I’m continuing my deep dives into the genetic pathways to get actionable insights as the previous ones have been incredible precise and useful. This time I’m looking at lipoprotein (lipid) genetic pathways.
Here is the general description of the pathways and their variants. I will put the finding about my own genome below it as an example of what useful and actionable insights you can get.
Lipoprotein_Pathway_Reference.pdf (565.8 KB)
Lipoprotein Genetic Profile — Top 10 Findings
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PCSK9 rs505151 (E670G) homozygous gain-of-function is confirmed across the full haplotype (rs505151 + rs562556 + rs662145 all homozygous). This is the dominant lipid-genetic finding and explains why aggressive LDLR-preservation therapy is mechanistically warranted. Discuss: is current LDL-C 48 / ApoB 50 the target, or should it go lower given the genotype?
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MYLIP/IDOL rs9370867 (N342S) homozygous is a second independent LDLR-degradation hit — compounds the PCSK9 finding by degrading LDLR intracellularly as well as at the surface. Discuss: this strengthens the case for LDLR-preservation drugs (ezetimibe, PCSK9 mAbs) over pure synthesis blockade.
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NPC1L1 rs41279633 (p.R406X) heterozygous — rare protective loss-of-function (~0.15% European frequency). Genetically equivalent to a “lifetime ezetimibe carrier.” Helps explain the exceptional LDL-C achieved on modest rosuvastatin dose. Discuss: this finding independently validates keeping ezetimibe in the regimen indefinitely; it is synergistic with the drug.
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APOA5 rs662799 (-1131T>C) homozygous risk — but TG is only 59 mg/dL. The genotype predicts elevated TG and CHD risk; the current regimen (particularly ~2.8 g/day omega-3 + tirzepatide + empagliflozin) is phenotypically overriding it. Discuss: the omega-3 dose is genetically well-justified and should not be reduced. If any TG-affecting agent is ever stopped, expect TG to rise more than average.
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**SLCO1B1 5 (rs4149056) absent + 1B heterozygous present → favorable statin pharmacogenomics. Genetic risk of statin myopathy is below population baseline. LILRB5 also absent. Discuss: no need for special myopathy surveillance; standard CK monitoring is sufficient.
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PNPLA3 I148M heterozygous + MTTP -493G>T heterozygous = hepatic lipid retention signature. The liver is genetically biased to retain lipid rather than export it. Serum lipids may underestimate total lipid burden. Discuss: add FibroScan / transient elastography at baseline and every 1–2 years; consider MRI-PDFF once for baseline hepatic fat quantification. Add vitamin E 200–400 IU if not already in the Momentous Multi.
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APOE is ε3/ε3 (both rs429358 and rs7412 reference). Neutral reference isoform — no ε4 elevated LDL/Alzheimer’s risk, no ε2 dysbetalipoproteinemia risk. Discuss: favorable finding that simplifies interpretation.
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LPA locus is genetically clean (rs10455872 and rs3798220 both absent), consistent with measured Lp(a) 13 nmol/L. Lp(a) is ~90% heritable and stable for life. Discuss: one confirmatory Lp(a) measurement and then it can be removed from routine monitoring. Substantial protective finding that requires no intervention.
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Strong HDL-favorable CETP signature (rs708272 hom + rs3764261 hom + rs5882 het + rs183130 hom) — explains HDL-C 69. Discuss: this is explanatory, not prognostic. No HDL-raising interventions needed. Keep focus on ApoB/LDL axis where the genetic vulnerabilities are.
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Forward-planning: PCSK9 monoclonal antibody (evolocumab/alirocumab) is the most mechanistically aligned future option if LDL-C/ApoB targets become more aggressive, if current regimen tolerance changes, or if secondary prevention goals escalate. Directly neutralizes the specific overactive protein identified in finding #1. Discuss: not needed at current LDL-C 48 / ApoB 50, but it is the obvious escalation path.
Bonus items (if time permits)
- CYP2C9*2 heterozygous (rs1799853) — minor relevance for current rosuvastatin (~10% CYP2C9 metabolism) but flag for any future warfarin, NSAID, or fluvastatin prescribing.
- *CYP3A5*3/3 — standard European non-expressor; no action needed, but flag for any future simvastatin/atorvastatin switch.
- UGT2B7*2 homozygous — modest effect on bempedoic acid glucuronidation; no dose change needed.
- Dual COQ2 heterozygous variants — weak biological rationale for continued ubiquinol; consider increasing from 100 mg EOD to 100–200 mg daily.
- Dual ABCG8 heterozygous variants — mild enterocyte cholesterol absorption increase; well-targeted by current ezetimibe.
Not issues to worry about
- Statin myopathy risk (SLCO1B1*5, LILRB5, GATM all clear or favorable)
- Rosuvastatin overexposure (ABCG2 Q141K absent)
- Lipoprotein(a) burden (measured low, genotype supports it)
- APOE ε4 risk or ε2 dysbetalipoproteinemia (both absent)
- Genetic blunting of statin response (HMGCR response variants absent)