Since 2003, the advances that have taken place in the field of genome sequencing is staggering; the first genome to be sequenced cost roughly $1 billion and took 13 years to complete. On the other hand, today, you can have your genome sequenced for about $200 and it only takes a few weeks. Perhaps because that progression has been so rapid, applying genomic and/or epigenetic testing in clinical practice is in its infancy and the comfort level among practitioners to use these types of tests to help guide treatment seems to be fairly low based on my interactions with practitioners of every kind. In contrast, the demand for these tests seems to grow daily. In this “Practitioner Corner,” I’d like to explore some basic concepts with the intent to increase the comfort level so that you can at least begin to talk to your patients about genomic and/or epigenetic testing (if they ask about a test they ordered off of Amazon, you’ll at least be able to have some type of response). I’m really not entirely sure how educated the average practitioner is, however, any time I’ve brought up genomics to colleagues, I tend to get blank stares. So I’ll go through some of the basics around genomic and epigenetic testing, go through a couple of the foundational genes and associated SNPs (single nucleotide polymorphisms) and how that information can influence our lifestyle recommendations, look at some targeted panels that can be ordered and how we can leverage the newest, and quite possibly one of the most significant tests available, epigenetic testing.
Genomic and Epigenetic Basics
First, let’s get the basics and nomenclature out of the way. What is the difference between genetics and genomics? For the purposes of this article, I’m going to keep this very high level.
Genetics is the study of individual genes (on their own, not as they relate to other genes) and their role in inheritance and are used clinically to screen for rare genetic disorders. Let’s take cystic fibrosis (CF) as an example. CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. So that one gene mutation will cause the disease.
Genomics, on the other hand, looks at the genome as a whole and looks at the interrelations and influence on the organism. I’m sure you’ve had some exposure to SNPs, even if you weren’t entirely sure of exactly what they are. Simply put, they are a type of DNA variant that occurs in more than 1 percent of the population. These variants do not act like mutations in that they do not guarantee an outcome. As such, genomic testing results indicate a potential for something happening. And with the ever-growing body of data that is being gathered, studied and published daily, we are able to make an astounding amount of tailored recommendations to our patients, all the way down to specific nutrients (I’ll explain more on that later). Even if there is no guarantee that a condition will present, this genomic information provides as accurate a map as we could ask for in terms of lifestyle recommendations and additional testing needs.
Lastly, I want to make sure to cover epigenetics. Epigenetics literally means “on top of or above genetics.” And what epigenetics do is affect how genes are “read” by cells; they externally modify DNA in order to turn genes “on” or “off.” So while genes are set in stone, the epigenetic expression can shift and drive how cells interact with their DNA. And just as genomic sequencing has advanced, so has our ability to test epigenetic expression through methylation at very specific genomic sites, called CPG islands. As you can imagine, having the level of visibility into how the epigenetic expression looks specific to each patient also lays a foundation for the ability to provide extremely focused, tailored recommendations.
Some Key SNPs
One way to look at SNPs is simply as a biomarker like any other. When you look at total cholesterol levels, if they’re above 250, is it a guarantee that the patient will have a heart attack? Of course not. But you use that biomarker to guide your next steps and course of action. SNPs are really no different.
Perhaps the most widely known SNP is in the MTHFR gene, and I’ll touch on the implications of this variation later in this article. However, first, there are other SNPs related to our patient’s most basic, foundational nutritional needs; imagine knowing if your patient is less likely to convert beta carotene to active vitamin A or if there is a potential deficiency in the transport of vitamin D into the target tissue. Or how about knowing how your patient metabolizes macronutrients? In the following sections, I’ll go through the SNPs associated with each of these, including the MTHFR variation. Again, this is not to provide a comprehensive report of each of these genes and SNPs—it is simply to demonstrate what information we can gather and use for our patient’s benefit.
First, let’s look at a gene associated with vitamin A. Practitioners recommend vitamin A all the time for immune function and vision and every multivitamin includes it (most often in a combination of something like retinyl palmitate and beta carotene or simply beta carotene on its own). And when we want people to increase their intake of foods that are rich in carotenoids, we turn to green leafy vegetables, carrots etc. But what if our patients cannot convert beta carotene to retinol? There is a certain variant that leads to an inactivity of beta, beta-carotene 15,15’-monooxygenase-1 (BCMO1), which is a key enzyme in vitamin A metabolism in mammals and can result in 54 percent lower conversion of beta carotene to retinol, effectively setting the stage for a functional deficiency of vitamin A. And we all know that vitamin A is necessary for more than immune function and vision, it plays a key role in maintaining iron levels as well as working synergistically with vitamin D to maintain proper calcium levels and activate vitamin K2.
Speaking of vitamin D, the same type of data as it relates to this key nutrient has also been well established; GC (Group specific component) is a gene responsible for the major protein that binds to vitamin D and transports it to tissues that need it. A variation in this gene may result in lower levels of vitamin D3 in the blood and tissues throughout the body. And CYP2R1 (Cytochrome P450 Family 2 Subfamily R Member 1) is a gene that encodes a member of the cytochrome P450 superfamily of enzymes that are responsible for beginning many of the first steps in the breakdown of medications and formation of cholesterol, steroids and other lipids. However, the main job of this enzyme is to convert vitamin D into the active ligand (form) for the vitamin D receptor. Variations in this gene have been associated with lower 25-OH levels (measurement of D3). So might your recommendations change based on whether a person is potentially going to struggle with vitamin D uptake and utilization?
As I mentioned, perhaps the most well-known SNP occurs in the MTHFR (methylenetetrahydrofolate reductase) gene. This is a gene that is responsible for making the enzyme called methylenetetrahydrofolate reductase. This enzyme is involved in the chemical reactions relating to the conversion of the vitamin folate into the form the cells can use, called 5-methyltetrahydrofolate (5-MTHF). Variations in this gene are associated with:
• Increased levels of homocysteine
• Elevated cholesterol levels
• Various neurological disorders
• Increased oxidative stress
• Impaired detoxification pathways
• Low folate levels
Let’s look at a couple of the most well established macronutrient related SNPs. PPARG (peroxisome proliferator activated receptor gamma) is a gene that’s important for the transcription of several different genes related to fat metabolism. It is found in fat tissue and helps monitor the storage of fat and the breakdown of lipids, as well as cell growth, the role of insulin and may help control oxidative stress and inflammation. The type of fat that it has been most closely linked to is monounsaturated fats and its impact on weight loss. One study found that a specific variation of this gene actually facilitated greater weight loss when >56 percent of fat was consumed as MUFA. So a keto diet plan that is heavy on saturated fat would not necessarily lead to weight loss if that specific variant is present. Other variations in this gene may lead to a loss of this gene’s function which can be associated with:
• Altered fat cell production
• Insulin resistance
• Increased obesity
• Decreased nitric oxide production
• Metabolic syndrome
Speaking of keto and saturated fat, when the APOA2 gene displays a certain variation it can facilitate an 84 percent greater risk of obesity when >22 grams of saturated fat are consumed in a day. So when looking at both PPRAG2 (as it relates to monounsaturated fat) and APOA2 (saturated fat), the picture can become clearer as to whether this person should consider a keto diet. And in a world where so many people are turning to keto-type diets that focus heavily on healthy fats and when so many gurus are blanketly recommending fat heavy diets, having this information about a person’s ability to effectively metabolize fat can be a game changer when it comes to providing dietary guidance.
More Testing Options Than Ever
In terms of the testing companies, there are a fair amount to choose from and so many of them have done an amazing job of providing information in a manner that is easily understood and reads like any other functional testing result. And you can certainly gain great insight from consumer friendly tests like 23&Me and AncestryDNA.
There are, however, more clinician geared companies such as Nutrigenomix and 3×4 that delve a little deeper into genes and SNPs that paint a more complete picture. At the time of this writing, I know of only one company that has put together separate, more robust system specific panels with multiple genes and SNPs. Toolbox Genomics offers Respiratory, Nutrition Optimization, Cardiometabolic, Cognitive, Detox, Endurance, Energy, GI (gatrointestinal) and Hormone panels, to name a few. The Detox panel, for instance, looks at 17 traits, 28 genes and 79 SNPs. So, while other companies are looking at a single gene or maybe a few, these panels represent a far more comprehensive approach. Toolbox has also worked together with Key Opinion Leaders, such as Dr. Rob Silverman, and developed highly targeted panels that look at genes and SNPs that tell the story of the gut/brain connection, the musculoskeletal system and even TBI/concussion.
When it comes to epigenetics, the history behind the development of the epigenetic testing is fascinating; in 2011, a gentleman named Steve Horvarth developed what was referred to as an “epigenetic clock,” which measured specific epigenetic patterns that were linked to aging and disease and compared that against what would normally be expected for someone of that age range. His test method focused on methylation and demethylation and was so accurate, he was able to accurately predict hundreds of people’s chronological age.
Commercially available epigenetic testing companies are far fewer in number than genomic testing companies. And because of how the tests work relative to age, they have been heavily marketed for providing people their true “biological” age versus their chronological age. But from a clinical perspective, what is exciting about this test is that we can do pre/post tests on people to measure whether a particular intervention is making a change at the genetic level.
I first heard Dr. [Jeffrey] Bland talk about DNA as it related to functional medicine years ago, but at the time, there wasn’t the abundance of resources we now have access to, including good quality education on the material (the American Nutrition Association has an outstanding course and certification program) and at that time, the testing companies certainly weren’t where they are now. As the data continues to pour in, the labs become even more efficient and epigenetics becomes more widely available, I think, too, the data we gain from these tests is going to be as important as every other test we run on our patients and these genomic biomarkers will inform our recommendations, result in the most personalized, tailored protocols and, ultimately, set the stage for the best clinical outcomes possible.
Top 5 Metabolic Genes
1. FTO (fat mass and obesity-associated protein): Associated with metabolic syndrome and elevated BMI (body mass index)
2. TCF7L2 (Transcription Factor 7 Like 2): Associated with blood sugar dysregulation and elevated BMI
3. IGF1 (insulin like growth factor 1): Associated with insulin resistance and T2D
4. IRS1 (Insulin Receptor Substrate 1): Associated with insulin resistance, however, when present, in combination with a low fat diet, it can further exacerbate insulin resistance
5. IDE (Insulin Degrading Enzyme): Associated with the insulin resistance as well as PCOS.
Adam Killpartrick, DC, CNS, CKNS, DACBN is widely-recognized as a leading authority in the dietary supplement industry. His expertise is derived from his extensive work within the supplement industry at all levels, ranging from his start as a clinical consultant for Biotics Research and progressing to the level of chief science officer and leadership executive at FoodScience Corporation, where he oversaw all research and product development for their complete portfolio of brands in both the human and pet divisions. He has had numerous peer reviewed publications on his innovations in the area of novel protein based nutrient delivery systems for poorly absorbed nutrients, including DIM and glutathione. He has also co-authored chapters in multiple food science and functional food textbooks. Dr. Killpartrick has currently shifted his focus to his private functional medicine practice and projects involving food science and nutrient analytics. He currently holds certifications as a Functional Medicine Practitioner, a Certified Nutrition Specialist, a Certified Ketogenic Nutrition Specialist as well as his Diplomate through the American Clinical Board of Nutrition.