In Familial hypercholesterolaemia OMIM 143890 (PCSK9, OMIM 143890), the master switch sits on the ↓ DOWN branch ([F] forced below); the healthy state is the OFF well. The forced corrective direction is to lower s toward OFF branch (polarity: clear). Classification: ✓ Recovers an existing standard. Direction only — no dose, no efficacy magnitude.
The disease maps to an R19 double-well whose corrective lever is read straight off the cusp (barrier 0.5396, γ 1.4691, spinodal 0.6854). The corrective direction is forced [F]; the agent names below are direction-concordant labels at grade [O] (no dose, no efficacy or safety magnitude). This is a research hypothesis offered to experts, not medical advice.
The emergence switch
The switch for Familial hypercholesterolaemia OMIM 143890 is an R19 double-well emerged from the real proximal-promoter DNA of PCSK9. Its geometry is fixed by measured stiffness γ (never fitted); the numbers below are read directly off that cusp.
emergent axis
↓ DOWN [F]
healthy branch
OFF
lesion
GOF
γ (stiffness)
1.4691
barrier
0.5396
spinodal
0.6854
s_on / s_off
1.2121 / -1.2121
fragility
0.27
corrective polarity
clear
forced direction
lower s toward OFF branch
Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically harder (barrier 0.5396 at neutral drive; lower barrier = smaller drive to supply). [O] -- no affinity/potency/dose/efficacy asserted.
The derived corrective lever
The cusp forces a corrective direction: lower s toward OFF branch. This is the load-bearing output of the framework — it is [F] forced, and it is falsifiable. 2 lever families are derived; the lead is h-restore (drive modulator).
Mechanism. remove / oppose the drive (clear the accumulating load that pins the disease branch)
Applies to. allele-agnostic (downstream/environmental tilt)
favoured when the switch is fragile -- a small drive shift recrosses the fold
Falsifier. If clearing/opposing the accumulating PCSK9 does NOT relieve the disease branch in a PCSK9 model, the h-restore(clear) lever is refuted for this axis.
EXCLUDED: gain-of-function -- the lesion is not a destabilised healthy product to stiffen; the corrective move is to clear/oppose the toxic drive (h-restore)
Falsifier. If a folding-stabiliser/chaperone does NOT re-deepen the healthy well for a residual PCSK9 allele (no rescue that a null allele lacks), the gamma-restore lever is refuted; null alleles are excluded by construction.
Agents mapped onto the lever
✓ Agreement with established practice. The corrective direction derived here (lower s toward OFF branch) independently matches an agent already in clinical use for this disease: anti-PCSK9 mAb (evolocumab, alirocumab) / PCSK9 siRNA (inclisiran); statin (HMG-CoA reductase inhibitor -> SREBP-2 -> LDLR up-regulation). The geometry recovered known medicine — this is a validation signal for the logic, not a new treatment claim by this kit.
Existing agents whose known action is direction-concordant with the derived lever (status as pinned in the corpus; no dose, no efficacy magnitude).
agent (class)
dir.
status
phase
map
anti-PCSK9 mAb (evolocumab, alirocumab) / PCSK9 siRNA (inclisiran)
Sabatine 2017 NEJM 376:1713 (evolocumab); Ray 2020 NEJM 382:1507 (inclisiran)
Endo 1976 (statin discovery); Brown & Goldstein 1997 (SREBP/LDLR)
decrease
approved
4
✓ in use
⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.
Direction-only candidate leads (corpus join)
Each lead is surfaced only because its known mechanism points the same way as the derived lever, and each comes with a source and a falsifier. None is a treatment.
Mechanism. Inhibits HMG-CoA reductase, depleting intracellular cholesterol and upregulating hepatic LDL-receptor expression so more LDL is cleared from plasma, lowering the atherogenic LDL drive that the PCSK9 gain-of-function (or LDLR loss) elevates. Direction: decrease / lower the pathological LDL-cholesterol drive. Allele scope: agnostic -- lowers LDL downstream of the FH lesion. Pathway-specific to LDL-cholesterol handling (mapped to familial hypercholesterolaemia). Ezetimibe (cholesterol-absorption inhibitor) and bempedoic acid (ATP-citrate lyase inhibitor) are concordant low-cost decrease instances; PCSK9 monoclonal antibodies are the high-cost instance of the same direction.
✓ This is a rediscovery. Statins are the approved, established first-line therapy for familial hypercholesterolaemia; recovered by the direction logic. Low-cost generic, versus high-cost PCSK9 monoclonal antibodies of the same direction.
Safety (qualitative; no magnitude). post-marketing safety profile on record (approved first-line for hypercholesterolaemia including familial hypercholesterolaemia; low-cost generic; qualitative; no magnitude)
Falsifier. If atorvastatin (HMG-CoA reductase inhibitor; statin class) (a pathway decrease agent) clearing/opposing the accumulating load does NOT relieve the DOWN [F] disease branch in a PCSK9 model, the h-restore(clear) direction is refuted for atorvastatin (HMG-CoA reductase inhibitor; statin class) here.
⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.
Evidence & provenance
What is reproduced vs. cited for this page.
element
grade
basis
R19 switch & cusp geometry (this page)
[V] verified
emerged from measured promoter γ of PCSK9; deterministic, 2×sha256 identical
corrective direction
[F] forced
forced by the cusp sign; falsifiable (see lever falsifiers)
mapped agents / leads
[O] open
direction-concordance only; corpus-pinned (2026-06-21); no dose, no efficacy/safety magnitude
Reading the agent column. VALIDATION SIGNAL -- the agent is already approved / established standard for this disease, so the direction logic recovered known clinical practice. Not a new claim by this kit. GENUINE HYPOTHESIS -- no approved indication for this disease; the direction match is a direction-only, untested [O] lead. Basis field grades the evidence (investigational here / in a related condition / off-label / speculative).