Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease

In the citing paper

“Proprotein convertase subtilisin-kexin type 9 (PCSK9) promotes degradation of LDL receptors, thereby diminishing the clearance of LDL from the circulation. 6”

In the citing paper

“In 2005, a causative association was established between the presence of loss-of-function mutations in PCSK9 and lifelong reductions in LDL-C associated with lower CHD risk (3).”

In the citing paper

“Genetic studies have shown that carriage of PCSK9 loss-of-function alleles is associated with lower LDL cholesterol levels and a reduced risk of myocardial infarction.7,8”

In the citing paper

“These data suggest that drugs that ultimately reduce LDL-C level predominantly through upregulation of LDL receptor expression should, barring any off-target adverse effects, lead to clinical benefit in proportion to the degree of LDL-C reduction.64”

In the citing paper

“Some of the most important human metabolic disease genes have been identified using germline genetic methods such as GWAS and whole exome sequencing42-44.”

In the citing paper

“Unlike gain-of-function PCSK9 variants (7), loss-of-function (LOF) variants enhance LDLR levels and promote LDLc clearance (4, 8).”

In the citing paper

“mutations conveying gain or loss of function of PCSK9 result in a higher or lower level of LDL cholesterol, respectively, which in turn is associated with a corresponding higher 7 or lower 6 risk of incident coronary heart disease.”

In the citing paper

“Whereas PCSK9 loss-of-function mutations carriers with lifelong reductions in LDL-C and coronary heart disease incidence, were not initially found at significantly reduced risk of stroke (3, 72), a much larger study of the UK Biobank database described the first genetic evidence of a protective effect of the R46L loss-of-function mutation on PCSK9 on ischemic stroke (73).”

In the citing paper

“and that lowering LDL-C reduces the risk of ASCVD proportionally to the absolute achieved reduction in LDL-C [2,51].”

In the citing paper

“The remarkable consistency among these studies, in addition to biological and experimental evidence, provides compelling evidence that LDL-C is causally associated with the risk of ASCVD”

In the citing paper

“Both studies had relatively short follow-up periods and the evidence from statin trials indicates that the clinical benefits of LDL-lowering may only emerge after about 1 year [51], so these trials may have underestimated the potential impact of longer-term treatment [120,290].”

In the citing paper

“These developments have enabled researchers to bridge the gap between the monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes contributing to the variable expression of rare, large-effect alleles26,93, and low-frequency and rare variants that influence common multifactorial traits94,95.”

In the citing paper

“At the same time, it has become increasingly evident now that not only the magnitude of LDL-C lowering is important but that the duration of exposure to elevated LDL-C levels is equally important [11,16,38].”

In the citing paper

“Additionally, increasing evidence also suggests that the duration of exposure to low LDL-C levels may be as important as the magnitude of LDL-C lowering [11][12][13][14][15][16].”

In the citing paper

“The exceptionally low rates of CV events observed in patients carrying mutations in PCSK9 or other similar genes despite only modestly low LDL-C levels strongly support this notion [11].”

In the citing paper

“Hobbs and Cohen sequenced the gene (126, 127) and identified low-frequency common variants (0.5 to 1%), which allowed epidemiological research documenting a protective effect on myocardial infarction (128).”