Novel Polymorphisms in Promoter Region of ATP Binding Cassette Transporter Gene and Plasma Lipids, Severity, Progression, and Regression of Coronary Atherosclerosis and Response to Therapy

Lutucuta, Silvia; Ballantyne, Christie M.; Elghannam, Hesham; Gotto, Antonio M.; Marian, Ali J.

doi:10.1161/hh0901.090301

Cited by 93 publications

(57 citation statements)

References 13 publications

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“…Recently, the polymorphisms in the promoter region of ABCA1, which corresponds to C()559)T in the present study and seems to be in tight linkage with G()273)C (r 2 =1, D¢-value=1), was found to be modestly, but not significantly (P=0.09), associated with the HDL-C level using LCAS subjects (Lutucuta et al 2001). The effect of the ABCA1 G()273)C polymorphism on the HDL-C level was significant, but still relatively weak (r 2 =0.0050).…”

Section: Discussionsupporting

confidence: 50%

“…The effect of the ABCA1 G()273)C polymorphism on the HDL-C level was significant, but still relatively weak (r 2 =0.0050). Accordingly, the sample size (n=372) in the previous study (Lutucuta et al 2001) seems to have been too small to detect the effect of polymorphisms on the HDL-C level clearly.…”

Section: Discussionmentioning

confidence: 84%

“…Patients with TD show characteristic HDL deficiency, defective apolipoprotein-mediated phospholipid and cholesterol efflux from cells, and the accumulation of macrophage foam cells in various tissues, including arteries (Clifton-Bligh et al 1972). Recent epidemiological studies have reported that ABCA1 polymorphisms were associated with the HDL-C level (Wang et al 2000;Clee et al 2001;Lutucuta et al 2001;Harada et al 2003). However, few of these findings have been replicated, and there are inconsistencies among previous association studies.…”

Section: Introductionmentioning

confidence: 99%

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A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

et al. 2004

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To investigate the effects of polymorphisms in the ATP-binding cassette transporter A1 (ABCA1) gene on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI), we performed association studies. Sequence analysis identified 14 polymorphisms in the promoter region of ABCA1. After considering linkage disequilibrium, three polymorphisms in the promoter region and 11 polymorphisms from the JSNP database were determined in 1,880 subjects recruited from the Suita Study, representing the general population in Japan. We evaluated the association between the ABCA1 genotype and HDL-C level adjusted not only for standard factors, but also for genetic factors including ApoA1 and ApoE genotypes. Of the 14 polymorphisms tested, the G()273)C (P=0.0074), C()297)T (P=0.0195), and IMS-JST071749(P=0.0093) polymorphisms were significantly associated with the HDL-C level in the Suita population. We could reconfirm that the G()273)C genotype was influential in another set of subjects (P=0.0310, n=743). However, the distribution of the ABCA1 G()273)C genotype in subjects with MI (n=598) was not different from that in the control population (n=801). These results indicate that ABCA1 G()273)C has a significant effect on the HDL-C level in the general Japanese population, but not on the incidence of MI.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

et al. 2004

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“…We analyzed the frequency distribution of the 584C͞T SNP in a well characterized population from the LCAS (20). The LCAS and selected substudies have been published (27)(28)(29).…”

Section: El Sequence Variants Are Associated With Plasma Hdl Cholestementioning

confidence: 99%

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Çilingiroğlu

Otvos

et al. 2003

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

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216

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High-density lipoprotein (HDL) protects against atherosclerosis. Endothelial lipase (EL) has been postulated to be involved in lipoprotein, and possibly HDL, metabolism, yet the evidence has been scarce and conflicting. We have inactivated EL in mice by gene targeting. EL ؊/؊ mice have elevated plasma and HDL cholesterol, and increased apolipoproteins A-I and E. NMR analysis reveals an abundance of large HDL particles. There is down-regulation of the transcripts for phospholipid transfer protein, but up-regulation of those for hepatic lipase and lipoprotein lipase. Plasma lecithin:cholesterol acyltransferase is unchanged despite an increase in hepatic mRNA; lecithin:cholesterol acyltransferase activity toward endogenous EL ؊/؊ substrate is, however, reduced by 50%. HDL clearance is decreased in EL ؊/؊ mice; both the structure of HDL and the presence of EL are factors that determine the rate of clearance. To determine EL's role in humans, we find a significant association between a single-nucleotide polymorphism 584C͞T in the EL (LIPG) gene and HDL cholesterol in a well characterized population of 372 individuals. We conclude that EL is a major determinant of HDL concentration, structure, and metabolism in mice, and a major determinant of HDL concentration in humans.lipoprotein metabolism ͉ atherosclerosis ͉ gene targeting

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“…A contribuição relativa de cada uma dessas fontes para o colesterol plasmático é variável e depende de fatores fisiológicos, como predisposição genética e peso corpóreo, e terapêuticos (BAYS et al, 2008 O gene que codifica a ABCA1 está localizado no cromossomo 9 e é composto por 50 éxons, 49 dos quais são codificadores da proteína (SANTAMARINA-FOJO et al, 2000). O polimorfismo de nucleotídeo único (SNP) -477C>T do ABCA1 foi associado com diferenças nas concentrações de apo AI em indivíduos tratados com fluvastatina (LUTUCUTA et al, 2001). Por outro lado, em indivíduos holandeses tratados com pravastatina não houve associação entre o SNP ABCA1 -14C>T e progressão de aterosclerose (ZWARTS et al, 2002).…”

Section: Hdl E O Transporte Reverso Do Colesterolunclassified

Efeito de hipolipemiantes sobre a expressão de genes envolvidos no transporte reverso do colesterol

Genvigir¹

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The efficacy of statins in reducing the risk of coronary events is not completely explained by their effects in decreasing cholesterol low-density lipoprotein (LDL-C). One of their additional effects may result from the change in concentration of highdensity lipoprotein (HDL), recognized as atheroprotective, mainly for the role in reverse cholesterol transport (RCT). The membrane transporters, as ATP-binding cassette, ABCA1 and ABCG1, and scavenger receptor BI (SRBI) are important proteins involved in the RCT and their genes are regulated by various transcription factors, including the liver-X-receptors (LXRs) . In order to evaluate the effects of lipid lowering on expression of ABC transporters and SRBI receptor, the mRNA expression of ABCA1, ABCG1, SCARB1, NR1H3 (LXRα) and NR1H2 (LRXβ) was assessed by real time PCR in HepG2 (hepatic origin) and Caco-2 (intestinal origin) cells treated with atorvastatin or simvastatin (10 µM) and/or ezetimibe (up to 5 µM) for 24 hours. Furthermore, the expression of these genes was evaluated in peripheral blood mononuclear cells (PBMC) of 50 normolipidemic (NL) and 71 hypercholesterolemic (HC) patients treated with atorvastatin (10mg/d/4 weeks, n = 48) or simvastatin and/or ezetimibe (10mg/d/4 or 8 weeks, n = 23). The possible association between ABCA1 C-14T and R219K polymorphisms and mRNA expression in PBMC was also evaluated by PCR-RFLP. SCARB1 was the most expressed in HepG2 and Caco-2 cells, followed by NR1H2, NR1H3, ABCG1 and ABCA1 in HepG2 or by ABCG1 and ABCA1 in Caco-2. The treatment with statins (1 or 10 µM) or ezetimibe (5 µM) for 12 or 24 hours, increased mRNA expression of ABCG1 but not ABCA1 and SCARB1 in HepG2 cells. Moreover, in HepG2 cells, atorvastatin also upregulated NR1H2 and NR1H3 only at 10.0 µM, meanwhile ezetimibe downregulated NR1H2 but did not change NR1H3 expression. In Caco-2 cells, atorvastatin or simvastatin treatment for 12 or 24 hours reduced the amount of ABCA1 transcript and did not alter the ABCG1 and SCARB1 expressions, despite the tendency to decrease ABCG1 mRNA expression after simvastatin treatment (p = 0.07). After treatment with ezetimibe alone (up to 5 µM) no change in mRNA expression was observed in Caco-2 cells; however, after 24 hours-simvastatin and ezetimibe treatments decreased the transcription of ABCA1 and ABCG1, but not of SCARB1. Unlike cell lines, in PBMC, NR1H2 and ABCG1 were the most expressed, followed by SCARB1 and ABCA1 and finally by the NR1H3. HC patients showed higher NR1H2 and NR1H3 basal expressions, but not of other genes, compared to NL (p <0.05). Moreover, in HC individuals, the ABCA1 basal expression was higher in individuals carrying -14T allele of -14C> T polymorphism when compared with -14CC carriers (p = 0.034). Treatment with statins, ezetimibe, or combined therapy downregulated ABCA1 and ABCG1 expression. For SCARB1, NR1H2 and NR1H3, no change in mRNA expression in PBMC was detected after treatments. After all phases of treatment, ABCA1 and ABCG1 as well as NR1H2 and NR1H3 were significantly corre...

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Novel Polymorphisms in Promoter Region of ATP Binding Cassette Transporter Gene and Plasma Lipids, Severity, Progression, and Regression of Coronary Atherosclerosis and Response to Therapy

Cited by 93 publications

References 13 publications

A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Efeito de hipolipemiantes sobre a expressão de genes envolvidos no transporte reverso do colesterol

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