The Impact of Partial and Complete Loss-of-Function Mutations in Endothelial Lipase on High-Density Lipoprotein Levels and Functionality in Humans

Singaraja, Roshni R.; Sivapalaratnam, Suthesh; Hovingh, Kees; Dubé, Marie‐Pierre; Castro-Perez, José; Collins, Heidi L.; Adelman, Steven J.; Riwanto, Meliana; Manz, Jasmin; Hubbard, Brian K.; Tietjen, Ian; Wong, Kenny K.; Mitnaul, Lyndon J.; Heek, Margaret van; Lin, Linus; Roddy, Thomas A.; McEwen, Jason; Dallinge-Thie, Geesje; Zee, Leonie van Vark-van der; Verwoert, Germaine C.; Winther, Michael D.; Duijn, Cornelia M. van; Hofman, Albert; Trip, Mieke D.; Marais, A. David; Asztalos, Bela F.; Landmesser, Ulf; Sijbrands, Eric J.G.; Kastelein, John J.P.; Hayden, Michael R.

doi:10.1161/circgenetics.111.962613

Cited by 57 publications

(48 citation statements)

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“…HDL (n=95), non-HDL (n=100), genome-wide association studies (GWAS; n=97), and non-GWAS (n=98) lipid genes are defined in Table I in the online-only Data Supplement. Size and the number of rare variants identified in each subset of the lipid geneset are presented in Table VIII in the online-only Data Supplement. by guest on May 11, 2018 http://atvb.ahajournals.org/ Downloaded from the established HDL genes are casually related to the extreme HDL-C phenotypes in our patient cohort and that, consistent with previous studies, 9,11,29 most of the affected individuals did not have a rare variant in a well-established HDL gene.…”

Section: Rare Variants In Established Hdl Genes Are Casually Related supporting

confidence: 91%

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Evidence of a Polygenic Origin of Extreme High-Density Lipoprotein Cholesterol Levels

Motazacker

Peter

Treskes

et al. 2013

ATVB

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Objective-There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL-C phenotypes. Approach and Results-We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid-unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). The extreme HDL cohort carried more rare nonsynonymous variants in the lipid geneset than both the general population (odds ratio, 1.39; P=0.019) and normal HDL-C (odds ratio, 1.43; P=0.040) cohorts. The prevalence of such variants in the lipid-related and lipid-unrelated genesets was similar in the control groups, indicative of equal mutation rates. In the extreme HDL cohort, however, there was enrichment of rare nonsynonymous variants in the lipid versus the control geneset (odds ratio, 2.23; P<0.0001), and 70% of the lipidrelated variants altered conserved nucleotides. The lipid geneset comprised 4 nonsense, 10 splice-site, and 8 coding indel variants, whereas the control geneset contained only 1 such variant. In the lipid geneset, 87% and 28% of the patients carried ≥2 and ≥5 rare variants. Correspondence to Mohammad Mahdi Motazacker, PhD, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands. E-mail m.m.motazacker@amc.uva.nl; or Jan A. Kuivenhoven, PhD, Molecular Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands. E-mail j.a.kuivenhoven@umcg.nl Conclusions-This Evidence of a Polygenic Origin of Extreme High-DensityLipoprotein Cholesterol Levels 14,20 Since the start of large-scale GWAS in 2008 until to date, the number of candidate genes associated with plasma lipid phenotypes has steadily increased. These studies have underscored that most candidate genes affect multiple lipoprotein traits, and this is especially true for genes affecting HDL and triglyceride (TG) metabolism. 16 With this in mind, we set out to assess the burden of rare variants in 195 lipid-associated genes in individuals with HDL-C levels in the range observed in heterozygotes for Mendelian disorders of HDL metabolism. Materials and MethodsMaterials and Methods are available in the online-only Supplement. We studied 40 individuals with very low and 40 with very high HDL-C levels (<1 st and >99 th percentile for age and gender) from general patient population in the center of the Netherlands. Written informed consent was obtained and the study protocol was approved by the IRB. Coding sequence and exon-intron boundaries of 195 lipid-re...

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Section: Rare Variants In Established Hdl Genes Are Casually Related supporting

confidence: 91%

“…by guest on May 11, 2018 http://atvb.ahajournals.org/ Downloaded from readily clarified. For example, 2 splice-site variants in APOC3 most probably gave rise to increased HDL-C in these patients as a direct consequence of enhanced lipoprotein lipase-mediated plasma triglyceride hydrolysis.…”

Section: Rare Variants In Genes Not Directly Associated With Hdl Metamentioning

confidence: 99%

Evidence of a Polygenic Origin of Extreme High-Density Lipoprotein Cholesterol Levels

Motazacker

Peter

Treskes

et al. 2013

ATVB

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“…80 Like HL, EL has also been shown to be capable of bridging HDL and other lipoproteins with cell surface proteoglycans. 202 An association between LIPG variation and HDL-C levels has been confirmed through GWAS, 77,203 and several studies suggest that mechanisms underlying the associations between the LIPG SNPs and HDL metabolism may involve loss of function 204 as well as impaired secretion of EL, both resulting in elevated levels of HDL-C. 205 Singaraja et al 206 identified and functionally characterized several partial and complete lossof-function LIPG mutations. Their impact on HDL-C is directly related to their effect on loss of EL function, supporting the hypothesis that antagonism of EL function would provide cardioprotection.…”

Section: Endothelial Lipasementioning

confidence: 94%

Mendelian Disorders of High-Density Lipoprotein Metabolism

Oldoni

Sinke

Kuivenhoven

2014

Circulation Research

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High-density lipoproteins (HDLs) are a highly heterogeneous and dynamic group of the smallest and densest lipoproteins present in the circulation. This review provides the current molecular insight into HDL metabolism led by articles describing mutations in genes that have a large affect on HDL cholesterol levels through their roles in HDL and triglyceride metabolism. Using this information from both human and animal studies, it is discussed how HDL is produced, remodeled in the circulation, affected by factors that control the metabolism of triglyceride-rich lipoproteins, how it helps maintain cellular cholesterol homeostasis, and, finally, how it is catabolized. It can be concluded that HDL cholesterol as a trait is genetically heterogeneous, with as many as 40 genes involved. In most cases, only heterozygotes of gene variants are known, and HDL cholesterol as a trait is inherited in an autosomal-dominant manner. Only 3 Mendelian disorders of HDL metabolism are currently known, which are inherited in an autosomal-recessive mode. an overview of the knowledge that has been obtained through mutations (or targeted disruption) of these genes and illustrates the current molecular details of HDL anabolism, conversion, and catabolism. The Table summarizes how mutations in these genes may affect atheroclerosis. TerminologyDefinitions of HDL and HDL-C The mobilization of cellular cholesterol by HDL, the transport of cholesterol by HDL in the circulation, and the hepatic uptake of HDL-C are generally considered as key to the function of this lipoprotein class. However, from a biochemical perspective, HDL-C is a mere figure indicating how much cholesterol is carried by the pool of HDL in blood. Unfortunately, the terms HDL and HDL-C are often used interchangeably. This leads to confusion and sometimes wrong interpretations. In the lay literature, HDL-C is often typed as the good cholesterol, suggesting that cholesterol is beneficial as long as it is in HDL that diverts from the multiple functions that are attributed to HDL that has little if nothing to do with its cholesterol component. In this review, HDL is used when either the particle or the pool of circulating HDL is meant, whereas HDL-C refers to the free cholesterol (FC) and cholesteryl ester (CE) carried by HDL in the circulation. HDL deficiency indicates that HDL and, therefore, HDL-C are (close to) absent. In an attempt to be comprehensive, we have combined genetic insights from both animal and human studies. Finally, the terms hypoalphalipoproteinemia and hyperalphalipoproteinemia are used when HDL-C concentrations are <10th percentile or >90th percentile for age and sex, respectively. Reverse Cholesterol Transport and Cellular Cholesterol HomeostasisReverse cholesterol transport is generally used to describe the transport of cholesterol by HDL from the vascular wall to the liver for excretion into bile as neutral sterol or bile acid. Despite ≈50 years of research, there is, as of yet, little evidence that HDL can transport cholesterol from the vessel...

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“…The heterogeneity of the vascular effects of HDL may be attributed to changes in the HDL-associated proteome and lipids, i.e., posttranslational protein modifi cations and changes in the amount and type of proteins and lipids bound to the HDL particle. In particular, HDL is susceptible to oxidation/ modifi cation in vitro by a variety of oxidants, such as metal with a reduced risk of coronary disease or myocardial infarction, although this does not apply for all associations [e.g., cholesteryl ester transfer protein (CETP )], and for some genes remains inconclusive ( 20,21 ).…”

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confidence: 99%

High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease

Riwanto

Landmesser

2013

Journal of Lipid Research

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The Impact of Partial and Complete Loss-of-Function Mutations in Endothelial Lipase on High-Density Lipoprotein Levels and Functionality in Humans

Cited by 57 publications

References 44 publications

Evidence of a Polygenic Origin of Extreme High-Density Lipoprotein Cholesterol Levels

Evidence of a Polygenic Origin of Extreme High-Density Lipoprotein Cholesterol Levels

Mendelian Disorders of High-Density Lipoprotein Metabolism

High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease

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