The effect of ABCA1 gene polymorphisms on ishaemic stroke and relationship with lipid profile

Department of Medicine and Therapeutics, University of Aberdeen, UK.
BMC Medical Genetics (Impact Factor: 2.08). 02/2007; 8(1):30. DOI: 10.1186/1471-2350-8-30
Source: PubMed


Ischaemic stroke is a common disorder with genetic and environmental components contributing to overall risk. Atherothromboembolic abnormalities, which play a crucial role in the pathogenesis of ischaemic stroke, are often the end result of dysregulation of lipid metabolism. The ATP Binding Cassette Transporter (ABCA1) is a key gene involved in lipid metabolism. It encodes the cholesterol regulatory efflux protein which mediates the transfer of cellular phospholipids and cholesterol to acceptor apolipoproteins such as apolipoprotein A-I (ApoA-I). Common polymorphisms in this gene affect High Density Lipoprotein Cholesterol (HDL-C) and Apolipoprotein A-I levels and so influence the risk of atherosclerosis. This study has assessed the distribution of ABCA1 polymorphisms and haplotype arrangements in patients with ischaemic stroke and compared them to an appropriate control group. It also examined the relationship of these polymorphisms with serum lipid profiles in cases and controls.
We studied four common polymorphisms in ABCA1 gene: G/A-L158L, G/A-R219K, G/A-G316G and G/A-R1587K in 400 Caucasian ischaemic stroke patients and 487 controls. Dynamic Allele Specific Hybridisation (DASH) was used as the genotyping assay.
Genotype and allele frequencies of all polymorphisms were similar in cases and controls, except for a modest difference in the ABCA1 R219K allele frequency (P-value = 0.05). Using the PHASE2 program, haplotype frequencies for the four loci (158, 219, 316, and 1587) were estimated in cases and controls. There was no significant difference in overall haplotypes arrangement in patients group compared to controls (p = 0.27). 2211 and 1211 haplotypes (1 = common allele, 2 = rare allele) were more frequent in cases (p = 0.05). Adjusted ORs indicated 40% and 46% excess risk of stroke for these haplotypes respectively. However, none of the adjusted ORs were statistically significant. Individuals who had R219K "22" genotype had a higher LDL level (p = 0.001).
Our study does not support a major role for the ABCA1 gene as a risk factor for ischaemic stroke. Some haplotypes may confer a minor amount of increased risk or protection. Polymorphisms in this gene may influence serum lipid profile.

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    • "In addition, the influence of ABCA1 gene variants on other lipid molecules and enzymes secondarily can mildly influence HDL concentration. Clee SM, Pasdar A and Li J et al. reported downward trend of TG level during RR,RK,KK genotypes and 219 K allele carriers [65,99,100]. This trend was replicated in our population, but no statistically significance found. "
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    ABSTRACT: Objectives Accumulating evidence suggested that dysregulation of cholesterol homeostasis might be a major etiologic factor in initiating and promoting neurodegeneration in Alzheimer's disease(AD). ATP-binding cassette transporter A1(ABCA1)[ideographic comma]hepatic lipase (HL, coding genes named LIPC) and cholesteryl ester transfer protein (CETP) are important components of high-density lipoprotein (HDL) metabolism and reverse cholesterol transport(RCT) implicated in atherosclerosis and neurodegenerative diseases. In the present study, we will investigate the possible association of several common polymorphisms(ABCA1R219K, CETPTaqIB and LIPC-250 G/A) with susceptibility to AD and plasma lipid levels. METHODS: Case--control study of 208 Han Chinese(104 AD patients and 104 non-demented controls) from Changsha area in Hunan Province was performed using the PCR-RFLP analysis. Cognitive decline was assessed using Mini Mental State Examination (MMSE) as a standardized method. Additionally, fasting lipid profile and the cognitive testing scores including Wechsler Memory Scale(WMS) and Wisconsin Card Sorting Test (WCST) were recorded.Results and conclusionsWe found significant differences among the genotype distributions of these three genes in AD patients when compared with controls. But after adjusting other factors, multivariate logistic regression analysis showed only ABCA1R219K(B = -0.903, P = 0.005, OR = 0.405, 95%CI:0.217-0.758) and LIPC-250 G/A variants(B = -0.905, P = 0.018, OR = 0.405, 95%CI:0.191-0.858) were associated with decreased AD risk. There were significantly higher levels of high-density lipoprotein cholesterol(HDL-C) and apolipoproteinA-I in the carriers of KK genotype and K allele(P < 0.05), and B2B2 genotype of CETP Taq1B showed significant association with higher HDL-C levels than other genotypes(F = 5.598, P = 0.004), while -250 G/A polymorphisms had no significant effect on HDL-C. In total population, subjects carrying ABCA1219K allele or LIPC-250A allele obtained higher MMSE or WMS scores than non-carriers, however, no significant association was observed in AD group or controls. Therefore, this preliminary study showed that the gene variants of ABCA1R219K and LIPC-250 G/A might influence AD susceptibility in South Chinese Han population, but the polymorphism of CETPTaq1B didn't show any association in despite of being a significant determinant of HDL-C.
    Full-text · Article · Nov 2012 · Lipids in Health and Disease
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    • "Since then, many other studies correlated the R219K variant with the lipid profile and risk for CAD in various populations and ethnicities [6,9-16]. Conversely, Pasdar et al. [10] did not support a major role of the ABCA1 gene as risk factor for ischemic stroke. Srinivasan et al.[11] found that the K219 allele frequency differs markedly between blacks and whites, and that the variant-allele modulates the association between age and HDL-C, as well as body fatness and TGs concentration in a beneficial manner only in whites. "
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    ABSTRACT: One of the important proteins involved in lipid metabolism is the ATP-binding cassette transporter A1 (ABCA1) encoding by ABCA1 gene. In this study we evaluated the single nucleotide polymorphisms (SNPs) of ABCA1 gene. We analyzed SNPs in chromosome 9 such as rs2230806 (R219K) in the position 107620867, rs2230808 (R1587K) in the position 106602625 and rs4149313 (I883M) in the position 106626574 according to gender and lipid profile of Greek nurses. The study population consisted of 447 (87 men) unrelated nurses who were genotyped for ABCA1 gene polymorphisms. Additionally, lipid profile [total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol (LDL-C) and apolipoprotein A1] was evaluated. The distribution of all three studied ABCA1 gene polymorphisms did not differ according to gender. However, only R219K genotype distribution bared borderline statistical significance (p = 0.08) between the two studied groups. Moreover, allele frequencies of R219K, R1587K and I88M polymorphisms did not differ according to gender. In general, blood lipid levels did not seem to vary according to ABCA1 gene polymorphisms, when testing all subjects or when testing only men or only women. However, a significant difference of LDL-C distribution was detected in all subjects according to R1587K genotype, indicating lower LDL-C levels with KK polymorphism (p = 0.0025). The above difference was solely detected on female population (p = 0.0053). The ABCA1 gene polymorphisms frequency, distribution and lipid profile did not differ according to gender. However, in the female population the KK genotype of R1587K gene indicated lower LDL-C levels. Further studies, involving a higher number of individuals, are required to clarify genes and gender contribution.
    Full-text · Article · Jun 2012 · Lipids in Health and Disease
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    • "The frequency of R allele of R219K polymorphism in our study was 72% similar to Pasdar et al [10] who reported 73.2% in controls (68% in patients with ischemic stroke) and Porchay et al [11] [D.E.S.I.R participants (Data from an Epidemiological Study on the Insulin Resistance)] who reported 71.7%. Conversely, Clee et al [5] reported frequency of 46% in Dutch men with proven CAD who participated in the Regression Growth Evaluation Statin Study. "
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    ABSTRACT: The ATP-binding cassette transporter A1 (ABCA1) is essential protein involved in lipid metabolism. The present study was undertaken to detect the possible association of polymorphisms in the ABCA1 gene [rs2230806 (R219K) and rs2230808 (R1587K)] and lipid profile in Greek young nurses. The study population consisted of 308 unrelated nurses who were genotyped and the ABCA1 polymorphisms were detected. Additionally, lipid profile [total cholesterol (TC), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) A] was evaluated. There was no difference in the genotypic and allelic frequencies of the R219K polymorphism according to lipid profile. The R1587K genotypes differed significantly according to TC, LDL-C and TGs concentration (p = 0.023, p = 0.014 and p = 0.047, respectively). Particularly, significant difference in TC, LDL-C and TGs concentration was detected between RK and RR genotypes (p = 0.006, p = 0.004, p = 0.014, respectively). Women with RK genotype compared to RR genotype had higher concentration of TGs (134.25 mg/dl vs 108.89 mg/dl, p = 0.014, respectively), total cholesterol (207.41 mg/dl vs 187.69 mg/dl, p = 0.006, respectively), and LDL-C (110.6 mg/dl vs 96.9 mg/dl, p = 0.004, respectively). These findings suggest that the R1587K polymorphism of ABCA1 gene was associated with lipid profile of Greek nurses. Women with RK genotype had higher TGs, total and LDL-C concentration compared to RR genotype. These observations may be significant in assessing the risk of CAD since a 1% change in LDL-C is associated with a 1% change of cardiovascular events. Also, TGs concentration were documented to play a significant role in women. However, this needs to be confirmed by larger studies.
    Full-text · Article · Apr 2011 · Lipids in Health and Disease
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