LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals

Haase, Christiane L; Tybjærg‐Hansen, Anne; Qayyum, Abbas Ali; Schou, Jesper Sølver; Nordestgaard, Børge G.; Frikke‐Schmidt, Ruth

doi:10.1210/jc.2011-1846

Cited by 249 publications

(146 citation statements)

References 38 publications

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“…the LCAT gene as the strongest marker of isolated variation in HDL-C levels (14). This indicates that variants in the LCAT gene associated with levels of HDL-C may be useful for a formal causality test of HDL-C levels for determining the risk of CVDs (15). The genotyping platforms typically used in GWASs include mostly common variants [minor allele frequency (MAF)>0.05] that are unlikely to tag most of the rare variants in the genome or to identify the true causative variant due to the small effect sizes of common variants.…”

Section: Discussionmentioning

confidence: 99%

Identification of genetic variants of lecithin cholesterol acyltransferase in individuals with high HDL-C levels

Naseri

Hedayati

Daneshpour

et al. 2014

Molecular Medicine Reports

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Abstract. Among the most common lipid abnormalities, a low level of high-density lipoprotein-cholesterol (HDL-C) is one of the first risk factors identified for coronary heart disease. Lecithin cholesterol acyltransferase (LCAT) has a pivotal role in the formation and maturation of HDL-C and in reverse cholesterol transport. To identify genetic loci associated with low HDL-C in a population-based cohort in Tehran, the promoter, coding regions and exon/intron boundaries of LCAT were amplified and sequenced in consecutive individuals (n=150) who had extremely low or high HDL-C levels but no other major lipid abnormalities. A total of 14 single-nucleotide polymorphisms (SNPs) were identified, of which 10 were found to be novel; the L393L, S232T and 16:67977696 C>A polymorphisms have been previously reported in the SNP Database (as rs5923, rs4986970 and rs11860115, respectively) and the non-synonymous R47M mutation has been reported in the Catalogue of Somatic Mutations in Cancer (COSM972635). Three of the SNPs identified in the present study (position 6,531 in exon 5, position 6,696 in exon 5 and position 5,151 in exon 1) led to an amino acid substitution. The most common variants were L393L (4886C/T) in exon 6 and Q177E, a novel mutation, in exon 5, and the prevalence of the heterozygous genotype of these two SNPs was significantly higher in the low HDL-C groups. Univariate conditional logistic regression odds ratios (ORs) were nominally significant for Q177E (OR, 5.64; P=0.02; 95% confidence interval, 1.2-26.2). However, this finding was attenuated following adjustment for confounders. Further studies using a larger sample size may enhance the determination of the role of these SNPs.

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Section: Discussionmentioning

confidence: 99%

Identification of genetic variants of lecithin cholesterol acyltransferase in individuals with high HDL-C levels

Naseri

Hedayati

Daneshpour

et al. 2014

Molecular Medicine Reports

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“…These results suggest that low plasma HDL-C concentrations from genetic factors, which account for only approximately 50% of the variation of HDL-C concentrations, do not directly cause MI, particularly when the LDL-C concentration is not increased. Similar to the ABCA1 study, the decrease in HDL-C due to the LCAT SNP would also decrease LDL-C via the CETP pathway (56 ), further complicating the interpretation of these results regarding the role of low plasma HDL concentration and CVD risk.…”

Section: The Evolving Role Of Hdl: Rct and Beyondmentioning

confidence: 96%

“…Further evidence of the lack of support for the efficacy of HDL-C-elevating drugs for the prevention of CVD has been found in recent Mendelian randomization studies, which are observational studies investigating possible causal linkages of genetic polymorphisms with biomarkers like HDL-C, as well as how genetic polymorphisms impact disease (55,56 ). For example, in a study of white individuals from Copenhagen, Denmark, lower plasma concentrations of HDL-C due to heterozygous loss-of-function mutations in the ATP binding cassette subfamily A member 1 (ABCA1) 4 gene were not associated with increased risk of ischemic heart disease, likely because of a concomitant decrease in LDL-C (55 ).…”

Section: The Evolving Role Of Hdl: Rct and Beyondmentioning

confidence: 99%

“…For example, in a study of white individuals from Copenhagen, Denmark, lower plasma concentrations of HDL-C due to heterozygous loss-of-function mutations in the ATP binding cassette subfamily A member 1 (ABCA1) 4 gene were not associated with increased risk of ischemic heart disease, likely because of a concomitant decrease in LDL-C (55 ). Similarly, in a Mendelian randomization study, a lecithincholesterol acyltransferase (LCAT) single nucleotide polymorphism (SNP) associated with decreased plasma HDL-C, in the general population, was not associated with increased risk of myocardial infarction (MI), despite low plasma HDL-C concentrations being robustly associated with increased risk of MI (56 ). These results suggest that low plasma HDL-C concentrations from genetic factors, which account for only approximately 50% of the variation of HDL-C concentrations, do not directly cause MI, particularly when the LDL-C concentration is not increased.…”

Section: The Evolving Role Of Hdl: Rct and Beyondmentioning

confidence: 99%

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The Changing Face of HDL and the Best Way to Measure It

Karathanasis¹,

Freeman

Gordon

et al. 2017

Clinical Chemistry

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BACKGROUND: HDL cholesterol (HDL-C) is a commonly used lipid biomarker for assessing cardiovascular health. While a central focus has been placed on the role of HDL in the reverse cholesterol transport (RCT) process, our appreciation for the other cardioprotective properties of HDL continues to expand with further investigation into the structure and function of HDL and its specific subfractions. The development of novel assays is empowering the research community to assess different aspects of HDL function, which at some point may evolve into new diagnostic tests. CONTENT:This review discusses our current understanding of the formation and maturation of HDL particles via RCT, as well as the newly recognized roles of HDL outside RCT. The antioxidative, antiinflammatory, antiapoptotic, antithrombotic, antiinfective, and vasoprotective effects of HDL are all discussed, as are the related methodologies for assessing these different aspects of HDL function. We elaborate on the importance of protein and lipid composition of HDL in health and disease and highlight potential new diagnostic assays based on these parameters.

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“…The effect of LCAT variations on lipid and lipoprotein levels and the relation between genotypes associated with low HDL-C levels and risk of ischemic cardiovascular diseases were investigated in the following two large prospective studies: The Copenhagen City Heart Study, which started in 1976 and enrolled more than 10,000 participants, and The Copenhagen General Population Study, which started in 2003 and is currently ongoing with more than 50,000 subjects enrolled 38) . Among four common variants in LCAT regulatory and coding regions, only one (S208T) was associated with reduction in HDL-C and apoA-I levels in both studies, without any other association with biochemical markers of inflammation, glucose metabolism, and kidney disease.…”

Section: General Populationmentioning

confidence: 99%

Role of LCAT in Atherosclerosis

Ossoli

Simonelli

Vitali

et al. 2016

J Atheroscler Thromb

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Lecithin:cholesterol acyltransferase (LCAT) is the only enzyme capable of esterifying cholesterol in plasma, thus determining the maturation of high-density lipoproteins. Because it maintains an unesterified cholesterol gradient between peripheral cells and extracellular acceptors, for a long time, LCAT has been considered as a key enzyme in reverse cholesterol transport. However, despite the fact that it has been more than 50 years since the identification of LCAT, the role of this enzyme in the pathogenesis of atherosclerosis is still debated. A number of studies have been conducted in different animal models, with contradictory results. Studies in humans, in particular in the general population, in subjects at high cardiovascular risk, and in carriers of genetic LCAT deficiency in an excellent model to evaluate the correlation between the reduction of LCAT activity and atherosclerosis also gave conflicting results. This review provides a comprehensive overview of the controversial findings obtained in animals and humans, strengthening the necessity of further investigation to establish how LCAT could be regulated in a promising therapeutic strategy to reduce cardiovascular risk.

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LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals

Abstract: Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.

Cited by 249 publications

References 38 publications

Identification of genetic variants of lecithin cholesterol acyltransferase in individuals with high HDL-C levels

Identification of genetic variants of lecithin cholesterol acyltransferase in individuals with high HDL-C levels

The Changing Face of HDL and the Best Way to Measure It

Role of LCAT in Atherosclerosis

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