Monogenic hypercholesterolemia: new insights in pathogenesis and treatment

Rader, Daniel J.; Cohen, Jonathan C.; Hobbs, Helen H.

doi:10.1172/jci200318925

Cited by 435 publications

(108 citation statements)

References 47 publications

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“…Similar findings were observed for 10 loci for LDL-C, 3 loci for TG and for 9 loci in TC. 24 It is already known that monogenic disorders 25 and rare variants also account for variation in circulating lipid levels. [26][27][28][29][30][31][32] This may help to explain why the explained variance is small compared with the high heritability of the traits, especially as many rarer variants are population specific, and might not have been well represented in our European data set, or not well tagged by the common SNPs under study.…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of circulating lipid levels

et al. 2011

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for the ENGAGE CONSORTIUM Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

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Section: Discussionmentioning

confidence: 99%

Genetic architecture of circulating lipid levels

et al. 2011

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“…Table S9 lists the 11 volunteers who had no apparent disease but had a positive family history of tachycardia, sudden death, and CAD and carried risk alleles. We provide this experience to broaden alertness to both genetic causation and risk of disease for adult-onset cardiovascular disease (58). Of the alleles listed in Tables S8 and S9, 13 alleles were found in HGMD (13,14).…”

Section: Incorporation Of Three-generation Pedigrees Into the Geneticmentioning

confidence: 98%

Personalized genomic disease risk of volunteers

Gonzalez-Garay

McGuire

Pereira

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Replacing traditional methods for genetic testing of inheritable disorders with next-generation sequencing (NGS) will reduce the cost of genetic testing and increase the information available for the patients. NGS will become an invaluable resource for the patient and physicians, especially if the sequencing information is stored properly and reanalyzed as bioinformatics tools and annotations improve. NGS is still at the early stages of development, and it is full of false-positive and -negative results and requires infrastructure and specialized personnel to properly analyze the results. This paper will explain our experience with an adult population, our bioinformatics analysis, and our clinical decisions to assure that our genetic diagnostics were accurate to detect carrier status and serious medical conditions in our volunteers.

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“…The clinical phenotype of these subjects is indistinguishable from two other autosomal dominant forms of hypercholesterolemia, both of which are caused by defective receptor-mediated clearance of LDL: (i) familial hypercholesterolemia, which is caused by mutations in the LDLR; and (ii) familial defective apolipoprotein B (apoB), caused by mutations in the ligand for the LDLR (13). This similarity raised the possibility that PCSK9 somehow lowers the amount or activity of LDLRs in liver.…”

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confidence: 99%

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

Rashid

Curtis

Garuti

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

638

529

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PCSK9 encodes proprotein convertase subtilisin͞kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg͞dl in Pcsk9 ؊/؊ mice versus 96 mg͞dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9 ؊/؊ mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.low-density lipoprotein receptor ͉ lipoproteins ͉ proteinase ͉ sterol regulatory element-binding protein

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Monogenic hypercholesterolemia: new insights in pathogenesis and treatment

Abstract: Familial hypercholesterolemiaHistorical perspective. Familial hypercholesterolemia (FH), the most common and most severe form of monogenic hypercholesterolemia, was the first genetic disease of lipid metabolism to be clinically and

Cited by 435 publications

References 47 publications

Genetic architecture of circulating lipid levels

Genetic architecture of circulating lipid levels

Personalized genomic disease risk of volunteers

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

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