A Guide to SNPs. Lisa Wilcox Used with Permission

Transcription

1 A Guide to SNPs What is an enzyme? An enzyme is a molecule that accelerates, or catalyzes, a chemical reaction. Enzymes allow chemical reactions to occur in milliseconds that might otherwise take millions of years. Enzymes facilitate more than 5000 biochemical reactions. Most enzymes are proteins. Enzymes operate optimally in a very narrow range of temperature and ph, and many drugs and poisons inhibit enzyme activity. (As an aside, this is one of the reasons Health Coaches are interested in ph-driven diets and a cautionary approach to the use of medications; any decrease in enzyme activity can have a downstream effect on health). Enzymes can be affected by minor mutations in the genetic code (DNA) that regulates that particular enzyme. A familiar example is PKU or phenylketonuria, a disease in which several mutations of the amino acids in the enzyme phenylalanine hydroxylase, responsible for catalyzing the degradation of phenylalanine, result in a buildup of phenylalanine in the body. PKU is commonly tested for at birth, and when a baby tests positive, simple dietary modifications are used to prevent the severe intellectual disability that would otherwise result from excessive phenylalanine levels. What is a SNP? A SNP (pronounced snip ) is a single nucleotide polymorphism, or a genetic mutation involving just one unit of the DNA sequence. SNPs are the most common type of genetic variation among people. Each SNP is a variation of a single nucleotide for example; cytosine (C) may replace the usual thymine (T) in a particular location on the DNA sequence. These two variations are called alleles. The study of SNPs is merely in its infancy. There are about 10 million SNPs in the human genome. SNPs and Enzymes Necessary to Detoxification Processes Certain SNPs have been identified that affect the enzymes that are critical to the body s detoxification processes. We are interested in these SNPs because chronically ill children typically have an impaired ability to detoxify. Central to detoxification in the body are two chemical reactions: methylation and sulfation. Methylation is the transfer of a methyl group a carbon atom linked to 3 hydrogen atoms (CH3) from one molecule to another. It occurs billions of times per second and is the means by which the body repairs its DNA, controls homocysteine levels, and recycles molecules necessary to detoxification. Sulfation is the process by which sulfate groups are attached to chemicals called phenols to enable their elimination. When phenolic compounds build up in the body due to an impaired ability to handle them, neurotransmitter function is diminished. (Aside: this is why some children may show improvements on a low-phenol diet, eliminating phenol-containing foods like apples, grapes, chocolate, food coloring, and certain herbs and spices; it may also help explain why antioxidant-rich concentrated berries sometimes do not help). Affected children commonly have as little as 20% of normal levels of sulfate in their bodies; effects include impaired detoxification of heavy metals and environmental toxins, diminished digestive enzymes, limited levels of a hormone that regulates socialization, and leaky gut. (Source: Kirkman labs blog). Sulfation also produces glutathione, a critical antioxidant in which many affected children are deficient. Methylation and sulfation processes are driven by enzymatic activity. Certain SNPs have been identified that either reduce or upregulate the activity of particular enzymes related to methylation and sulfation, thus compromising an individual s methylation and sulfation capacity. We are interested in these SNPs in part because they may make an individual more vulnerable to environmental toxins, and certain nutrient deficiencies. In other words, children with one or more SNPs that restrict their detoxification capacity may have a lower tolerance for environmental toxins be they from chemical exposures, EMF exposures, medications, stress, or other factors. They may reach their total load sooner. And yet, once we identify a child s particular vulnerabilities, we may be able to compensate for diminished or upregulated enzymatic activity by using specific diet, supplements, and lifestyle practices (similar to the way PKU can be addressed with simple dietary modification). In addition, all individuals healthy or not can benefit from practices that regulate enzymatic activity to support methylation and sulfation processes. The following document is a catalogue of just a few common SNPs that have been identified and can be tested for; along with a brief summary of the effect each has on enzyme reactions in the body. Included are suggestions for supporting each type of SNP. This document is not exhaustive, and only includes a handful of SNPs that are known to have a direct effect on detoxification processes.

2 The information contained herein is a very simple overview of complex biological processes. It has been sourced from the Epidemic Answers Health Coach Training Course lectures as well as broad online encyclopedic resources, such as Wikipedia, and NIH (National Institutes of Health). These broad-based sources are a good starting point to further your understanding of the role of genes and their associated mutations in disease. A keyword search using any of these online resources will yield basic information as well as links to more detailed resources. A list of other resources used in compiling this overview is included below, and many are great places to start a more in-depth study of SNPs. Possibly the best resource for a complete explanation of these processes, as well as methods to address findings in the context of healing chronically ill children is Dr. Amy Yasko s book Autism: Pathways to Recovery, available online and included with links in the list below. The text is dense, but it is highly recommended that Epidemic Answers-trained Health Coaches invest some time in understanding it. 1. Hyman, Mark, MD: Maximizing Methylation: The Key to Healthy Aging (drhyman.com blog, 2/8/2011), available at drhyman.com/blog/2011/02/08/maximizing-methylation-the-key-to-healthy-aging-2/ 2. Newman, Larry: What You Should Know Facts About Methylation, Sulfation, and Oxidative Stress (kirkmanlabs.com blog, 11/10/2009), available at 3. Hyman, Mark, MD: Autism: Is It All in the Head? (Journal of Alternative Therapies in Health and Medicine, Vol 14 No 6: Nov/Dec 2008, p12-18), available at 4. Bowers, Katherine, et al: Glutathione Pathway Gene Variation and Risk of Autism Spectrum Disorders (J Neurodev Disord, June 2011: p ), available at 5. Kern, Janet K, et al: Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism (Int K Environ Res Public Health, Aug 2013, p ), available at 6. Japanese Single Nucleotide Polymorphisms Database, and gwas.cgi?srt=disease_trait&pg=1&column=data_origin&value=nhgri 7. NCBI database of SNPs, and 8. SNPedia; (Note: This is a wiki site; information is open-sourced so be cautious of the reliability of information from this resource. Cautions aside, it offers a broad catalogue of SNPs with simple explanations.) 9. Wikigenes Collaborative Publishing; Another wiki site with a vast database of articles searchable by keyword; not a resource in itself so much as a good place to link to resources on specific gene-related topics 10. Yasko, Amy, (PhD, CTN, NHD, AMD, HHP, FAAIM): Autism: Pathways to Recovery (Neurological Research Institute 2009), available at Methylation Maps : Some illustrative diagrams can be found at Disclaimer: Many of the resources provided herein are broad, and often include information from a variety of sources, some of which may be more reliable or relevant than others. Epidemic Answers does not vouch for the veracity of any specific information found within these references. Use your own best judgment in determining the reliability of any source of information.

3 Common SNPs The following is a list of just a few SNPs that may be tested for and that are known or theorized to have an impact on chronic illness, detoxification, or methylation: Gene: MTFHR (encodes the enzyme methylene tetrahydrofolate reductase) FUNCTION: Converts folate to its bio-available form, which then reacts with homocysteine to form methionine EFFECT: A compromised ability to perform this conversion, meaning the body cannot produce methyl groups at a healthy rate. Methyl groups are required for numerous processes within the body; impairment can have a wide variety of health consequences. SNPs in this gene have been associated with neural tube defects, Alzheimer s disease, colon cancer, schizophrenia, and acute leukemia. SUPPORT: Supplement with a methylated form of folate ADDITIONAL INFO: 10% of northern Europeans and 15% of southern Europeans have an MTHFR SNP; individuals with a particular SNP in both copies of their MTHFR gene are referred to as homozygotic ; these individuals typically have elevated blood levels of homocysteine, particularly if intake of folic acid is low MTHFR mutations can further be identified by type: A1298C These individuals may not be predisposed to high levels of homocysteine These individuals may have difficulty converting BH2 to BH4, which is required for serotonin and dopamine synthesis, and for ammonia detoxification These individuals may be at increased risk for aluminum retention These individuals may benefit from moderate protein consumption, extra care against bacterial load and dysbiosis, foods and other supports that aid the body in detoxifying ammonia, and the monitoring of BH4 levels. C677T Affects the conversion of homocysteine to methionine Individuals may be predisposed to higher levels of homocysteine, which can be measured in lab tests; high levels of homocysteine are associated with both heart disease and Alzheimer s disease. Individuals have difficulty metabolizing folic acid. Individuals may be able to bypass this problem by taking a special methylated form of folate: 5MTHF, sometimes sold as methylfolate. Another form of folate, 5 formyl folate (folinic) has other advantages but will not bypass the mutation. Gene: MTR (encodes the enzyme methionine synthase) FUNCTION: Helps to convert homocysteine to methionine on the long way around the methylation cycle by regenerating and utilizing B12 EFFECT: Increased activity in this gene can lead to a greater than normal need for B12 as it is used up at a faster rate. SUPPORT: Test for B12 deficiency and supplement with the appropriate combination and type of B12 for your nutrigenomic profile and clinical status.

4 Gene: MTRR (encodes the enzyme methionine synthase reductase) FUNCTION: Enables the regeneration of B12 for the MTR reaction EFFECT: B12 becomes even further depleted; medical literature indicates mutation in this gene may be a risk factor for neural tube defects, Down Syndrome, and Alzheimer s disease. SUPPORT: Test for B12 deficiency and supplement with the appropriate combination and type of B12 for your nutrigenomic profile and clinical status. Gene: CBS (encodes the enzyme cystathionine beta synthase) FUNCTION: Converts homocysteine to glutathione EFFECT: Elevated cysteine levels; increased levels of sulfur groups; increased ammonia; and decreased Glutathione. Excess sulfur groups activate the stress response, producing cortisol. Individuals may have elevated adrenaline and decreased dopamine, norepinephrine, and serotonin; decreased serotonin may lead to blood sugar issues; may predispose to an imbalance in zinc/copper ratio and excess copper. Dr. Yasko argues that CBS mutations may generate excess ammonia that requires detoxification. SUPPORT: CBS mutations may need to be addressed before methylation support or supplementation is begun. See Yasko, Autism: Pathways to Recovery, referenced above for guidance. In individuals where CBS activity has resulted in an open gate or drained transulfuration pathway, targeted mineral supplementation may be advised. Individuals may test for molybdenum and manganese deficiency, glutathione deficiency, and excess ammonia. Individuals with this mutation are also advised to be cautious in their use of sulfur-containing supplements, sulfur-containing foods such as eggs, garlic, onions, broccoli, legumes, and meat, sulfur containing medications (which would include sulfur chelating agents such as DMSA and DMPS, Epsom Salt baths, alpha lipoic acid, and even supplemental glutathione until the CBS mutation is in check. ADDITIONAL INFO: Note: Every human being needs sulfur. The appropriate amount of sulfur will vary from individual to individual depending on SNPs and the person s clinical picture. Misunderstanding of this SNP has sometimes resulted in radical elimination of sulfur foods and supplements. This is not advised. In the words of Dr. Amy Yasko, it is important not to throw the baby out with the bathwater when it comes to sulfur. Work with a knowledgeable practitioner to address this SNP. Gene: SUOX (encodes the enzyme sulfite oxidase) FUNCTION: Detoxifies the body of sulfite groups by converting them to sulfate groups using molybdenum (an essential trace mineral); EFFECT: Diminished sulfate levels; decreased detoxification capacity; may lead to imbalance in zinc/copper ratio the result of which can be excess copper. SUPPORT: Moderate ingestion of sulfur based compounds in food and supplements; avoid sulfites in foods as they are not easily detoxified; support any accompanying mineral deficiencies with food and supplements if indicated, looking especially at molybdenum and magnesium levels on laboratory tests. ADDITIONAL INFO: The effect of this mutation is magnified in individuals who also have CBS and NOS mutations. Gene: NOS (encodes the enzyme nitric oxide synthase) FUNCTION: Important to ammonia detoxification in the urea cycle EFFECT: Elevated ammonia levels, decreased enzyme activity that may be further decreased by omega 3 EFAs. SUPPORT: It may be advisable to limit omega 3 supplementation to alternate days; may need to avoid high dose lipid supplementation and other lipid donor supplements. May need to intensify CBS support if both mutations are present. (see Yasko for guidance)

5 Gene: COMT (encodes the enzyme catechol-o-methyltransferase) FUNCTION: Deactivates dopamine EFFECT: Elevated dopamine levels; fewer methyl groups; implicated in AD(H)D, mood swings, and bipolar disorder SUPPORT: Prioritize detoxification support; B12 supplements non-methylated forms ADDITIONAL INFO: These individuals may have a reduced tolerance for supplementation with methyl groups (like the methylfolate mentioned as helpful with MTFHR mutations or methylcobalamin (the methylated form of B12) as a result of COMT s impact on dopamine production. Knowing status can help inform more effective supplement choices that take the person s individual capacity to handle methyl donors into account. May help explain why some other reasonable choices sometimes backfire. This is the most studied of all SNPs, and several variations on this gene have been identified, with different characteristics depending on the specific variation. Gene: ACAT (encodes the enzyme acetyl CoA acetyltransferase) FUNCTION: Important to ketone metabolism; prevents accumulation of excess cholesterol EFFECT: May contribute to gut dysbiosis; specifically; may promote C-diff overgrowth; may deplete B12. SUPPORT: Probiotic supplements; prioritize gut health support; B complex; B12 supplements; CoQ10 supplements; glutathione supplements; possibly low levels of alpha lipoic acid supplements Gene: BHMT (encodes the enzyme betaine homocysteine S-methyltransferase) FUNCTION: Helps convert homocysteine to methionine in a secondary methylation cycle EFFECT: May affect norepinephrine levels and stress tolerance; implicated in AD(H)D SUPPORT: Not known; different BHMT SNPs may require different approaches Gene: AHCY (encodes the enzyme adenosyl homocysteinase) FUNCTION: Plays a complex role crucial to methylation processes EFFECT: Because this enzyme has complex interactions with other enzymes, effects can vary depending on the status of other SNPs SUPPORT: Monitor amino acid levels to ensure that proper protocols are in place Gene: SHMT (encodes the enzyme serine hydroxymethyltransferase) FUNCTION: Contributes to new DNA synthesis; can shift methylation away from the long route and the short route into a side reaction EFFECT: Shifting methylation away from the long and short route may impair methylation function; may be associated with leaky gut SUPPORT: Prioritize gut health support; supplementation with folinic acid (5-methylfolate) may be appropriate; supplementation with lactoferrin may be appropriate. Gene: GST(M1, P1, and T1) (encodes the enzyme Glutathione S-Transferase) FUNCTION: Metabolizes the antioxidant glutathione EFFECT: Diminished capacity to detoxify from exposure to heavy metals, solvents, pesticides, herbicides, and polycyclic aromatic hydrocarbons SUPPORT: Supplement with glutathione; minimize chemical exposures

6 A note on the importance of lab testing: One of the challenges facing a health coach is how to balance a client s financial constraints with the cost of special diets, supplements, therapies, and lab testing. Often, a particular protocol becomes popular among certain communities, and it seems like a good idea to go ahead and try it on individuals with similar concerns. We MUST remember that the same downstream symptom in two individuals might have very different upstream causes. Similarly, the same upstream cause in two individuals may have very different downstream effects. A specific example is that in some functional medicine communities (and autism communities too), supplementation with methylfolate and methyl-b complex vitamins has become a widely used protocol that produces great results in many people. However, refer back to the COMT description: individuals with this SNP may have a reduced tolerance for supplementation with methyl groups. Another common error is to assume that certain SNPs determine someone s response to a particular supplement or that having genetic information eliminates the need for any clinical data or lab tests. Remember that genetic information may be part of a road map and is best viewed alongside relevant clinical lab data. A third common error is to assume that lifestyle modifications cannot influence the expression of relevant SNPs. In truth, the genetic information is best used to help refine and inform lifestyle modifications, as well as supplement and food choices. Methylation impairments may be viewed as fault lines that could benefit from targeted support when trying to prevent or reverse a chronic illness. Under optimal conditions a person would source the genetic information and then work with a licensed practitioner to perform lab testing to round out the current clinical picture before blindly treating with specialized supplements. The more information you have to work with, and the more help in interpreting that information from knowledgeable medical advisors, the better you are able to create an individualized plan to restore health. In situations where genetic testing is not feasible, clients should be aware that finding the right supplement (and even diet) may require some trial-and-error; and that the wrong supplements may exacerbate existing issues or even create new problems. Highly potent or specialized supplements, or high dosages, should be avoided in a trial-and-error approach. Regular lab testing for vitamin and mineral levels, heavy metals, and organic acids are advisable to ensure that the approach being used is beneficial rather than harmful. Any trial-and-error approach is best undertaken with a client s full understanding of the risks involved, under the supervision of a medical professional, and while monitoring as many indications of health and improvement as possible. For specific guidance on how to support methylation SNPs, a terrific resource is Dr. Amy Yasko s Autism: Pathways to Recovery (Neurological Research Institute 2009), available at Autism-Pathways-to-Recovery.pdf