> People with two broken PCSK9 genes have close to zero LDL and have noticeably completely plaque free arteries as adults. I do think this does pretty fatal damage to the theory that you must have some other health issue for LDL to be bad.
i'm not sure i follow this extrapolation from low-ldl individuals to any direct statement about causes and effects at higher ldl levels.
if there was, for instance, some thought-harmless virus endemic to a large portion of the population which somehow caused plaque buildup but only at sufficiently high ldl levels, people with naturally low levels their entire lives would still have plaque free arteries and we would still, as we do, see a broader range of plaque buildup among people with high levels. how do you propose to distinguish this hypothetical (and admittedly most likely biologically incoherent) explanation from yours by only looking at people with naturally low levels?
your assertion that such individuals are an excellent approximation to an experiment on the arterial health effects of lifetime low ldl seems reasonable enough, but you then appear to draw unfounded conclusions about the nature of potential inverse effects at higher ldl levels.
The point I was making re double variants having even more apparent protection is simply that these people continue the dose response curve you expect to see all the way to the extreme low end. Single variant people have massive protection, double variant people have essentially 100%.
You are correct that it doesn't rule out lipids + unknown additional factor(s). However: If there is a mystery factor, it must be close to universal. We know from autopsy studies of non-cardiac deaths that fatty streaks are present in virtually all children and that by 30 most people have advanced fibrous plaques (including soft plaque invisible to calcium score tests). The double variant people don't. So LDL is at minimum a necessary, limiting factor.
It also doesn't exclude that there is some more specific subset of the low density lipids that cause problems (this is what switching to ApoB testing is supposed to get at). Which is actually where we are at in the first place with LDL-C measurement being a refinement over previously looking at total cholesterol.
i'm not sure i follow this extrapolation from low-ldl individuals to any direct statement about causes and effects at higher ldl levels.
if there was, for instance, some thought-harmless virus endemic to a large portion of the population which somehow caused plaque buildup but only at sufficiently high ldl levels, people with naturally low levels their entire lives would still have plaque free arteries and we would still, as we do, see a broader range of plaque buildup among people with high levels. how do you propose to distinguish this hypothetical (and admittedly most likely biologically incoherent) explanation from yours by only looking at people with naturally low levels?
your assertion that such individuals are an excellent approximation to an experiment on the arterial health effects of lifetime low ldl seems reasonable enough, but you then appear to draw unfounded conclusions about the nature of potential inverse effects at higher ldl levels.