Ben Sima Genome Analysis (23andMe v4, March 2026)

Priority SNPs — Metabolic & Liver Focus

MTHFR (Methylation / Homocysteine)

• rs1801133 (C677T): GG = CC on plus strand = wildtype, no risk allele
• rs1801131 (A1298C): GT = heterozygous = one copy of minor allele
• Net: Normal MTHFR function. No methylation concern. No special folate needs.

PNPLA3 (Liver Fat / NAFLD)

• rs738409 (I148M): CC = wildtype, no risk allele
• This is a big deal. PNPLA3 I148M (GG) is the strongest genetic risk factor for NAFLD/NASH. Ben does NOT carry it.
• His elevated ALT is environmental/metabolic, not genetic destiny. Very responsive to lifestyle.

TM6SF2 (Liver Fat)

• rs58542926: Not genotyped on this chip. Cannot assess.

APOC3 (Triglycerides)

• rs2854117 (T-455C): CC = homozygous minor allele — RISK
• rs2854116 (C-482T): TT = homozygous minor allele — RISK
• rs5128 (SstI): CC = wildtype
• rs662799 (APOA5 -1131T>C): AA = wildtype
• APOC3 promoter variants: Both promoter SNPs are homozygous risk. APOC3 inhibits lipoprotein lipase. This genotype = HIGHER baseline triglycerides and slower triglyceride clearance.
• This explains the trig spike to 361 in December 2025. Genetically predisposed to hypertriglyceridemia.
• The OMAD-driven drop to 143 is impressive GIVEN this genotype.

TCF7L2 (Type 2 Diabetes)

• rs7903146: CC = wildtype, protective
• rs12255372: GG = wildtype, protective
• No genetic T2D risk from TCF7L2. His insulin resistance is metabolic, not genetic.

HFE (Hemochromatosis / Iron)

• rs1800562 (C282Y): GG = wildtype, no risk
• rs1799945 (H63D): CC = wildtype, no risk
• No hemochromatosis mutations. His ferritin of 535 (July 2025) was metabolic/inflammatory, not hereditary hemochromatosis. The blood donation strategy was still correct (it worked — 535→95).

APOE (Cardiovascular / Alzheimer’s)

• rs429358: TT
• rs7412: CC
• This is APOE ε3/ε3 — the most common genotype (~60% of population). Neutral cardiovascular and Alzheimer’s risk. Not ε4 carrier.

FTO (Obesity/Appetite)

• rs9939609: AT = heterozygous, one risk allele
• Modest effect: ~1.3x obesity risk, ~1 kg higher weight on average. Associated with increased appetite/reduced satiety signaling.
• Manageable with the fasting protocol he’s already doing.

PPARG (Insulin Sensitivity)

• rs1801282 (Pro12Ala): CC = wildtype, no protective allele
• The Ala allele is protective for insulin sensitivity. Ben doesn’t have it.
• Combined with no TCF7L2 risk: his insulin resistance is driven by adiposity/diet, not strong genetic predisposition, but he also lacks the protective variant.

ADRB2 (Beta-2 Adrenergic Receptor)

• rs1042713 (Gly16Arg): AA = homozygous Arg16
• Associated with reduced beta-2 receptor downregulation. May affect: bronchodilator response, fat mobilization during exercise, blood pressure.

COMT (Catechol-O-Methyltransferase)

• rs4680 (Val158Met): AG = heterozygous
• Intermediate COMT activity. Neither warrior (Met/Met, slow COMT, higher dopamine) nor worrier stereotype fully applies.

Vitamin D Metabolism

• rs2282679 (GC/DBP): GT = heterozygous, one risk allele for lower vitamin D
• rs1544410 (VDR BsmI): TT = variant
• rs2228570 (VDR FokI): AG = heterozygous
• Moderate genetic tendency toward lower vitamin D levels. Should monitor 25(OH)D and supplement if low.

Lactase Persistence

• rs4988235 (LCT -13910C>T): GG = CC on coding = lactose intolerant genotype
• Ben is genetically lactose non-persistent. Whether he’s symptomatic is another question.

FADS1 (Fatty Acid Desaturase)

• rs174547: CT = heterozygous
• Intermediate ability to convert plant omega-3 (ALA) to EPA/DHA. Should prioritize preformed omega-3 (fish oil, fatty fish) over flaxseed/chia.

Alpha-1 Antitrypsin

• rs28929474 (Pi*Z): CT = heterozygous carrier of Z allele
• One copy of the Z variant of SERPINA1. Carriers (MZ) have ~60-80% normal AAT levels. Usually asymptomatic but:
  • Mildly increased risk of liver disease (AAT polymerization in hepatocytes)
  • Should absolutely not smoke (accelerated emphysema in carriers)
  • Could contribute marginally to his elevated ALT if AAT polymers accumulate in liver
  • Worth checking serum AAT level once

ADH1B (Alcohol Metabolism)

• rs1229984: CT = heterozygous, one fast-metabolism allele
• Faster conversion of ethanol to acetaldehyde. May experience more flushing/discomfort from alcohol = natural aversion. Protective against alcoholism.

Celiac/Autoimmune

• rs2187668 (HLA-DQ2.5): CC = no DQ2.5 risk haplotype
• rs2241880 (ATG16L1): AG = heterozygous for Crohn’s risk variant (modest effect)

NQO1 (Quinone Reductase)

• rs1800566 (P187S): AG = heterozygous
• Reduced NQO1 enzyme activity. Affects detoxification of quinones, benzene metabolites. Minor relevance.

TMPRSS6 (Iron Regulation)

• rs855791: GG = may affect hepcidin regulation and iron absorption. Given his ferritin history, worth noting.

SH2B3/LNK

• rs3184504: TT = homozygous risk
• Associated with elevated blood counts, autoimmune conditions, and cardiovascular risk. An inflammatory SNP.

FUT2 (Secretor Status)

• rs601338: AG = heterozygous secretor
• Secretor status affects gut microbiome composition and susceptibility to norovirus.

MELATONIN (Sleep/Glucose)

• rs10830963 (MTNR1B): CG = heterozygous risk
• Associated with higher fasting glucose and impaired insulin secretion, especially with late eating.
• DIRECTLY RELEVANT: this variant means eating late at night causes more glucose dysregulation than in non-carriers. His OMAD timing matters — eating window should be earlier in the day if possible.

OXTR (Oxytocin Receptor)

• rs53576: GG = homozygous G
• Associated with higher empathy, social sensitivity, and better stress coping. The “social” genotype.

DRD2 (Dopamine D2 Receptor)

• rs1800497 (Taq1A): GG = A2/A2, normal D2 density
• rs6277: GG = normal
• Normal dopamine receptor density. No addiction risk from this locus.

BDNF

• rs6265 (Val66Met): CC = Val/Val, wildtype
• Normal BDNF secretion. Good for neuroplasticity, exercise-induced cognitive benefits.

OPRM1 (Opioid Receptor)

• rs1799971: AA = wildtype
• Normal opioid receptor function.

GSTP1

• rs1695: AG = heterozygous Ile/Val
• Reduced glutathione S-transferase activity. Mildly reduced detox capacity for certain carcinogens.

Summary: Key Actionable Findings

HIGH PRIORITY

1. APOC3 double-homozygous risk — genetically predisposed to high triglycerides. OMAD is working against this. Keep it up. Consider fish oil 2-4g/day EPA+DHA.
2. MTNR1B risk carrier — late eating specifically bad for glucose. OMAD window should be midday/early afternoon, not evening.
3. Alpha-1 Antitrypsin carrier (MZ) — check serum AAT level. Could contribute to liver enzyme elevation. Never smoke.
4. Lactose intolerant genotype — may be subclinically reactive to dairy. Consider eliminating and tracking symptoms.

MODERATE PRIORITY

5. No PNPLA3 risk — liver issues are metabolic, fully reversible with lifestyle. Very good news.
6. No HFE mutations — ferritin was inflammatory, not hereditary. Confirms blood donation was right intervention.
7. No TCF7L2 risk — insulin resistance is environmental. Reversible.
8. APOE ε3/ε3 — neutral. No special Alzheimer’s concern.
9. FTO heterozygous — modest appetite/obesity effect. Fasting mitigates.
10. SH2B3 homozygous — inflammatory tendency. Anti-inflammatory diet beneficial.
11. Vitamin D tendency — supplement and monitor.
12. FADS1 heterozygous — use preformed omega-3 (fish oil), not plant sources.

NOT CONCERNING

• MTHFR: normal
• HFE: normal
• COMT: intermediate (balanced)
• DRD2: normal
• BDNF: normal (Val/Val)
• APOE: ε3/ε3 (neutral)

B12 Pathway SNPs (detailed analysis added 2026-03-18)

• TCN2 rs1801198: CG = heterozygous risk. Reduced transcobalamin II → lower B12 delivery to tissues.
• FUT2 rs602662: AG = heterozygous secretor. Intermediate B12 absorption.
• MTR rs1805087: AA = wildtype. Normal methionine synthase.
• MTRR rs1801394: AG = heterozygous risk. Reduced B12 cofactor recycling.
• MTHFR A1298C rs1801131: GT = heterozygous. Mild folate metabolism effect.
• CBS rs234706: AG = heterozygous. Possibly faster transsulfuration = faster B12/folate consumption.
• Net assessment: Modest B12 vulnerability stack. TCN2 het + MTRR het + CBS het = possible functional B12 insufficiency even with normal serum B12. Recommend MMA + homocysteine testing and methylated B-complex supplementation.

Skin-Related Findings

MC1R — Pigmentation & Skin Sensitivity

• rs1805008 (R160W): CT — HETEROZYGOUS RISK ⚠️
  • One copy of the R160W variant. MC1R variants reduce eumelanin production, leading to lighter/more sun-sensitive skin. R160W is classified as a strong “r” (loss-of-function) variant.
  • Associated with: increased sun sensitivity, reduced tanning ability, increased skin cancer risk, tendency toward dry/sensitive skin.
  • Carriers have reduced melanocortin signaling → less skin barrier protection.
• rs1805007 (R151C): CC — wildtype ✅
• rs2228479 (V92M): GG — wildtype ✅
• rs1805005 (V60L): GG — wildtype ✅

FLG (Filaggrin) — Skin Barrier

• rs61816761 (R501X): GG — wildtype ✅
  • No filaggrin loss-of-function. The most common genetic cause of eczema/ichthyosis is ruled out. Your dry skin is NOT from filaggrin deficiency.

IL-13 — Atopic/Inflammatory Skin Risk

• rs20541 (R130Q): AG — HETEROZYGOUS RISK ⚠️
  • The A allele (Gln130) produces a more active form of IL-13, a Th2 cytokine. Associated with increased risk of atopic dermatitis, eczema, and allergic skin conditions.
• rs1800925 (IL13 promoter): CT — HETEROZYGOUS RISK ⚠️
  • T allele increases IL-13 expression. Combined with R130Q het, you have both increased expression AND increased activity of IL-13.

SPINK5 — Skin Barrier Protease Inhibitor

• rs2303067: AG — HETEROZYGOUS ⚠️
  • SPINK5 encodes LEKTI, a protease inhibitor critical for skin barrier integrity. Variants reduce barrier function and increase atopic dermatitis risk.

BCMO1 — Beta-Carotene → Vitamin A Conversion

• rs12934922 (A379V): AT — HETEROZYGOUS RISK ⚠️
• rs7501331 (R267S): CT — HETEROZYGOUS RISK ⚠️
  • Double heterozygous = ~45% reduced conversion of beta-carotene to retinol. Vitamin A is essential for skin cell turnover and moisture retention. You may have functionally low retinol status if relying on plant sources.

Psoriasis Risk SNPs

• rs10484554 (HLA-C*06:02 tag): CT — HETEROZYGOUS RISK ⚠️
• rs12191877: CT — HETEROZYGOUS RISK ⚠️
  • HLA-C*06:02 is THE major psoriasis risk allele. Heterozygous carriers have ~3-4x increased psoriasis risk vs population.
• rs4112788 (LCE3 cluster): AG — HETEROZYGOUS RISK ⚠️
  • LCE3C/LCE3B deletion tag. Late cornified envelope proteins involved in skin barrier repair after inflammation. Risk allele = impaired barrier repair.
• rs6887695 (IL12B): CG — HETEROZYGOUS RISK ⚠️
  • IL-12B is a psoriasis GWAS hit. One risk allele.
• rs479844 (OVOL1): AG — HETEROZYGOUS — modest eczema/skin risk

FADS1 — Omega Fatty Acid Metabolism

• rs174547: CT — HETEROZYGOUS — reduced delta-5 desaturase activity → lower conversion of plant omega-3/omega-6 to their long-chain forms. Relevant to skin because arachidonic acid and EPA/DHA are critical for skin inflammation regulation.

Summary

Strong psoriasis risk profile (HLA-C het + LCE3 het + IL12B het). Combined with IL-13 overexpression (two het risk variants) and reduced vitamin A conversion (BCMO1 double het), there is a clear genetic basis for dry, inflammation-prone skin. Filaggrin is normal, so the barrier issue is inflammatory rather than structural.

Nicotine & Addiction-Related Findings

CHRNA5-A3-B4 Cluster — Nicotinic Acetylcholine Receptors

• rs16969968 (CHRNA5 D398N): AG — HETEROZYGOUS RISK ⚠️
  • The A allele (Asn398) reduces alpha-5 subunit function. This is the single strongest genetic risk factor for nicotine dependence and heavy smoking. Heterozygotes have intermediate risk (~1.3x OR for nicotine dependence).
  • However: this variant primarily predicts escalation to heavy smoking (>20 cigs/day), not initial addiction. At 3mg pouch doses, you’re nowhere near the threshold where this allele typically manifests.
• rs1051730 (CHRNA3): AG — HETEROZYGOUS — in perfect LD with rs16969968, confirms one risk haplotype.
• rs12914385 (CHRNB4): CT — HETEROZYGOUS — same risk haplotype.

CYP2A6 — Nicotine Metabolism Rate

• rs1801272: AA — wildtype ✅
• rs28399433: AA — wildtype ✅
  • No slow-metabolizer variants detected. You are likely a normal metabolizer of nicotine. This means you clear nicotine at a standard rate (~2 hour half-life for cotinine).
  • Slow metabolizers are actually protected from addiction (nicotine lingers longer, less urge to re-dose). Normal/fast metabolizers have slightly higher addiction risk because the effect wears off sooner, creating more re-dosing motivation.
• CYP2B6 rs3745274: GG — wildtype ✅ — normal secondary metabolism.

Dopamine System

• DRD2/ANKK1 rs1800497 (Taq1A): GG — wildtype ✅
  • No reduced D2 receptor density. This is protective — people with the A1 allele have fewer D2 receptors and are more vulnerable to all addictions.
• DRD4 rs1800955: CT — HETEROZYGOUS
  • Modest effect on novelty seeking. Not a major addiction variant.
• SLC6A3 (DAT) rs27072: CC — wildtype ✅
• SLC6A3 rs40184: CC — wildtype ✅
  • Normal dopamine transporter. No variant that would increase addiction vulnerability.

Opioid/Reward System

• OPRM1 rs1799971: AA — wildtype ✅
  • Normal mu-opioid receptor. The G allele is associated with altered reward processing and higher addiction risk. You don’t have it.

GABA System

• GABRA2 rs279858: CT — HETEROZYGOUS
• GABRA2 rs567926: AG — HETEROZYGOUS
  • GABRA2 variants are associated with alcohol dependence and general externalizing behavior, not specifically nicotine. Modest signal.

Serotonin

• HTR2A rs6311: TT — HOMOZYGOUS VARIANT
• HTR2A rs6313: AA — HOMOZYGOUS VARIANT
  • These are in LD. The TT/AA combination is associated with altered serotonin 2A receptor expression. More relevant to anxiety/impulsivity than substance addiction per se, but can influence stress-related substance use patterns.

MAOA — Monoamine Oxidase A

• rs6323: T (hemizygous, X-linked)
  • T allele = HIGH MAOA activity. This means faster breakdown of serotonin, dopamine, and norepinephrine. High MAOA activity is generally protective against impulsive behavior and addiction. This is the “warrior gene” discussion, but you have the high-activity form, which is the less-discussed, more common, and behaviorally protective version.
  • Interesting note re: our nicotine research — tobacco contains MAO inhibitors (harmane, norharmane) that suppress this enzyme. Since you have the high-activity form, the MAO inhibition from tobacco smoke would produce a larger relative effect on your monoamine levels. This means if you ever smoked tobacco (not nicotine pouches), the reinforcing effect would be disproportionately strong for you. But with pouches (no MAOIs), this is irrelevant.

DBH — Dopamine Beta-Hydroxylase

• rs1611115: CC — wildtype ✅
  • Normal dopamine-to-norepinephrine conversion. The T allele reduces DBH activity (higher dopamine, lower NE), which is associated with increased addiction risk.

BDNF

• rs6265: CC — Val/Val wildtype ✅ — already noted. Normal neuroplasticity, good for breaking habits.

Summary — Nicotine Addiction Risk Profile

Your genome shows ONE meaningful addiction risk factor: heterozygous CHRNA5 D398N. Everything else in your dopamine system (DRD2, DAT, DBH), opioid system (OPRM1), and monoamine metabolism (MAOA high activity) is protective or neutral. CYP2A6 is normal (not slow metabolizer, so no extra protection there, but not fast either).

Net assessment: slightly above average genetic susceptibility to nicotine specifically (CHRNA5 het), but below average susceptibility to addiction generally (protective DRD2, OPRM1, DBH, MAOA, BDNF). At 3mg pouches with no MAOIs, the CHRNA5 variant is unlikely to be clinically relevant — it primarily predicts escalation to heavy smoking, which involves a completely different delivery/reinforcement profile.

Exercise-Related SNPs

Power vs Endurance Profile

ACTN3 R577X (rs1815739): CT = heterozygous (RX)

• One copy of X (stop codon) = you produce alpha-actinin-3 but at reduced levels
• RR = sprint/power elite, XX = endurance elite, RX = versatile/hybrid
• You have functional fast-twitch fibers but not maximal alpha-actinin-3 expression
• Confidence: 🟢 HIGH — most replicated exercise gene finding

ACE I/D proxy (rs4343): AG = heterozygous (I/D equivalent)

• rs4343 is in complete LD with ACE I/D. AG = ID genotype
• II = endurance (lower ACE, better efficiency), DD = power (higher ACE, more angiotensin II)
• ID = intermediate — again, versatile/hybrid
• Confidence: 🟢 HIGH — well-replicated

PPARGC1A Gly482Ser (rs8192678): CC = GG on coding strand = wildtype Gly/Gly

• This is the FAVORABLE genotype. GG = higher PGC-1α expression = better mitochondrial biogenesis
• Associated with endurance athlete status and better VO2max training response
• Confidence: 🟢 HIGH — PGC-1α is the master regulator of mitochondrial biogenesis

PPARD (rs2016520): CT = heterozygous

• C allele associated with enhanced endurance adaptation and fat oxidation
• One copy = moderate endurance advantage
• Confidence: 🟡 MODERATE

ADRB2 Arg16Gly (rs1042713): AA = Arg/Arg (wildtype)

• Associated with better bronchodilation and potentially better endurance in some studies
• Confidence: 🟡 MODERATE

ADRB2 Gln27Glu (rs1042714): CC = Gln/Gln (wildtype)

• Some association with lipolysis regulation; wildtype is neutral
• Confidence: 🟡 MODERATE

ADRB3 Trp64Arg (rs4994): AA = wildtype (Trp/Trp)

• No variant = normal beta-3 adrenergic receptor function for fat mobilization during exercise
• Confidence: 🟡 MODERATE

UCP2 (rs660339): GG = wildtype

• Normal mitochondrial uncoupling protein 2. No metabolic efficiency variant.
• Confidence: 🟡 LOW-MODERATE

Hypoxic / Cardiovascular Response

HIF1A Pro582Ser (rs11549465): CC = wildtype (Pro/Pro)

• No enhanced hypoxic response variant. The Ser allele is associated with higher HIF-1α stability and better adaptation to altitude/hypoxia.
• Confidence: 🟡 MODERATE

VEGFA (rs2010963): GG = wildtype

• Normal vascular endothelial growth factor expression
• rs1572312: GG = wildtype
• No enhanced angiogenesis variants
• Confidence: 🟡 MODERATE

AGT Met235Thr (rs699): AA = wildtype (Met/Met)

• Lower angiotensinogen levels. Associated with lower blood pressure response to exercise. This is the “endurance favorable” genotype.
• Confidence: 🟡 MODERATE

AGTR1 (rs5186): AC = heterozygous

• One copy C allele = slightly altered angiotensin II receptor expression
• Minor effect on BP response to training
• Confidence: 🟡 LOW

Recovery / Injury Risk

IL-6 -174G>C (rs1800795): GG = wildtype (high IL-6 producer)

• GG = higher baseline IL-6 production = stronger acute inflammatory response to exercise
• Better for signaling adaptation, but may mean slower recovery between hard sessions
• Confidence: 🟢 HIGH

TNF-alpha -308G>A (rs1800629): GG = wildtype (low TNF producer)

• GG = lower TNF-α production = FAVORABLE for recovery
• Reduced chronic inflammation risk from training
• Confidence: 🟢 HIGH

COL1A1 Sp1 (rs1800012): AC = heterozygous

• One risk allele. Altered collagen type I alpha-1 chain.
• Associated with modestly increased risk of tendon/ligament injuries (ACL, Achilles)
• Confidence: 🟡 MODERATE — meta-analyses show small but significant effect

COL5A1 (rs12722): CT = heterozygous

• One risk allele for soft tissue injury. COL5A1 affects collagen fibril assembly.
• Carriers have increased Achilles tendinopathy risk
• Confidence: 🟡 MODERATE

MMP3 (rs679620): CC = homozygous

• Matrix metalloproteinase 3. CC may affect tendon remodeling rate.
• Confidence: 🟡 LOW-MODERATE

Muscle & Neurological

BDNF Val66Met (rs6265): CC = Val/Val (wildtype)

• Already noted — normal neuroplasticity, normal exercise-induced BDNF response
• Confidence: 🟢 HIGH

COMT Val158Met (rs4680): AG = heterozygous (Val/Met)

• Intermediate dopamine metabolism. Not warrior (Met/Met) or worrier (Val/Val).
• Balanced pain tolerance and stress response
• Confidence: 🟢 HIGH

DRD2/ANKK1 (rs1800497): GG = wildtype (normal D2 density)

• Full dopamine D2 receptor density. Normal reward/motivation circuitry.
• Confidence: 🟢 HIGH

CNTF (rs1800169): GG = wildtype

• Normal ciliary neurotrophic factor. No muscle mass vulnerability.
• Confidence: 🟡 MODERATE

VDR FokI (rs2228570): AG = heterozygous

• One risk allele. VDR affects muscle strength and function via vitamin D.
• Heterozygotes have intermediate muscle strength response to vitamin D.
• Reinforces need for vitamin D supplementation.
• Confidence: 🟡 MODERATE

Fat Mobilization & Metabolism

ADRA2A (rs1800544): CG = heterozygous

• Alpha-2A adrenergic receptor. Affects fat mobilization during exercise.
• Heterozygous = intermediate — not impaired, not enhanced
• Confidence: 🟡 LOW-MODERATE

PPARG Pro12Ala (rs1801282): CC = wildtype (Pro/Pro)

• Already noted — no protective Ala allele. Less insulin sensitivity benefit from exercise.
• The literature shows Pro/Pro subjects are “negative responders” to aerobic training for glucose tolerance compared to Ala carriers.
• Confidence: 🟡 MODERATE

Lactate / Pain

MCT1 (rs7136446): CT = heterozygous

• Monocarboxylate transporter 1. Affects lactate clearance from muscles.
• Heterozygous = intermediate lactate transport capacity
• Confidence: 🟡 LOW-MODERATE

TRPV1 (rs8065080): CT = heterozygous

• Transient receptor potential vanilloid 1. Affects pain perception.
• Intermediate pain sensitivity during high-intensity exercise
• Confidence: 🟡 LOW

1. Sleep Architecture & Chronotype

CLOCK rs1801260 (3111 T>C)

• Genotype: AA (TT on plus strand) = wildtype
• No evening chronotype allele. This is the “neutral” genotype — not genetically pushed toward morning or evening.

PER2 rs2304672

• Genotype: GG = wildtype
• No advanced sleep phase variant. Normal PER2 function.

PER2 rs934945

• Genotype: CC = wildtype
• Normal circadian period.

PER3 rs228697

• Genotype: CG = heterozygous
• One copy of the G allele. PER3 variants are associated with sleep timing and duration preferences. The G allele in some studies links to slightly shorter sleep duration and morning preference. 🟡 MODERATE confidence — PER3 associations are modest and sex-dependent.

MTNR1B rs10830963

• Genotype: CG = heterozygous (already documented above)
• Melatonin receptor variant — later melatonin effects on glucose, but also associated with later chronotype preferences.

DEC2/BHLHE41 rs73598374

• Genotype: CC = wildtype
• The rare P384R mutation (heterozygous) causes “natural short sleep” (6hrs with no deficits). Ben does NOT carry this mutation. His 6.5-7.5hr sleep need is not DEC2-mediated — it’s within normal range, not the rare genetic short-sleep phenotype. 🟢 HIGH confidence.

GNB3 rs5443

• Genotype: CT = heterozygous
• G-protein beta-3 subunit. The T allele (825T) is associated with shorter sleep duration in some studies (PMC4320759). Heterozygous = intermediate effect. This may contribute to the lower end of his natural sleep range (6.5hrs). 🟡 MODERATE confidence.

COMT rs4680 (Val158Met)

• Genotype: AG = heterozygous (Val/Met)
• Intermediate dopamine/catecholamine clearance. Val/Val = fast clearance (warrior). Met/Met = slow clearance (worrier). Val/Met = balanced. This affects stress resilience, executive function, and how quickly dopamine/norepinephrine are cleared in the prefrontal cortex. 🟢 HIGH confidence for the mechanism; the “warrior/worrier” labels are oversimplified.

NPAS2 rs2305160

• Genotype: AA = wildtype
• NPAS2 is a paralog of CLOCK that operates in the forebrain. Wildtype = no circadian disruption.

ARNTL/BMAL1 rs4757144

• Genotype: AG = heterozygous
• BMAL1 is the core circadian activator. This variant has been associated with metabolic syndrome risk in some populations but circadian effects are mild. 🟡 LOW-MODERATE confidence.

Sleep Synthesis

Ben’s genetic sleep profile is NORMAL, not a short-sleeper mutation. His 6.5-7.5hr range is likely the genuine physiological minimum, not DEC2-mediated resilience. The PER3 het + GNB3 het may nudge him toward the shorter end of normal. His CLOCK is wildtype (not a genetic night owl), which is consistent with naturally waking at 7am. The MTNR1B het means his melatonin system is somewhat metabolically sensitive — another reason not to eat late.

Practical: 7hrs is your genetic floor, not excess. The 5am shift for workouts is fighting your neutral chronotype but not fighting a strong evening-type allele, so it’s sustainable with consistent light exposure. Bright light immediately at 5am wake + light restriction after 8pm would maximize circadian entrainment.

2. Caffeine Metabolism

CYP1A2 rs762551

• Genotype: AC = heterozygous = SLOW CAFFEINE METABOLIZER
• AA = fast metabolizer (CYP1A2*1A/*1A). AC or CC = slow metabolizer (one or two copies of *1F allele). Ben carries one *1F allele = intermediate-to-slow caffeine metabolism. Caffeine half-life is likely 5-8 hours rather than the typical 3-5 hours for fast metabolizers. 🟢 HIGH confidence — this is one of the best-replicated nutrigenomics findings.
• Cardiovascular implication: In slow metabolizers, >2 cups/day increases MI risk (Cornelis et al., JAMA 2006). In fast metabolizers, coffee is protective. Ben’s 1-2 cups/day is within the safe zone, but 3+ cups would be inadvisable.
• Sleep implication: Combined with no DEC2 protection, caffeine consumed after ~10am may still be active at bedtime (10pm). This is likely contributing to sleep quality issues if any exist.

AHR rs4410790

• Genotype: CT = heterozygous
• AHR regulates CYP1A2 expression. The T allele is associated with lower habitual coffee consumption in GWAS (likely because these individuals are more sensitive to caffeine’s effects and self-limit). 🟡 MODERATE confidence.

ADORA2A rs2472297

• Genotype: CT = heterozygous
• Adenosine A2A receptor. The T allele is associated with increased caffeine sensitivity and caffeine-induced anxiety. Heterozygous = intermediate sensitivity. Combined with slow CYP1A2 metabolism, this means caffeine hits harder AND lingers longer. 🟢 HIGH confidence for the mechanism.

Caffeine Synthesis

Ben is a genetically slow caffeine metabolizer who is also moderately caffeine-sensitive at the receptor level. His self-observed pattern (one cup = wired on workdays) is genetically validated. His 1-2 cups/day is the maximum advisable dose for his genotype.

Practical:

• Keep coffee to 1-2 cups, consumed before 10am (caffeine still in system 6-8hrs later)
• The “context-dependent” effect he described (vacation = more tolerant) makes sense: stress hormones upregulate CYP1A2, so on workdays he may actually metabolize caffeine slightly faster but also have more sympathetic drive amplifying the effect
• Switch to half-caf or green tea for afternoon if needed
• No coffee after noon if sleep quality matters

3. Cardiovascular Deep Dive

Lp(a) — Lipoprotein(a)

• rs10455872: AA = wildtype (no risk allele)
• rs3798220: TT = wildtype (no risk allele)
• 🟢 HIGH confidence. Lp(a) is genetically determined and barely modifiable by lifestyle. Both major risk SNPs are wildtype. His Lp(a) is almost certainly normal. This is genuinely good news — elevated Lp(a) is a major independent CVD risk factor affecting ~20% of people, and Ben doesn’t carry it.

9p21 (CDKN2A/2B) — Coronary Heart Disease Risk Locus

• rs10757274: AG = heterozygous risk
• rs2383206: AG = heterozygous risk
• rs1333049: CG = heterozygous risk
• 🟢 HIGH confidence. 9p21 is the strongest GWAS locus for CHD (not driven by traditional risk factors like cholesterol). Three heterozygous hits = moderate genetic risk. Meta-analyses show ~25% increased CHD risk per risk allele. Ben carries one risk allele at each of three linked SNPs — this represents a SINGLE risk haplotype in heterozygous form (they’re in linkage disequilibrium), so the net effect is ~1.25-1.5x baseline CHD risk, NOT multiplicative across the three SNPs.
• This risk is NOT mediated through lipids or blood pressure — it operates through vascular inflammation and cell cycle regulation. Meaning: even if his lipid panel is perfect, this genetic risk persists. Exercise and anti-inflammatory diet are the primary mitigators.

AGT rs699 (M235T)

• Genotype: AA = Met/Met = wildtype (endurance-favorable)
• Already documented. Lower angiotensinogen = lower baseline BP tendency.

AGTR1 rs5186 (A1166C)

• Genotype: AC = heterozygous risk
• Angiotensin II type 1 receptor gain-of-function variant. The C allele is associated with increased receptor expression and higher BP responsiveness to angiotensin II. Combined with normal AGT = the renin-angiotensin system is slightly upregulated at the receptor level even though the substrate is normal. Net effect: mild BP sensitivity, especially to sodium. 🟡 MODERATE confidence.

ADD1 rs4961 (Gly460Trp)

• Genotype: GG = Gly/Gly = wildtype
• No salt-sensitive hypertension variant. Good news for sodium intake.

CETP rs708272 (TaqIB)

• Genotype: GG = B2B2 homozygous
• CETP transfers cholesterol from HDL to LDL. The B2 allele (G) = lower CETP activity = HIGHER HDL. This is generally cardioprotective. 🟢 HIGH confidence. Ben likely has naturally higher HDL levels.

SORT1 rs599839

• Genotype: AG = heterozygous
• Sortilin 1. The G allele is associated with lower LDL-C and lower CHD risk (GWAS-validated). One protective copy. 🟡 MODERATE confidence.

FTO rs9939609

• Genotype: AT = heterozygous risk
• Already known from metabolic analysis. One obesity-risk allele. ~1.3kg higher weight tendency. Modifiable by exercise.

Cardiovascular Synthesis

Mixed picture. The good: normal Lp(a) (huge), high HDL tendency (CETP), normal blood pressure genetics (AGT wildtype, ADD1 wildtype), one SORT1 protective allele. The bad: heterozygous 9p21 CHD risk locus (~1.3x risk, non-lipid-mediated) and one AGTR1 gain-of-function allele.

Net risk: slightly above average for CHD, driven by the 9p21 locus, but with several protective factors.

Practical:

• Anti-inflammatory lifestyle is the primary mitigation for 9p21 risk (exercise, omega-3, no excessive saturated fat — all of which he’s already doing)
• Monitor BP periodically given AGTR1 het
• Lp(a) test is NOT needed (genetically normal) — can remove from blood draw list
• HDL should be naturally good (CETP) — if it’s low on blood work, that’s an environmental signal worth investigating
• Added homocysteine to blood draw (MTHFR wildtype but MTRR het)

4. Cancer Risk SNPs

8q24 rs6983267

• Genotype: GG = homozygous risk
• 🟢 HIGH confidence. The G allele is the risk allele for colorectal cancer, and Ben is GG (homozygous). This is the strongest common genetic variant for CRC, conferring ~1.4-1.5x lifetime risk. The mechanism is enhancer-mediated regulation of MYC oncogene. This is a POPULATION-LEVEL risk — it doesn’t mean cancer is likely, but it means CRC screening should not be delayed or skipped.

TP53 rs1042522 (Pro72Arg)

• Genotype: CG = heterozygous (Pro/Arg)
• 🟡 MODERATE confidence. The Arg72 allele (G) is more efficient at triggering apoptosis but also more susceptible to degradation by HPV E6 protein. Pro72 (C) is better at DNA repair and cell cycle arrest. Heterozygous = both functions present. Some cancer types show mild risk increase with one allele, others with the other — it’s cancer-type-specific and the heterozygous state is generally considered neutral.

MC1R rs1805008 (R160W)

• Genotype: CT = heterozygous (already documented)
• Reduced melanocortin signaling. Mild increase in skin cancer risk (melanoma), especially with UV exposure. Already flagged in skin section.

GSTP1 rs1695 (I105V)

• Genotype: AG = heterozygous (already documented)
• Reduced phase II detoxification. Modest increase in exposure to carcinogens. Cruciferous vegetables upregulate this pathway.

TERT rs2736100

• Genotype: CC = homozygous risk
• 🟡 MODERATE confidence. TERT encodes telomerase reverse transcriptase. The C allele is associated with longer telomeres but ALSO increased cancer risk (paradoxically — longer telomeres = more cell divisions before senescence = more mutation opportunities). Meta-analyses show CC genotype has increased risk for lung, bladder, and glioma cancers specifically. The magnitude is modest (~1.2-1.3x per allele).

BRCA1 / BRCA2

• BRCA1 rs1799950: TT — not a known pathogenic allele at this position
• BRCA1 rs16942: TT — common variant, not pathogenic
• BRCA1 rs799917: GG — common variant, not pathogenic
• BRCA2 rs144848: AA — wildtype, no N372H variant
• 🟢 HIGH confidence that NO major BRCA pathogenic variants detected. (Caveat: 23andMe v4 only tests common SNPs, not the full gene sequencing done in clinical BRCA testing. Rare private mutations would be missed.)

Lynch Syndrome (Mismatch Repair)

• MLH1 rs1800734: GG = wildtype
• MSH2 rs2303428: TT = wildtype
• CHEK2 rs17879961: AA = wildtype
• 🟢 HIGH confidence: no common Lynch syndrome markers detected. Same caveat as BRCA — rare mutations need full sequencing.

APC rs1801155 (I1307K)

• Genotype: TT = wildtype
• No APC I1307K risk allele (common in Ashkenazi Jewish population for CRC). 🟢 HIGH confidence.

ATM rs1801516

• Genotype: GG = wildtype
• No ATM DNA repair variant. Good.

Cancer Synthesis

The main finding is the 8q24 GG homozygous — this is a genuine, well-validated colorectal cancer susceptibility locus. Combined with TERT CC (longer telomeres / increased general cancer risk) and GSTP1 het (reduced detox), the picture favors a proactive screening approach.

Practical:

• Begin colonoscopy screening at 45 (current guidelines) or earlier if any family history of CRC — do NOT defer
• Cruciferous vegetables regularly (upregulate GSTP1 pathway, which is your weak link)
• Fish oil / aspirin have some CRC-protective evidence (fish oil already in stack)
• MC1R het → sun protection, annual derm skin check
• The BRCA/Lynch panel is clean on common variants — reassuring but not comprehensive

5. Pharmacogenomics

CYP2D6 (Codeine, Tramadol, SSRIs, Beta-blockers, Tamoxifen)

• *rs3892097 (4 allele): CC = wildtype (no null allele)
• *rs1065852 (10 allele): GG = wildtype (no reduced function)
• *rs16947 (2 allele): AG = heterozygous
• rs1135840: CG = heterozygous
• Predicted phenotype: Normal (Extensive) Metabolizer
• 🟢 HIGH confidence. CYP2D6*1/*2 is a normal function diplotype. Ben metabolizes CYP2D6 substrates at standard rates. No dose adjustments needed for codeine, tramadol, most SSRIs, or beta-blockers.

CYP2C19 (PPIs, Clopidogrel, some SSRIs)

• *rs4244285 (2 allele): GG = wildtype
• *rs4986893 (3 allele): GG = wildtype
• *rs12248560 (17 allele): CC = wildtype (no rapid metabolizer allele)
• Predicted phenotype: Normal (Extensive) Metabolizer
• 🟢 HIGH confidence. Standard PPI dosing, standard clopidogrel activation. No issues.

CYP2C9 (Warfarin, NSAIDs, some oral hypoglycemics)

• *rs1799853 (2 allele): CC = wildtype
• *rs1057910 (3 allele): AC = heterozygous = CYP2C91/3
• Predicted phenotype: INTERMEDIATE Metabolizer
• 🟢 HIGH confidence. ⚠️ THIS IS THE KEY FINDING. CYP2C9*3 reduces enzyme activity by ~80% for that allele. Heterozygous = roughly 50% reduced clearance of CYP2C9 substrates.
  • Warfarin: Would need ~25% dose reduction if ever prescribed. CRITICAL to mention to prescribing physician.
  • NSAIDs (ibuprofen, naproxen, celecoxib): Slower clearance = higher sustained levels = increased GI bleeding and cardiovascular risk. Should use lower doses or shorter courses than standard.
  • Diclofenac: Particularly affected — avoid if possible.
  • Phenytoin: Would need dose reduction if ever prescribed for seizures.
  • Losartan: Reduced activation (losartan is a prodrug converted by CYP2C9). May need alternative ARB if prescribed for BP.

CYP3A4 rs2740574

• **Genotype: TT = wildtype (1/1)
• Normal CYP3A4 activity. This enzyme handles ~50% of all drugs (statins, calcium channel blockers, many antibiotics, immunosuppressants). No issues. 🟢 HIGH confidence.

CYP3A5 rs776746

• **Genotype: CC = 3/3 = non-expressor
• CYP3A5 is not expressed. This is the most common genotype in Europeans. CYP3A4 compensates. Mainly relevant for tacrolimus dosing (transplant drug) — would need standard or lower dose. 🟢 HIGH confidence.

SLCO1B1 rs4149056 (Statin Transporter)

• Genotype: CC = wildtype (521TT = Val/Val)
• Normal hepatic uptake of statins. No increased risk of statin-induced myopathy. If statins are ever needed, standard dosing is fine. 🟢 HIGH confidence.

VKORC1 rs9923231 (Warfarin Sensitivity)

• Genotype: CC = wildtype (low sensitivity)
• Normal warfarin sensitivity. Combined with CYP2C9*3 het, the net warfarin picture: start at ~25% reduced dose (for CYP2C9) but with normal VKORC1 sensitivity. 🟢 HIGH confidence.

DPYD rs3918290 (5-Fluorouracil Toxicity)

• Genotype: CC = wildtype
• No DPD deficiency. If ever needed, fluorouracil chemotherapy would be metabolized normally. 🟢 HIGH confidence. This is a life-or-death pharmacogenomic variant (DPD-deficient patients can die from standard 5-FU doses).

NAT2 (Isoniazid, Sulfonamides, Caffeine secondary pathway)

• *rs1801280 (5 allele): TT = homozygous SLOW allele
• *rs1799930 (6 allele): AG = heterozygous
• *rs1799931 (7 allele): GG = wildtype
• Predicted phenotype: SLOW Acetylator
• 🟡 MODERATE confidence. NAT2*5/*5 or *5/*6 diplotype = slow acetylation. This means:
  • Isoniazid (TB drug): Higher risk of hepatotoxicity at standard doses. Need reduced dose/monitoring.
  • Sulfonamide antibiotics: Increased hypersensitivity risk.
  • Aromatic amines (from well-done meat/char): Slower detoxification = potentially higher cancer risk from heterocyclic amines. This connects to the CRC risk (8q24 GG) — another reason to avoid heavily charred meat.
  • Caffeine is partly cleared through NAT2 — slow acetylation adds to the slow CYP1A2 picture. Caffeine lingers even longer than CYP1A2 alone would predict.

ABCB1 rs1045642 (P-glycoprotein / MDR1)

• Genotype: AA (3435TT on coding strand) = reduced P-glycoprotein function
• 🟡 MODERATE confidence. P-gp is an efflux pump that removes drugs from cells (especially brain, gut, liver). TT genotype = lower P-gp expression = MORE drug penetration into the brain and tissues. This means:
  • Opioids: Potentially stronger effect at standard doses (more crosses BBB).
  • Digoxin: Higher bioavailability — would need monitoring.
  • Some chemotherapy drugs: Potentially more effective but also more toxic.
  • General principle: Ben may be more sensitive to drugs that are P-gp substrates. Start low.

HLA-B*5701 rs2395029

• Genotype: TT = wildtype (HLA-B*5701 negative)
• No risk of abacavir hypersensitivity (HIV drug). No risk of flucloxacillin hepatotoxicity. 🟢 HIGH confidence.

ADH1B rs1229984 (Alcohol Metabolism)

• Genotype: CT = heterozygous = fast alcohol metabolizer
• Already documented. One copy of the fast ADH1B*2 allele = rapid ethanol → acetaldehyde conversion.

ALDH2 rs671

• Genotype: GG = wildtype
• Normal acetaldehyde clearance. No “Asian flush” variant. Combined with fast ADH1B, net: rapid ethanol metabolism with normal acetaldehyde clearance. Alcohol effects are briefer but acetaldehyde doesn’t accumulate. 🟢 HIGH confidence.

Pharmacogenomics Synthesis

Two critical findings to put on a medical card:

1. *CYP2C9*1/3 (Intermediate Metabolizer) — affects warfarin, NSAIDs, and several other drugs. If ever prescribed warfarin, dose must be reduced ~25%. NSAIDs should be used at lower doses.

2. NAT2 Slow Acetylator — affects isoniazid and sulfonamides. If ever treated for TB, need dose reduction and liver monitoring.

Other notable:

• ABCB1 TT = more drug penetration to brain. May be more sensitive to opioids and CNS-active drugs.
• CYP1A2 AC = slow caffeine metabolism (already covered).
• ADH1B fast + ALDH2 normal = efficient alcohol processing.
• SLCO1B1 wildtype = no statin myopathy risk.
• DPYD wildtype = 5-FU safe if ever needed.

6. Gut / Microbiome Predisposition

FUT2 rs601338 (Secretor Status)

• Genotype: AG = heterozygous (Se/se)
• 🟢 HIGH confidence. FUT2 determines “secretor status” — whether ABO blood group antigens are secreted into mucus and saliva. GG = non-secretor (associated with altered gut microbiome, resistance to norovirus, but higher risk of Crohn’s and lower B12 absorption). AG = secretor (with one non-secretor allele). Ben IS a secretor (one functional allele is sufficient), but with intermediate expression.

FUT2 rs602662

• Genotype: AG = heterozygous — confirms secretor status with intermediate expression. Already documented in B12 section.

ATG16L1 rs2241880 (T300A)

• Genotype: AG = heterozygous
• 🟡 MODERATE confidence. ATG16L1 is essential for autophagy — specifically xenophagy (clearance of intracellular bacteria). The T300A variant (G allele) reduces autophagy efficiency. One copy = modestly reduced clearance of intracellular pathogens (e.g., adherent-invasive E. coli). Associated with Crohn’s disease risk in GWAS. Het = ~1.3x increased risk.

NOD2 (Crohn’s Disease Major Gene)

• rs2066844: CC = wildtype
• rs2066845: GG = wildtype
• rs2066847: DD (no insertion) = wildtype
• 🟢 HIGH confidence. All three major NOD2 frameshift/missense variants are absent. NOD2 is the strongest genetic risk factor for Crohn’s disease. Clean.

HLA-DQ2 rs2187668

• Genotype: CC = negative for HLA-DQ2.5
• 🟢 HIGH confidence. HLA-DQ2.5 is present in ~95% of celiac disease patients. CC = negative. Celiac disease is essentially ruled out genetically.

HLA-DQ8 rs7454108

• Genotype: TT — need to verify orientation, but likely negative for DQ8 as well. Between DQ2-negative and DQ8-negative, celiac disease genetic risk is near zero.

IL-23R rs11209026

• Genotype: GG = wildtype
• The A allele is PROTECTIVE against Crohn’s and psoriasis. GG = no protective allele. Given his psoriasis SNPs (HLA-C*06:02 het, IL12B het), the absence of this protective variant is relevant.

Gut Synthesis

Net IBD risk: low but not zero. NOD2 clean (major) but ATG16L1 het (minor) and no IL-23R protection. The bigger gut story is the connection to his other systems:

• Secretor status (FUT2 AG): Shapes which bacteria colonize the gut. Secretors tend to have higher Bifidobacterium levels. This affects B12 absorption (already flagged) and overall gut barrier function.
• ATG16L1 het: Reduced autophagy may mean less efficient clearance of dysbiotic bacteria. During fasting periods, autophagy is upregulated — another reason OMAD/fasting benefits him specifically.
• Celiac: Ruled out genetically. Gluten is not a concern from an autoimmune standpoint (may still cause non-celiac symptoms, but that’s not genetic).
• Psoriasis-gut axis: His psoriatic SNPs (HLA-C*06:02, IL-23R wildtype) connect to gut inflammation via the IL-23/IL-17 axis. Psoriasis is increasingly recognized as a systemic disease with gut microbiome involvement. His fasting and fish oil are addressing this axis.

Practical:

• Fasting/OMAD is genetically appropriate — upregulates autophagy (compensating for ATG16L1 het)
• Probiotic foods (fermented vegetables, etc.) may support Bifidobacterium given secretor status
• Celiac is ruled out — no need for gluten avoidance on genetic grounds
• The charred meat caution (from NAT2 slow + 8q24 GG) applies here too — heterocyclic amines from charring affect gut epithelium