Multi-hit model: a glucuronidation defect alone is necessary but not sufficient
u/drwillpowers
r/DrWillPowers2026-04-14T13:22:58Z
Dr Will Powers’ own statements and theorizing
Summary (paraphrased)
Replying to [username removed]'s question about why East Asian populations — with roughly 60–70% homozygous UGT2B17 deletion prevalence — don't show higher PFS rates, Powers states that glucuronidation failure alone is insufficient: it was merely the first statistically visible marker. Genome review shows it must combine with additional defects — sulfation, hydroxylation, ABCC, LRP2, or SLCO defects. The more fragile the baseline system, the more likely PFS becomes. He also mentions an observed slight Asian preponderance in his own patient population, while cautioning that his sample is too small to conclude anything.
Key points (paraphrased)
- Multi-hit model: a glucuronidation defect alone is necessary but not sufficient.
- Required co-defects include sulfation, hydroxylation, ABCC, LRP2, and SLCO variants.
- Baseline fragility gradient determines PFS likelihood.
- Possible Asian preponderance in his practice — flagged as an underpowered observation.
- Directly answers the strongest population-genetics objection to the UGT theory.
Why it’s in the corpus
The multi-hit threshold model — his answer to the strongest epidemiological objection to the UGT-centered theory. Essential for stating the genetics claims precisely: risk-modifier combinations, not single-gene causation.
Context — the post Powers was replying toVerbatim third-party text, shown for context only — not Powers’ statement. Usernames removed.ShowHide
Powers' comment replies to [username removed], who asked how the model reconciles very common UGT2B17 deletion in East Asian populations with the low severe-side-effect rates in large regional finasteride/dutasteride trials — if reduced glucuronidation makes 5α-reductase a critical escape pathway, adverse events should be far more common there.
(Parent context recovered from the r.genit.al mirror on 2026-10-09; Powers' comment text itself is from John's user-provided export.)
Some fields on this page come from the release’s Markdown edition, which carries text the JSON edition omits.
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