Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

Abifadel, Marianne; Varret, Mathilde; Rabès, Jean-Pierre; Allard, Delphine; Ouguerram, Khadija; Devillers, Martine; Cruaud, Corinne; Benjannet, Suzanne; Wickham, L. Alexandra; Erlich, D.; Derré, Aurélie; Villéger, Ludovic; Farnier, Michel; Beucler, I.; Bruckert, Éric; Chambaz, Jean; Chanu, B.; Lecerf, Jean‐Michel; Luc, Gérald; Moulin, Philippe; Weissenbach, Jean; Prat, Annik; Krempf, Michel; Junien, Claudine; Seidah, Nabil G.; Boileau, Cathérine

doi:10.1038/ng1161

Cited by 2,570 publications

(1,667 citation statements)

References 6 publications

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“…PCSK9 is the most established one, since it has been known for more than a decade that gain‐of‐function and loss‐of‐function variants in the PCSK9 gene increase (Abifadel et al , 2003) and decrease (Cohen et al , 2006) the risk of CAD and MI, respectively. GWAS also identified an association between common variants in the PCSK9 gene and both cholesterol levels (Teslovich et al , 2010) and CAD (Myocardial Infarction Genetics Consortium et al , 2009).…”

Section: Novel Therapeutics In Lipid Metabolismmentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

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Section: Novel Therapeutics In Lipid Metabolismmentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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“…PCSK9 was found to be expressed mostly in liver hepatocytes, and the localization of its gene was linked to autosomal dominant hypercholesterolaemia (ADH) 7. Shortly thereafter, PCSK9 has emerged as a genetically validated target for regulating plasma low‐density lipoprotein (LDL) cholesterol (LDL‐C) levels via hepatic low‐density lipoprotein receptor (LDLR) degradation 8, 9.…”

Section: Introductionmentioning

confidence: 99%

Enhanced pro‐protein convertase subtilisin/kexin type 9 expression by C‐reactive protein through p38MAPK‐HNF1α pathway in HepG2 cells

Cui

Zhu

et al. 2016

J Cellular Molecular Medi

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Plasma C‐reactive protein (CRP) concentration is associated positively with cardiovascular risk, including dyslipidemia. We suggested a regulating role of CRP on pro‐protein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low‐density lipoprotein (LDL) metabolism, and demonstrated the PCSK9 as a pathway linking CRP and LDL regulation. Firstly, experiments were carried out in the presence of human CRP on the protein and mRNA expression of PCSK9 and LDL receptor (LDLR) in human hepatoma cell line HepG2 cells. Treatment with CRP (10 μg/ml) enhanced significantly the mRNA and protein expression of PCSK9 and suppressed the expression of LDLR. Of note, a late return of LDLR mRNA levels occurred at 12 hrs, while the LDLR protein continued to decrease at 24 hrs, suggesting that the late decrease in LDLR protein levels was unlikely to be accounted for the decrease in LDL mRNA. Secondly, the role of PCSK9 in CRP‐induced LDLR decrease and the underlying pathways were investigated. As a result, the inhibition of PCSK9 expression by small interfering RNA (siRNA) returned partly the level of LDLR protein and LDL uptake during CRP treatment; CRP‐induced PCSK9 increase was inhibited by the p38MAPK inhibitor, SB203580, resulting in a significant rescue of LDLR protein expression and LDL uptake; the pathway was involved in hepatocyte nuclear factor 1α (HNF1α) but not sterol responsive element‐binding proteins (SREBPs) preceded by the phosphorylation of p38MAPK. These findings indicated that CRP increased PCSK9 expression by activating p38MAPK‐HNF1α pathway, with a certain downstream impairment in LDL metabolism in HepG2 cells.

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“…The relevance of PCSK9 to coronary heart disease was determined from human genetic studies that identified gain‐of‐function mutations in the PCSK9 gene associated with elevated serum LDL‐C levels and premature coronary heart disease 24, 25, 26. Conversely, loss‐of‐function PCSK9 mutations are associated with lower serum LDL‐C levels, lower lifelong exposure of vascular structures to LDL, and marked reduction of risk of coronary heart disease 27, 28, 29.…”

Section: Mechanism Of Action Of Pcsk9 Inhibitorsmentioning

confidence: 99%

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

Handelsman

Lepor

2018

JAHA

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Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

Cited by 2,570 publications

References 6 publications

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

Enhanced pro‐protein convertase subtilisin/kexin type 9 expression by C‐reactive protein through p38MAPK‐HNF1α pathway in HepG2 cells

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

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