Genetic Testing & SNP Interpretation for Functional Medicine

Your genes are not your destiny. They are your blueprint — a set of tendencies, vulnerabilities, and strengths that interact with everything you eat, breathe, think, and do. Functional medicine uses genetic data not to predict fate but to personalize intervention. The same methylfolate dose that heals one person destabilizes another. The same sulfur-rich diet that detoxifies one body overwhelms another. Genetics explains why.

What SNPs Are

A Single Nucleotide Polymorphism (SNP, pronounced “snip”) is a variation at a single position in the DNA sequence. Where the “normal” sequence might read cytosine (C), a SNP substitutes thymine (T). These variations are common — the human genome contains roughly 4–5 million SNPs per individual.

Most SNPs have no functional consequence. But some occur in genes coding for enzymes, receptors, or transport proteins critical to metabolic pathways. These functional SNPs can alter enzyme speed, binding affinity, or protein stability.

Heterozygous vs Homozygous:

• Heterozygous (+/-): One copy of the variant, one normal copy. Enzyme function is partially reduced — typically 30–50% loss of activity depending on the specific SNP.
• Homozygous (+/+): Two copies of the variant. Enzyme function is more significantly impaired — typically 50–80% loss of activity.
• Wild type (-/-): No variant. Normal enzyme function.

The clinical impact of any SNP depends on the total metabolic load, nutrient status, toxin exposure, and other genetic variants working in concert. A single SNP rarely acts alone.

Getting Your Genetic Data

Direct-to-consumer testing:

• 23andMe: Health + Ancestry service provides raw data download. Covers ~600,000+ SNPs. Reduced SNP coverage in newer chips for some methylation-related variants.
• AncestryDNA: Similar raw data availability. Primarily ancestry-focused but covers many health-relevant SNPs.

Interpretation tools (raw data upload):

• Genetic Genie: Free methylation and detox profile. Quick overview of MTHFR, COMT, CBS, VDR, and related SNPs.
• StrateGene by Dr. Ben Lynch: The most clinically useful tool. Provides pathway-based interpretation — shows how SNPs interact in context, not just individual variants. Includes methylation, transsulfuration, biopterin, and neurotransmitter pathways.
• Opus23: Professional-grade software (practitioner access). Deep SNP interaction analysis.
• Nutrahacker: Supplement and dietary recommendations based on genetic data.

Clinical genetic panels: Some functional medicine practitioners order targeted panels through labs like Genomic Insight, IntellxxDNA, or MaxGen Labs for more comprehensive coverage including pharmacogenomics.

Key SNPs and Clinical Implications

MTHFR (Methylenetetrahydrofolate Reductase)

The most discussed SNP in functional medicine — and for good reason. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF), the active form of folate that donates a methyl group to convert homocysteine to methionine. This reaction is the entry point for the entire methylation cycle.

C677T (rs1801133):

• Heterozygous (C/T): ~30% reduced enzyme activity
• Homozygous (T/T): ~60–70% reduced enzyme activity
• Prevalence: ~10–15% homozygous in Caucasian populations, higher in Hispanic/Italian populations (up to 25%)
• Clinical consequence: Reduced 5-MTHF production → elevated homocysteine → impaired methylation (DNA repair, neurotransmitter synthesis, estrogen clearance, phospholipid metabolism, creatine synthesis)
• Lab findings: Elevated homocysteine (>8 umol/L), low RBC folate, possibly elevated MCV

A1298C (rs1801131):

• Less impact on homocysteine than C677T
• Primarily affects BH4 (tetrahydrobiopterin) recycling. BH4 is the essential cofactor for:
  • Phenylalanine hydroxylase (phenylalanine → tyrosine)
  • Tyrosine hydroxylase (tyrosine → L-DOPA → dopamine)
  • Tryptophan hydroxylase (tryptophan → 5-HTP → serotonin)
  • Nitric oxide synthase (arginine → nitric oxide)
• Clinical: Neurotransmitter synthesis impairment — depression, anxiety, ADHD, mood instability. Less about homocysteine, more about brain chemistry.

Compound heterozygous (C677T +/- AND A1298C +/-): Clinically significant. Combined effect can approach that of C677T homozygous.

MTHFR Treatment Protocol:

1. Methylfolate (5-MTHF): Start low — 400 mcg. Some patients react strongly. Titrate up gradually to 1–5 mg based on homocysteine levels and symptom response. Brands: Thorne Methyl-Guard, Seeking Health, Pure Encapsulations.
2. Methylcobalamin (methyl-B12): 1000–5000 mcg sublingual or hydroxocobalamin injection. B12 works synergistically with folate in the methionine synthase reaction.
3. Riboflavin (B2): 25–100 mg/day. B2 is the direct cofactor for the MTHFR enzyme — it literally makes the enzyme work faster. Underappreciated intervention. Studies show riboflavin lowers homocysteine specifically in MTHFR 677TT individuals.
4. Avoid folic acid: Synthetic folic acid (in supplements and fortified foods — flour, cereal, bread) must be converted by MTHFR to become active. With impaired MTHFR, unmetabolized folic acid accumulates and may block folate receptors, paradoxically worsening folate function. Read labels. Choose methylfolate or folinic acid instead.
5. P5P (pyridoxal-5-phosphate, active B6): 25–50 mg/day. Supports the transsulfuration pathway — the alternate route for homocysteine clearance via CBS.
6. TMG (trimethylglycine/betaine): 500–1500 mg/day. Provides methyl groups via the BHMT pathway — a backup methylation route independent of MTHFR.

Overmethylation: If methylfolate or methyl-B12 cause anxiety, insomnia, irritability, heart palpitations, or headaches — the patient is overmethylated. Reduce dose immediately. Some patients (especially those with slow COMT) cannot handle aggressive methyl donor supplementation. Niacin (B3, nicotinic acid form — not niacinamide) at 50–100 mg can quickly absorb excess methyl groups and relieve symptoms.

COMT (Catechol-O-Methyltransferase)

COMT methylates and inactivates catecholamines (dopamine, norepinephrine, epinephrine) and catechol estrogens (2-OH and 4-OH estrogen metabolites). It requires SAMe as the methyl donor and magnesium as a cofactor.

Val158Met (rs4680):

• Val/Val (GG — “fast COMT”): Enzyme works 3–4x faster. Catecholamines and catechol estrogens are rapidly cleared.

  • Clinical: Lower baseline dopamine and norepinephrine. May need more stimulation to feel engaged. Handles stress biochemically better (clears stress hormones quickly). May tolerate higher doses of methyl donors, SAMe, green tea.
  • Personality tendency: “Warrior” phenotype — performs well under pressure but may lack motivation at baseline.

• Met/Met (AA — “slow COMT”): Enzyme works 3–4x slower. Catecholamines and catechol estrogens accumulate.

  • Clinical: Higher baseline dopamine (good for focus, creativity) but vulnerable to catecholamine overload under stress. Pain sensitivity increased. Estrogen clearance impaired — higher breast cancer risk in women with slow COMT and high 4-OH estrogen.
  • Personality tendency: “Worrier” phenotype — performs well in calm conditions, overwhelmed by stress.
  • Avoid: Excess methyl donors (methylfolate, methyl-B12, SAMe) can flood the system. Green tea catechols compete for COMT. High-dose catechol-containing supplements (quercetin, EGCG).
  • Support: Magnesium (300–600 mg/day — COMT cofactor), lower-dose methylfolate (400–800 mcg max), stress management, adequate sleep.

• Val/Met (AG — “intermediate”): One fast, one slow copy. Balanced. Most common genotype.

COMT-MTHFR interaction: This is the most important gene–gene interaction in functional medicine. Slow COMT + MTHFR C677T homozygous = need methylfolate for MTHFR but cannot tolerate high doses due to COMT. Solution: very low-dose methylfolate (200–400 mcg), prioritize riboflavin and hydroxocobalamin, use folinic acid instead of methylfolate as a gentler alternative.

MAO (Monoamine Oxidase)

MAO-A and MAO-B break down serotonin, dopamine, and norepinephrine. Variants affect neurotransmitter clearance speed. Slow MAO-A = higher serotonin and norepinephrine levels (can manifest as anxiety, aggression, or resilience depending on context). Fast MAO-A = rapid serotonin depletion (depression risk). MAO-B primarily handles dopamine — slow MAO-B may be protective against Parkinson’s.

Clinical note: MAO genes are on the X chromosome. Men (XY) have one copy — variants are fully expressed. Women (XX) have two copies — may be heterozygous with moderated effects.

CBS (Cystathionine Beta-Synthase)

CBS converts homocysteine to cystathionine in the transsulfuration pathway — the route that produces glutathione, taurine, and sulfate.

CBS upregulation (C699T and others): Increased enzyme activity drives excess flux through transsulfuration. Results in:

• Elevated taurine, sulfate, and ammonia
• Rapid depletion of homocysteine (paradoxically low homocysteine despite MTHFR variants)
• Excess sulfur metabolite production — sulfur sensitivity (react to cruciferous vegetables, garlic, onions, eggs, NAC, alpha-lipoic acid, MSM, Epsom salt baths)

Treatment: Temporarily limit high-sulfur foods and supplements. Support ammonia clearance (ornithine, activated charcoal, yucca root). Address CBS before aggressively pushing methylation. Use molybdenum (150–500 mcg/day) to support sulfite oxidase (converts toxic sulfites to sulfate). Low-dose CBS support is often needed before methylfolate can be tolerated.

VDR (Vitamin D Receptor)

Multiple SNPs (Taq, Bsm, Fok, Apa) affect vitamin D receptor sensitivity. Variants can impair cellular response to vitamin D even when serum 25-OH-D levels are adequate.

Clinical implication: Patients with VDR variants may need higher serum vitamin D levels (60–80 ng/mL) to achieve the same biological effect. They may require higher supplemental doses (5,000–10,000 IU/day) and should have 25-OH-D and 1,25-OH-D levels monitored. VDR variants also affect calcium absorption, immune function, and bone density.

VDR Taq variant also affects dopamine production — consider in patients with mood issues and vitamin D insufficiency.

GAD (Glutamic Acid Decarboxylase)

GAD converts glutamate (excitatory neurotransmitter) to GABA (inhibitory neurotransmitter). Requires P5P (active B6) as cofactor.

GAD variants: Reduced GABA production → glutamate/GABA imbalance → anxiety, insomnia, seizure susceptibility, sensory processing issues, excitotoxicity.

Support: P5P (25–50 mg), magnesium (glutamate antagonist via NMDA receptor), taurine (GABA-A agonist, 500–2000 mg), L-theanine (modulates glutamate, 200–400 mg), pharmaGABA (100–200 mg). Avoid MSG, aspartame, excess glutamate-rich foods in sensitive individuals.

DAO (Diamine Oxidase)

DAO is the primary enzyme that degrades histamine in the gut. SNPs in the AOC1 gene (which encodes DAO) reduce histamine clearance capacity.

Clinical picture: Histamine intolerance — headaches, flushing, hives, nasal congestion, heart palpitations, anxiety, menstrual cramps (estrogen stimulates histamine release), GI symptoms after high-histamine foods (aged cheese, fermented foods, wine, smoked fish, vinegar, leftover meat).

Support: DAO enzyme supplementation before meals (Seeking Health Histamine Block, NaturDAO), low-histamine diet, quercetin (mast cell stabilizer, 500–1000 mg 2x/day), vitamin C (supports DAO activity, 1–2 g/day), B6/P5P (DAO cofactor), copper (DAO cofactor — but check ceruloplasmin and copper levels first).

PEMT (Phosphatidylethanolamine N-Methyltransferase)

PEMT converts phosphatidylethanolamine to phosphatidylcholine (PC) — a critical component of cell membranes, bile, and VLDL particles. The PEMT pathway is the endogenous source of choline.

PEMT variants: Impaired PC synthesis → increased dietary choline requirement. Particularly significant in women (estrogen normally upregulates PEMT — postmenopausal women with PEMT variants are at highest risk).

Clinical consequences: Fatty liver (PC needed for VLDL export of triglycerides from liver), muscle damage, cognitive impairment, bile insufficiency.

Support: Dietary choline (eggs — 147 mg per egg, liver, lecithin). Supplemental choline (phosphatidylcholine 1200–2400 mg/day, or CDP-choline/citicoline 250–500 mg for cognitive focus). The adequate intake for choline (550 mg/day men, 425 mg/day women) may be insufficient for PEMT variant carriers.

APOE (Apolipoprotein E)

APOE is the lipid transport protein. Three alleles: E2, E3, E4.

• APOE E2/E2: Efficient fat clearance. Lower LDL. Rarely associated with Type III hyperlipoproteinemia.
• APOE E3/E3: Most common genotype. “Neutral” — standard dietary fat response.
• APOE E3/E4: One copy of E4. Moderately increased Alzheimer’s risk (2–3x). Increased LDL response to saturated fat.
• APOE E4/E4: Two copies of E4. Significantly increased Alzheimer’s risk (8–12x). Strongly elevated LDL on high-saturated-fat diets. Higher inflammatory response.

APOE4 clinical guidance: Reduce saturated fat intake (replace with monounsaturated fats — olive oil, avocado). Prioritize omega-3 fatty acids (DHA is neuroprotective, 1–2 g/day). Exercise is particularly protective in APOE4 carriers. Manage metabolic syndrome aggressively. Consider early cognitive screening. Avoid head trauma (APOE4 impairs neuronal repair after injury). Ketogenic diets may still be beneficial for APOE4 carriers despite the saturated fat concern — MCT oil-based ketosis avoids long-chain saturated fat.

SOD2 (Superoxide Dismutase 2)

SOD2 is the mitochondrial antioxidant enzyme that converts superoxide radicals to hydrogen peroxide (which is then cleared by catalase and glutathione peroxidase).

Ala16Val (rs4880): The Val variant reduces SOD2 transport into mitochondria, impairing mitochondrial antioxidant defense. Homozygous Val/Val individuals have increased oxidative stress and mitochondrial damage.

Support: MnSOD requires manganese as cofactor. Mitochondrial antioxidant support: CoQ10 (200–400 mg), PQQ (10–20 mg), alpha-lipoic acid (300–600 mg, but check CBS status first), NAC (600–1800 mg), mitochondria-targeted antioxidants (MitoQ).

GST/GPX (Glutathione-Related Enzymes)

GSTM1 and GSTT1: Glutathione S-transferase genes. Approximately 50% of the population has a deletion of GSTM1 (null genotype) and ~20% have GSTT1 null. Null genotypes = absent enzyme activity → impaired Phase II glutathione conjugation → reduced detoxification of environmental chemicals, heavy metals, and oxidative metabolites.

GPX1 (Glutathione Peroxidase): Variants reduce the ability to use glutathione to neutralize hydrogen peroxide. Increased oxidative damage, selenium-dependent (selenium is GPX cofactor).

Clinical: GST/GPX null or impaired individuals need enhanced glutathione support (NAC, liposomal glutathione, whey protein, glycine), selenium (200 mcg/day), and reduced toxin exposure. These are the patients who react strongly to environmental chemicals, perfumes, and solvents.

FUT2 (Fucosyltransferase 2)

FUT2 determines “secretor status” — whether ABO blood group antigens are secreted into mucosal surfaces and body fluids.

Non-secretor (homozygous variant): ~20% of the population. Clinical consequences:

• Reduced vitamin B12 absorption (B12 binds to intrinsic factor, which is affected by secretor status)
• Altered microbiome composition (Bifidobacterium levels tend to be lower in non-secretors)
• Increased susceptibility to Crohn’s disease, celiac disease, and certain infections (Norovirus resistance is actually higher in non-secretors)
• May need higher B12 supplementation and targeted probiotic support

HLA-DR (Human Leukocyte Antigen)

HLA-DR genes encode immune recognition molecules. Certain HLA-DR haplotypes are associated with impaired clearance of biotoxins.

Mold susceptibility: HLA-DR haplotypes 4-3-53, 11-3-52B, 12-3-52B, and 14-5-52B are associated with Chronic Inflammatory Response Syndrome (CIRS) from mold exposure. These individuals cannot mount an effective antibody response to mold toxins — the toxins recirculate instead of being cleared. This is why some people get devastating illness from mold while their housemates are unaffected.

Lyme susceptibility: HLA-DR 15-6-51 and 16-5-51 are associated with persistent Lyme inflammation. The immune system cannot properly present Borrelia antigens for clearance.

Clinical: HLA-DR testing is essential in patients with chronic mystery illness, especially with mold exposure history. Treatment for CIRS follows the Shoemaker Protocol: cholestyramine/welchol (bile acid sequestrants to bind biotoxins), VIP nasal spray, and environmental remediation.

Dr. Ben Lynch’s “Dirty Genes” Framework

Dr. Ben Lynch’s model distinguishes between genes that are “born dirty” (genetic SNPs you inherited) and genes “acting dirty” (epigenetic — your lifestyle is impairing gene function regardless of genetics).

The principle: Before supplementing based on genetic data, clean up the basics. Poor sleep, processed food, dehydration, sedentary lifestyle, toxin exposure, and chronic stress make every gene “act dirty.” A patient with perfect MTHFR genetics but terrible sleep, high stress, and a processed food diet will have impaired methylation.

Protocol: Clean up lifestyle first (sleep, diet, movement, stress, toxin avoidance) → retest functional markers (homocysteine, MMA, neurotransmitter metabolites) → then supplement strategically based on remaining deficits. This prevents the common mistake of stacking supplements based on raw genetic data without considering the total picture.

Genetics loads the gun. Lifestyle pulls the trigger. Functional medicine aims to keep the safety on.