Genotypic Effect of ABCG1 Gene Promoter -257T&gt;G Polymorphism on Coronary Artery Disease Severity in Japanese Men

Furuyama, Shoudai; Uehara, Yoshio; Zhang, Bo; Baba, Yasuhiko; Abe, Satomi; Iwamoto, Takahiro; Miura, Shin-ichiro; Saku, Keijiro

doi:10.5551/jat.e380

Cited by 29 publications

(16 citation statements)

References 28 publications

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“…Such a lack of association between ABCG1 SNPs and plasma TC, low-density lipoprotein cholesterol or HDL-cholesterol was in agreement with the analysis of the rs1378577 ABCG1 SNP in a small Japanese population of 109 male patients with coronary artery disease 13 and with a recent study analyzing 2 other ABCG1 SNPs in a large cohort of 1021 Chinese coronary artery disease patients. 22 Consistent with our findings, the absence of Abcg1 in mice was not accompanied by alteration of plasma lipid levels in Abcg1 −/− mice as compared with control animals.…”

Section: Discussionsupporting

confidence: 60%

“…11 Among the 104 SNPs described in the ABCG1 gene, 3 were identified in the 5′ regulatory region, 12 a region which may modulate ABCG1 gene expression. Only the 2 more proximal rs1378577 and rs1893590 SNPs, located at positions −134 (T/G) and −204 (A/C) from the transcription start site (NM_207627.1), respectively, have been reported as functional in either a population of 109 Japanese men with coronary artery disease 13 or in the 1473 Spanish subjects in the Hortega study. 14 To elucidate the potential role(s) of ABCG1 in lipid metabolism in humans, our strategy was, therefore, to determine the genotype of these 2 ABCG1 promoter variants (rs1893590 and rs1378577) in the dyslipidemic population of the lipid-lowering Regression Growth Evaluation Statin Study (REGRESS).…”

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confidence: 99%

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Human ATP–Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation

Olivier

Tanck

Out

et al. 2012

ATVB

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Objective— The physiological function of the ATP–binding cassette G1 (ABCG1) transporter in humans is not yet elucidated, as no genetic disease caused by ABCG1 mutations has been documented. The goal of our study was, therefore, to investigate the potential role(s) of ABCG1 in lipid metabolism in humans. Methods and Results— Here we report that among the 104 polymorphisms present in the ABCG1 gene, the analysis of the frequent functional rs1893590 and rs1378577 single nucleotide polymorphisms located in the regulatory region of ABCG1 in the Regression Growth Evaluation Statin Study population revealed that both ABCG1 single nucleotide polymorphisms were significantly associated with plasma lipoprotein lipase (LPL) activity. Moreover, we observed that plasma LPL activity was modestly reduced in Abcg1 −/− mice as compared with control mice. Adipose tissue and skeletal muscle are the major tissues accounting for levels and activity of plasma LPL in the body. However, beyond its lipolytic action in the plasma compartment, LPL was also described to act locally at the cellular level. Thus, macrophage LPL was reported to promote foam cell formation and atherosclerosis in vivo. Analysis of the relationship between ABCG1 and LPL in macrophages revealed that the knockdown of ABCG1 expression (ABCG1 knockdown) in primary cultures of human monocyte–derived macrophages using small interfering RNAs led to a marked reduction of both the secretion and activity of LPL. Indeed, LPL was trapped at the cell surface of ABCG1 knockdown human monocyte–derived macrophages, likely in cholesterol-rich domains, thereby reducing the bioavailability and activity of LPL. As a consequence, LPL–mediated lipid accumulation in human macrophage foam cells in the presence of triglyceride-rich lipoproteins was abolished when ABCG1 expression was repressed. Conclusion— We presently report that ABCG1 controls LPL activity and promotes lipid accumulation in human macrophages in the presence of triglyceride-rich lipoproteins, thereby suggesting a potential deleterious role of macrophage ABCG1 in metabolic situations associated with high levels of circulating triglyceride-rich lipoproteins together with the presence of macrophages in the arterial wall.

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Section: Discussionsupporting

confidence: 60%

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confidence: 99%

Human ATP–Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation

Olivier

Tanck

Out

et al. 2012

ATVB

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“…[11][12][13] Increased apoB levels and accelerated atherosclerosis on LDLr Variants associated with reduced and increased CAD risk in absence of effects on plasma lipids. 16,17 Cholesterol accumulation in tissues (lung); no effect on plasma lipoprotein levels. 18 Accelerated atherosclerosis in ABCA1 Both rare and common variants are associated with low or high HDL-C levels.…”

Section: Genesmentioning

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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“…28 This polymorphism is located 19 720 base pairs upstream of the ATG start site of the main transcript. In the CCHS, the frequency of the minor allele (G allele) was 0.21 and did not tag the Odds ratios for myocardial infarction and ischemic heart disease in the Copenhagen Ischemic Heart Disease Study (CIHDS) and in the Copenhagen City Heart Study (CCHS) and CIHDS combined.…”

Section: Discussionmentioning

confidence: 99%

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

Schou

Frikke‐Schmidt

Kardassis³

et al. 2012

ATVB

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Objective-ATP binding cassette transporter G1 (ABCG1) facilitates cholesterol efflux from macrophages to mature high-density lipoprotein particles. Whether genetic variation in ABCG1 affects risk of atherosclerosis in humans remains to be determined. Methods and Results-We resequenced the core promoter and coding regions of ABCG1 in 380 individuals from the general population. Next, we genotyped 10 237 individuals from the Copenhagen City Heart Study for the identified variants and determined the effect on lipid and lipoprotein levels and on risk of myocardial infarction (MI) and ischemic heart disease (IHD). g.Ϫ376CϾT, g.-311TϾA, and Ser630Leu predicted risk of MI in the Copenhagen City Heart Study, with hazard ratios of 2.2 (95% confidence interval: 1.2-4.3), 1.7 (1.0 -2.9), and 7.5 (1.9 -30), respectively. These results were confirmed for g.Ϫ376CϾT in a case-control study comprising 4983 independently ascertained IHD cases and 7489 controls. Expression levels of ABCG1 mRNA were decreased by approximately 40% in g.Ϫ376CϾT heterozygotes versus noncarriers (probability values: 0.005-0.009). Finally, in vitro specificity protein 1 (Sp1) bound specifically to a putative Sp1 binding site at position Ϫ382 to Ϫ373 in the ABCG1 promoter, and the presence of the Ϫ376 T allele reduced binding and transactivation of the promoter by Sp1. Key Words: ABC transporter Ⅲ atherosclerosis Ⅲ ischemic heart disease Ⅲ ABCG1 Ⅲ myocardial infarction M acrophages are key elements in the development of atherosclerosis. 1,2 Because these cells are unable to limit their lipid uptake, they rely on efficient cholesterol efflux transporters to prevent lipid accumulation. 3,4 ATP binding cassette transporter G1 (ABCG1) is a transmembrane cholesterol transporter that effluxes cellular cholesterol from macrophages by delivering cholesterol to mature high-density lipoprotein (HDL) particles. 5 As discussed by Westerterp et al, it is controversial whether whole-body Abcg1 knockout mice have increased atherosclerosis. 6 In Abcg1 Ϫ/Ϫ /Apolipoprotein E-deficient mice fed a wild-type diet, atherosclerosis was decreased, 7 whereas in Abcg1 Ϫ/Ϫ mice fed an atherogenic diet, atherosclerosis was increased. 8 Whether genetic variation in ABCG1 affects risk of disease in humans remains to be determined. Conclusion-This is the first report of a functional variant inBecause ABCG1 has been reported to be a key transporter of cholesterol from lipid-poor to mature HDL particles based on in vitro studies, we reasoned that genetic variation in ABCG1 might affect levels of HDL cholesterol in plasma.Therefore, to increase the likelihood of identifying genetic variants with effect on HDL cholesterol, 9,10 we resequenced the core promoter, coding regions, and consensus splice sites of ABCG1 in individuals in the general population with the lowest 2% (nϭ190) and highest 2% (nϭ190) HDL cholesterol levels for age and sex. Next, we genotyped 10 237 individuals from the general population, the Copenhagen City Heart Study (CCHS), for the variants identified, and determine...

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Genotypic Effect of ABCG1 Gene Promoter -257T>G Polymorphism on Coronary Artery Disease Severity in Japanese Men

Cited by 29 publications

References 28 publications

Human ATP–Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation

Human ATP–Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation

Mendelian Disorders of High-Density Lipoprotein Metabolism

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

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