Genetic Variation in
            <i>ABCG1</i>
            and Risk of Myocardial Infarction and Ischemic Heart Disease

Schou, Jesper Sølver; Frikke‐Schmidt, Ruth; Kardassis, Dimitris; Thymiakou, Efstathia; Nordestgaard, Børge G.; Jensen, Gorm; Grande, Peer; Tybjærg‐Hansen, Anne

doi:10.1161/atvbaha.111.234872

Cited by 34 publications

(23 citation statements)

References 38 publications

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“…42,43 However, nothing is yet known about an epigenetic impact of ABCG1 on the development of MI. A human cell culture study showed a reduction of macrophage ABCG1 expression when higher triglyceride levels were present in the culture media.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels

Pfeiffer¹,

Wahl²,

Pilling³

et al. 2015

Circ Cardiovasc Genet

166

186

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Background Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. Methods and Results Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (β coefficient=−0.049; P=8.26E-17) and triglyceride levels (β=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06–1.25). Conclusions Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels

Pfeiffer¹,

Wahl²,

Pilling³

et al. 2015

Circ Cardiovasc Genet

166

186

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“…Recent genetic association studies in humans identified functional variants in ABCG1 associated with increased risk of coronary artery disease (Xu et al 2011;Schou et al 2012), suggesting an important role of ABCG1 in the protection from atherosclerosis and cardiovascular disease.…”

Section: Atp-binding Cassette Transporter G1mentioning

confidence: 99%

HDL Biogenesis, Remodeling, and Catabolism

Zannis

Fotakis

Κούκος

et al. 2014

Handbook of Experimental Pharmacology

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In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research.

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“…248 Little is known about the role of ABCG1 in human metabolism. Schou et al 249 reported a functional ABCG1 promoter variant that associates with increased risk of myocardial infarction and ischemic heart disease in the general population but without affecting levels of HDL-C or other lipids or lipoproteins. Abellán et al, 15 however, described a significant association between promoter variant and HDL-C levels.…”

Section: Atp-binding Cassette Transporter G1mentioning

confidence: 99%

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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Genetic Variation in ABCG1 and Risk of Myocardial Infarction and Ischemic Heart Disease

Cited by 34 publications

References 38 publications

DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels

DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels

HDL Biogenesis, Remodeling, and Catabolism

Mendelian Disorders of High-Density Lipoprotein Metabolism

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