Loss-of-function variants in PCSK9 are associated with significantly lower LDL cholesterol levels and protection against cardiovascular disease without increasing the risk of other diseases.

“and these were folks that were walking around with an LDL cholesterol between 10 and 30 milligrams per deciliter and they were completely event free and of course the first a hundred percent but your significant reduction and their reductions I believe we actually went back and did a calculation to see if their reductions how congruent they were with some of the more recent Mendelian randomization and they're very similar and it's not surprising because that's effectively how you would model a reduction a lifetime exposure reduction the thing that interested me cuz I remember at the time like many people unsure I sort of had this concern which is well that if cholesterol levels I mean I'm now realize I was being naive but my concern was God if if your LDL is low that must mean you can't make hormones it must mean that you're gonna get some other awful disease and so the interesting thing to me was those people didn't have any of these other phenotypes they didn't seem to have deficiencies or deficits as a result of that”

“where now you found these people who had the opposite of fh these are people who were basically missing their pcsk9 not completely just significantly underexpressed and these were people that as adults walked around with neonate levels of ldl cholesterol 10 20 30 milligrams per deciliter”

“there are these people walking around with uh ldlc of like 10 to 20 milligrams per deciliter and and these are adults right so you normally we just never see that in adults and they weren't doing anything different right they just like they weren't on some crazy diet or clearly weren't taking any medication”