 2014).

Nutrigenomics & Aging: What Do We Know?

Our genes definitely influence the aging process, though the relationships are anything but simple. Rob Kachko, a naturopathic physician specializing in healthy aging, stressed that any aging-associated gene data must be viewed in the context of an individual’s diet, living conditions, and environmental exposures.

For example, everyone knows that the BRCA gene significantly increases risk of breast and ovarian cancer. But the degree to which it raises risk has changed over the decades. Kachko noted that in the period from 1920-1939, having the BRCA gene increased risk by a factor of 2.7. In 1949-1959, the risk increase was 3.7. By 1960, the BRCA-associated risk rose to a factor of 7.7. The gene itself did not change over the decades, our environment did.

Though not technically a genetic test, telomere length is a gene-related marker that is definitely related to aging. In general, short telomeres indicate more rapid aging; longer ones are statistically associated with longevity.

Telomere length indicates the ability of DNA to replicate. The Mediterranean diet, legumes, nuts, sea vegetables, fruits and dairy products all increase telomere length, while red and processed meats and soft drinks shorten them. Likewise, the TCFL2 gene is tied to cardiometabolic risk, which can be normalized with a Mediterranean-style diet.

The PON-1 gene codes for an anti-atherosclerotic enzyme involved in lipid metabolism. PON-1 activity level can vary by as much as 40-fold from person to person. Activity of the gene can be up-regulated by a number of foods and supplements, including yerba mate, cranberry extracts, vitamin C, zinc, Chinese or red sage, Turkish oregano, pomegranate juice. A Mediterranean diet also helps.

There are many other genes that influence the aging of various organ systems. But the jury’s still out on which warrant clinical attention. As mentioned earlier, we don’t really need sophisticated tests to know that our patients will age more healthfully by taking up a Mediterranean diet and avoiding soda.

On the other hand, if the gene tests provide the needed catalyst for change, then they’re well worth it.

Genes & Detoxification

We’ve all seen patients who get very sick when following a “detox” protocol, who react acutely to environmental toxin exposures, or who say they cannot tolerate commonly used meds or supplements, even at relatively low doses.

This is very likely because their genes predispose them to compromises in phase II liver deconjugation pathways, says Leah Holland, ND, PhD.

The main processes in Phase II are: acetylation, glucuronidation, sulfation, amino acid breakdown, methylation, and utilization of glutathione.

These processes are regulated by a host of different genes: UGT1A1, 2 & 3, SULT1A1 & 2, and COMT are just a few that you may have encountered. According to Dr. Holland, 80% of people who have multiple chemical sensitivities have SNPs in these genes that result in impairment of Phase II processing.

In these cases, the tests can definitely shed some light on what’s going on. Phase II impairment can be partially overcome by supplementing with vitamin C, riboflavin, pantothenic acid, increased intake of cruciferous vegetables, and avoidance of alcohol.

Opus23: Exploring Gene Networks

Several speakers at the MUIH conference utilize Opus23—a new analytic software system--in their practices, and find it extremely helpful in personalizing therapeutic recommendations.

Opus23 was developed byDr. Peter D’Adamo—the popularizer of the Blood Type Diet-- and his students at the Center of Excellence in Generative Medicine at the University of Bridgeport. It takes the over 700,000 SNPs in a typical 23andMe report, and winnows out the clinically relevant and actionable ones. It also provides information on how to modulate gene expression with natural products, and dietary and lifestyle change.

Underlying this product is a series of apps that receive updates from genomic databases, so that the content is always current.

Many genetic tests—and the clinicians who use them--focus on single SNP mutations; yet genes work in networks. In Opus23, you can see these networks in clinically meaningful categories (neurodegenerative disease, aging-related, endocrine-related, auto-immune/inflammatory, etc).

There is a gene mapper that you can populate with data from a patient, to determine how specific genes are—or are not—playing together. If, for example, you are working with someone with type 2 Diabetes, you can discover which networks or SNPSs are impaired and then click to see what natural approaches will modulate the risk.

You can also utilize data to look at how well someone might respond to specific drugs based on pharmacogenetics.

There is definitely a learning curve with Opus23. It takes time and training, but clinicians who use the system say it greatly expands their abilities to make smart clinical decisions based on genetic data.

Prof. Liz Lipski, PhD, CNS, IFMCP is the Director of Academic Development for the Nutrition Programs at Maryland University of Integrative Health. She’s also on faculty at the Institute for Functional Medicine, and the Metabolic Medicine Institute Fellowship in Metabolic and Nutritional Medicine. She’s the author of Digestive Wellness, & Digestive Wellness for Children.