Parking these articles in advance of the Improve-It trial results on ezetimibe and effects of this enterocyte NPC1L1 inhibitor on cardiac events in ACS patients. I am not aware of confirmed NPC1L1 inactivating mutations.
Obviously a rationale for believing in PCSK9 cardiac outcomes trials are the human genetics situations. Human genetics, along with the loss of function and gain of function mutations can be a reason to predict pharmacological effects of an inhibitor or antibody sequestering agent.
N Engl J Med. 2006 Mar 23;354(12):1264-72.
Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
Cohen JC1, Boerwinkle E, Mosley TH Jr, Hobbs HH.
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Abstract
BACKGROUND:A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.
METHODS:We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.
RESULTS:Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).
CONCLUSIONS:These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
Copyright 2006 Massachusetts Medical Society.
Am J Hum Genet. 2006 Sep;79(3):514-23. Epub 2006 Jul 18.
Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.
Zhao Z1, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH.
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Abstract
Elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) play a central role in the development of atherosclerosis. Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) that are associated with lower plasma levels of LDL-C confer protection from coronary heart disease. Here, we show that four severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wild-type PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the circulation and identified the first known individual who has no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for two inactivating mutations in PCSK9, had a strikingly low plasma level of LDL-C (14 mg/dL). The very low plasma level of LDL-C and apparent good health of this individual demonstrate that PCSK9 plays a major role in determining plasma levels of LDL-C and provides an attractive target for LDL-lowering therapy.
PMID: 16909389 [PubMed - indexed for MEDLINE] PMCID: PMC1559532
Science. 2013 May 10;340(6133):689-90. doi: 10.1126/science.1239101.
Genetics. Simple genetics for a complex disease.
Cohen JC1, Hobbs HH.
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PMID: 23661745 [PubMed - indexed for MEDLINE] PMCID: PMC3839083
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