A Common PCSK9 Haplotype, Encompassing the E670G Coding Single Nucleotide Polymorphism, Is a Novel Genetic Marker for Plasma Low-Density Lipoprotein Cholesterol Levels and Severity of Coronary Atherosclerosis

Chen, S.N.; Ballantyne, C.M.; Gotto, Antonio M.

doi:10.1016/j.accreview.2005.09.096

Cited by 46 publications

(80 citation statements)

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“…The p.E670G common SNP accounts for 3.5% of LDL-C level variability, with higher levels with the GG genotype, intermediate with the AG genotype, and lowest with the AA genotype. Plasma total cholesterol, apo B, and lipoprotein a (Lp(a)) levels were also associated with the p.E670G SNP in these populations [Chen et al, 2005]. These associations were not found in the Dallas Heart Study [Kotowski et al, 2006].…”

Section: Impact Of Pcsk9 Variants On Chdmentioning

confidence: 95%

“…Some of them have been associated with low cholesterol levels in association studies done in different populations. Two common SNPs, -161C4T and p.I474 V, were associated with reduced plasma levels in a Japanese sample [Shioji et al, 2004], but not in the Dallas Heart Study [Kotowski et al, 2006] or in Caucasian populations [Chen et al, 2005].…”

Section: Biological Relevancementioning

confidence: 99%

“…This polymorphism c.dup61_63CTG (formerly designated c.43_44insCTG) is an in-frame insertion of one leucine (p.L21dup or p. L15_L16insL) that is common both in African American (allele frequency 0.27) and Caucasian populations (allele frequency 0.143) [Chen et al, 2005;Yue et al, 2006]. This variant was found to be present at higher frequency in a low LDL-C population than in a normal population and to segregate with a hypocholesterolemic phenotype in three hypobetalipoproteinemia families.…”

Section: Biological Relevancementioning

confidence: 99%

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Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

et al. 2009

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Hypercholesterolemia is one of the major causes of coronary heart disease (CHD). The genes encoding the low-density lipoprotein receptor and its ligand apolipoprotein B, have been the two genes classically implicated in autosomal dominant hypercholesterolemia (ADH). Our discovery in 2003 of the first mutations of the proprotein convertase subtilisin kexin 9 gene (PCSK9) causing ADH shed light on an unknown actor in cholesterol metabolism that since then has been extensively investigated. Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD. In this review, we focus on reported variants, and their biological, clinical, and functional relevance. We also highlight the spectrum of hypercholesterolemia or hypobetalipoproteinemia phenotypes that are already associated with mutations in PCSK9. Finally, we present future prospects concerning this therapeutic target that might constitute a new approach to reduce cholesterol levels and CHD, and enhance the effectiveness of other lipid-lowering drugs.

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Section: Impact Of Pcsk9 Variants On Chdmentioning

confidence: 95%

Section: Biological Relevancementioning

confidence: 99%

Section: Biological Relevancementioning

confidence: 99%

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Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

et al. 2009

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“…128 Plasma PCSK9 levels are increased not only in patients with FH but also in patients with Familial Combined Hypercholesterolemia. 129 These suggest that rare missense mutations in PCSK9 may worsen the clinical phenotype of patients carrying LDLR mutations.…”

Section: Natural Mutations Determining Pcsk9 Levelsmentioning

confidence: 99%

Pcsk9

Seidah

Awan

Chrétien³

et al. 2014

Circulation Research

516

197

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“…11 The other three PCSK9 variants have been reported previously as polymorphisms or variants that are likely not linked to LDL cholesterol levels. 12 The presence of two LDLR variants led to the question of whether the variants were present on the same chromosome (ie, in cis) or on different chromosomes (ie, in trans). As the patient was adopted and had no knowledge of her biological parents or other family members, family studies could not be pursued.…”

Section: Resultsmentioning

confidence: 99%

LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

et al. 2008

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Familial hypercholesterolemia (FH) is the most common form of autosomal-dominant hypercholesterolemia, and is caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Heterozygous FH is characterized by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular disease, whereas homozygous FH results in more severe LDL cholesterol elevation with death by 20 years of age. We present here the case of an African-American female FH patient presenting with a myocardial infarction at the age of 48, recurrent angina pectoris and numerous coronary artery stents. Her pretreated LDL cholesterol levels were more typical of a homozygous FH pattern and she was resistant to conventional lipid-lowering treatment, yet her other clinical parameters were not necessarily consistent with homozygous FH. Genetic testing revealed two LDLR variants on the same chromosome: one a novel missense mutation in exon 14 (Cys681Gly) and the other a promoter variant (IVS1-217C4T) previously shown to result in increased LDLR transcription. Disease-associated PCSK9 or APOB mutations were not identified in this individual. Overall, her genetic and clinical profile suggests that enhanced expression of the mutant LDLR allele resulted in a severe phenotype with characteristics of both heterozygous and homozygous FH.

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A Common PCSK9 Haplotype, Encompassing the E670G Coding Single Nucleotide Polymorphism, Is a Novel Genetic Marker for Plasma Low-Density Lipoprotein Cholesterol Levels and Severity of Coronary Atherosclerosis

Cited by 46 publications

References 0 publications

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

Pcsk9

LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

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