ATP-binding Cassette Transporter 1 Gene Research Articles

Exosome-based malaria vaccine, a miracle of nanomedicine

Exosomes are the nano-size subpopulation of extracellular vesicles secreted by all living cells and they originated from the endosomes. In general, it is involved in Inter-Cellular communication. Exosomes transport several bioactive molecules (DNA, RNA, protein, etc.) from parental cells to recipient cells. This event showcases cellular health or pathologic status1. The invention of the exosome adds a new chapter in nanomedicine. After the event now nanomedicine overcome several limitations (toxicity, immune rejection, biocompatibility, stability, and target-specific drug transport). The current decade of scientific investigation suggests that exosomes have active participation in host-pathogen intercellular communication in several parasitic infected diseases including malaria2. Malaria is a lethal parasitic infectious disease that led to large population death globally. It is spared in the human host after biting of parasite load female anopheles bite. This parasitic development happens in a circulating system with red bold cells and this maturation face boosts of exosome secretion3. In Malaria ABCA1 (ATP-binding-cassette transporter 1) gene is most vital for exosome biogenesis and maintaining host-pathogen communication4. Experimental data shows that the ABCA1 gene knockout reduces the chance of cerebral Malaria5. In disease progression phage host-pathogen cell-to-cell interaction happens via exosome cargos miRNA and proteins, Both ingredients of exosome efficiently regulate genetic expression. Malaria-infected cells derived exosomes carry miRNA451a which is related to red blood cells (RBC) maturation and related to vascular permeability. Malaria derives exosome-associated noncoding RNA, and fragments of genomic DNA of Plasmodium involved in suppressing the innate immune cells activity6. The immune system suppresses during malaria, and infected RBCs derive exosome (Fig. 1) downregulation natural killer cell activity against parasites. Infected RBCs-derived exosome protein and inflammatory molecules suppress the immune system. During malaria, exosomes play a vital role in reducing T-cell proliferation and downregulating T-cell–mediated immune response7. The vaccine development for Malaria is most challenging because of the complex life cycle of Plasmodium and surface protein diversity, although some limited success stories there8. At the current time, large-scale malaria vaccine development and delivery focus on exosomes9. Exosome-based plasmid delivery plays the role in anti-malaria antigenic immune memory development and promotes humoral immunity10. In malarial, exosome is the most promising drug resistance overcoming tool. Although exosome-based vaccine needs more clinical investigation, it is the most efficient, has less immunogenic rejection, and it is capable across biological braise. The infected RBC derives exosome-related miRNA is the most exciting part of the malaria Vaccine research but it required deep investigation before being used. Infected RBC derives exosome-related mediated host immune system reprogramming is still unexplored side of the exosome-based malaria research domain. Detailed investigation is needed regarding host cells derived exosome cargos (inflammatory molecules, miRNAs) and malaria development multiple stages associate exosome heterogeneity11 to develop exosome base efficient malaria vaccine. Now the question comes about why malaria research focuses on exosomes? The exosome-based malarial treatment approach is innovative because it supports early diagnosis and therapeutic aspects it is more promising with null toxicity with less immune rejection, compare with the other approaches, exosomes have some advantages such as boosting the immune system against malaria, surface engineering exosomes are more efficient compared with other (liposome) approaches in drug delivery in the case of malaria. Exosome is a smart tool for malarial drug delivery because they provide better stability of the drug in the biological system and help them cross the biological barriers. The feasible aspect of exosome-based malaria research depends on the expertise in exosome research. It is possible if we develop an expert group and some of the exosome-related advanced equipment. Once this facility is established and maintained by a trained expert, that reduces the production cost of the downstream product. Exosome-based malarial treatment research adds a new chapter to parasitology research. Exosome helps to decode the malaria-associated pathological complication at the more detailed molecular level. We hope, this innovative approach will save large-scale populations from malaria globally.Figure 1: Exosome and malaria. (A) Infected red blood cells (RBCs) derive exosomes that inhibit RBCs development and suppression of immune response against malaria. (B) Exosome surface modification, drug delivery an innovative approach in exosome associate malaria vaccine development.Ethical approval and consent of publication None. Sources of funding None. Author contribution D.M. and R.D. has conceptualized the project. D.M., S.G., R.M., P.S.G., and A.A. have written the manuscript. A.D. and S.K.J. has guided the project. All authors have done the editing. All authors have contributed significantly in preparation of the manuscript. Conflict of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not Applicable. Guarantor All Authors. Availability of data and materials None.

Association of ABCA1 R219K and C69T single nucleotide polymorphisms with type 2 diabetes mellitus: A case control study

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with alterations in the metabolism of carbohydrates, proteins and lipids. ATP binding cassette transporter 1 (ABCA1) encoding the ABCA1 protein plays a critical role in the reverse cholesterol transport of high‑density lipoprotein-cholesterol (HDL-c) metabolism. ABCA1 gene single nucleotide polymorphisms (SNPs) have been found to be associated with abnormalities in the serum levels of HDL‑c, thereby disrupting the cholesterol removing ability of cells. The aim of the present study was to determine the association between the R219K and C69T SNPs of ABCA1 gene variants and T2DM. For this purpose, a case control study was conducted among 50 patients with T2DM who were selected as cases, and 50 age‑ and sex‑matched patients without comorbidities were selected as the controls. Venous blood samples were collected from all participants following overnight fasting. Plasma glucose, glycated hemoglobin (HbA1c) and lipid profile estimations were performed using an autoanalyzer with standard methods. ABCA1 gene polymorphisms were determined using the polymerase chain reaction‑restriction fragment length polymorphism method. The body mass index for both the case and control groups was found to be above the revised cut‑off value for obesity. HDL‑c levels were below the optimum level in the case and control group. The distribution of genotype and dominant alleles of the C69T and R219K SNPs of the ABCA1 gene did not differ significantly between the case and control groups. The present study suggests the existence of a defective ABCA1 genotype in the studied population, predisposing these individuals to a decrease in serum HDL‑c levels. This interferes with cholesterol sequestration from foam cells and creates an inflammatory state, which is aggravated by obesity. Thus, HDL‑c becomes dysfunctional from inflammation‑mediated structural modifications and paves the way for atherogenic dyslipidemia associated with T2DM.

Correlation of R219K polymorphism of ABCA1 gene and the risk of Alzheimer's disease in the southwest of Iran

IntroductionAlzheimer's disease (AD), as a neurodegenerative disease, is the most common reason for dementia in the elderly. ATP- binding cassette transporter 1 (ABCA1) is a cell membrane transporter protein which is involved in cholesterol efflux. The aim of this study is to evaluate the correlation between polymorphisms of G/A (rs2230806) in ABCA1 gene with sporadic Alzheimer's disease in the southwest of Iran. MethodsThis case-control study was conducted in 180 subjects, including 100 sporadic AD patients and 80 healthy subjects. Genotypes of all samples were determined using the PCR–restriction fragment length polymorphism (PCR–RFLP) technique. ResultsThe analysis of the R219K Polymorphism of ABCA1 gene indicated that there was no significant distinction between AD patients and controls. In this study when groups were stratified by age and sex, results showed that in the control group with less than 75 years, the risk of developing AD was significantly lower than subjects who were older than 75 years (P = 0.019, OR = 0.46, 95% CI = 0.24–0.88). A significant difference was detected in the risk of AD between patient and control in females older than 75 years (P = 0.028). ConclusionThe results of this study confirm that aging is an important risk factor for AD. Also, it has been found that AD is more prevalent in women compared to men. However, our results do not support the hypothesis that R219K polymorphism in the rs2230806 region of the ABCA1 as a genetic risk factor for developing AD in our study population.

The effect of ABCA1 gene DNA methylation on blood pressure levels in a Chinese hyperlipidemic population.

Hypertension is an important public health challenge worldwide. Epigenetic studies are providing novel insight into the underlying mechanisms of hypertension. We investigated the effect of DNA methylation in ATP-binding cassette transporter 1 (ABCA1) gene on blood pressure levels in a Chinese hyperlipidemic population. We randomly selected 211 individuals with hyperlipidemia who had not received any lipid-lowering treatment at baseline from our previous statin pharmacogenetics study (n = 734). DNA methylation loci at the ABCA1 gene were measured by MethylTarget, a next generation bisulfite sequencing-based multiple targeted cytosine-guanine dinucleotide methylation analysis method. Mean DNA methylation level was used in statistical analysis. In all subjects, higher mean ABCA1_B methylation was positively associated with systolic blood pressure (SBP) (β = 8.27, P = 0.008; β = 8.78, P = 0.005) and explained 2.7% and 5.8% of SBP variation before and after adjustment for lipids, respectively. We further divided all patients into three groups based on the tertile of body mass index (BMI) distribution. In the middle tertile of BMI, there was a significantly positive relationship between mean ABCA1_A methylation and SBP (β = 0.89, P = 0.003) and DBP (β = 0.32, P = 0.030). Mean ABCA1_A methylation explained 11.0% of SBP variation and 5.3% of DBP variation, respectively. Furthermore, mean ABCA1_A methylation (β = 0.79; P = 0.007) together with age and gender explained up to 24.1% of SBP variation. Our study provides new evidence that the ABCA1 DNA methylation profile is associated with blood pressure levels, which highlights that DNA methylation might be a significant molecular mechanism involved in the pathophysiological process of hypertension.

Evidence of association of circulating epigenetic-sensitive biomarkers with suspected coronary heart disease evaluated by Cardiac Computed Tomography.

Circulating biomarkers available in clinical practice do not allow to stratify patients with coronary heart disease (CHD) prior the onset of a clinically relevant event. We evaluated the methylation status of specific genomic segments and gene expression in peripheral blood of patients undergoing Cardiac Computed Tomography (CCT) for CHD (n = 95).We choose to investigate cholesterol metabolism. Methylation and gene expression of low density lipoprotein receptor (LDLR), sterol regulatory element-binding factor 2 (SREBF2) and ATP-binding cassette transporter 1 (ABCA1) were evaluated by qRT-PCR. Calcium score (CACS), stenosis degree, total plaque volume (TPV), calcified plaque volume (CPV), non-calcified plaque volume (NCPV) and plaque burden (PB) were assessed in all CHD patients (n = 65). The percentage of methylation at the specific analyzed segment of LDLR promoter was higher in CHD patients vs healthy subjects (HS) (n = 30) (p = 0.001). LDLR, SREBF2 and ABCA1 mRNAs were up-regulated in CHD patients vs HS (p = 0.02; p = 0.019; p = 0.008). SREBF2 was overexpressed in patients with coronary stenosis ≥50% vs subjects with stenosis <50% (p = 0.036). After adjustment for risk factors and clinical features, ABCA1 (p = 0.005) and SREBF2 (p = 0.010) gene expression were identified as independent predictors of CHD and severity. ROC curve analysis revealed a good performance of ABCA1 on predicting CHD (AUC = 0.768; p<0.001) and of SREBF2 for the prediction of disease severity (AUC = 0.815; p<0.001). Moreover, adjusted multivariate analysis demonstrated SREBF2 as independent predictor of CPV, NCPV and TPV (p = 0.022; p = 0.002 and p = 0.006) and ABCA1 as independent predictor of NCPV and TPV (p = 0.002 and p = 0.013).CHD presence and characteristics are related to selected circulating transcriptional and epigenetic-sensitive biomarkers linked to cholesterol pathway. More extensive analysis of CHD phenotypes and circulating biomarkers might improve and personalize cardiovascular risk stratification in the clinical settings.

A Meta-Analysis of the Associations Between the ATP-Binding Cassette Transporter ABCA1 R219K (rs2230806) Polymorphism and the Risk of Type 2 Diabetes in Asians.

Asians have relatively low insulin secretion capacity and readily develop type 2 diabetes mellitus (T2DM) when insulin resistant. For that reason, insufficient insulin secretion is critical factor for Asians at the early stage of T2DM. ATP-binding cassette transporter1 (ABCA1) is a membrane protein responsible for cholesterol efflux and its function is also important for secreting insulin in pancreatic β-cells. Given the importance of its role, different polymorphisms of ABCA1 gene might contribute differently to the development of T2DM. Here, we analyzed the association between a variant form of ABCA1 gene called ABCA1 rs2230806 and the prevalence of T2DM in a large sample size by pooling all of the case-control studies published. Relevant case-control studies were identified by searching PubMed, EMBASE, Cochrane Library, Korean scientific database, Chinese medical databases, and the Indian medical database. The association was evaluated using five genetic models such as the allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Heterogeneity of each genetic model was determined by the I2 test. A total of eight studies (7 published studies and one data set from the Korean Genetic Epidemiology Study) were eligible, satisfying Hardy-Weinberg equilibrium and included 2755 T2DM patients (case) and 16 635 nondiabetic subjects (control). All subjects in the studies were Asians. Each genetic model exhibited heterogeneity. In all genetic models, ABCA1 rs2230806 had a significant association with prevalence of T2DM: AG (OR=0.78, 95% CI: 0.61-0.98), RG (OR=0.72, 95% CI: 0.51-1.03), DG (OR=0.73, 95% CI: 0.55-0.97), HMG (OR=0.62, 95% CI: 0.41-0.96), and HTG (OR=0.78, 95% CI: 0.61-0.99). There was no single study that changed the overall effects in allelic genetic model with random effects. No publication bias existed in any models except the RG model. In conclusion, middle-aged and elderly adults with the minor allele of ABCA1 rs2230806 will have a lower risk of T2DM. This is the first meta-analysis to evaluate the association in Asians.

Correction: A Meta-Analysis of the Associations Between the ATP-Binding Cassette Transporter ABCA1 R219K (rs2230806) Polymorphism and the Risk of Type 2 Diabetes in Asians.

Asians have relatively low insulin secretion capacity and readily develop type 2 diabetes mellitus (T2DM) when insulin resistant. For that reason, insufficient insulin secretion is critical factor for Asians at the early stage of T2DM. ATP-binding cassette transporter1 (ABCA1) is a membrane protein responsible for cholesterol efflux and its function is also important for secreting insulin in pancreatic β-cells. Given the importance of its role, different polymorphisms of ABCA1 gene might contribute differently to the development of T2DM. Here, we analyzed the association between a variant form of ABCA1 gene called ABCA1 rs2230806 and the prevalence of T2DM in a large sample size by pooling all of the case-control studies published. Relevant case-control studies were identified by searching PubMed, EMBASE, Cochrane Library, Korean scientific database, Chinese medical databases, and the Indian medical database. The association was evaluated using five genetic models such as the allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Heterogeneity of each genetic model was determined by the I2 test. A total of eight studies (7 published studies and one data set from the Korean Genetic Epidemiology Study) were eligible, satisfying Hardy-Weinberg equilibrium and included 2755 T2DM patients (case) and 16 635 nondiabetic subjects (control). All subjects in the studies were Asians. Each genetic model exhibited heterogeneity. In all genetic models, ABCA1 rs2230806 had a significant association with prevalence of T2DM: AG (OR=0.78, 95% CI: 0.61-0.98), RG (OR=0.72, 95% CI: 0.51-1.03), DG (OR=0.73, 95% CI: 0.55-0.97), HMG (OR=0.62, 95% CI: 0.41-0.96), and HTG (OR=0.78, 95% CI: 0.61-0.99). There was no single study that changed the overall effects in allelic genetic model with random effects. No publication bias existed in any models except the RG model. In conclusion, middle-aged and elderly adults with the minor allele of ABCA1 rs2230806 will have a lower risk of T2DM. This is the first meta-analysis to evaluate the association in Asians.

ABCA1 gene polymorphism and oxidative stress in polycystic ovary syndrome: Role of antioxidant therapy for prevention and control

Polycystic ovary syndrome (PCOS) is a common health problem that affects women in childbearing age. Recent studies discussed the relation of oxidative stress with PCOS and suggested that the antioxidants may improve the prognosis of PCOS. Changes happened in ATP binding cassette transporter 1 (ABCA1) gene encoding a protein regulating entry and exit from cell membrane may contribute to dyslipidemia in patients with PCOS. The role of oxidative stress and ABCA1 gene polymorphism in the pathogenesis of PCOS was evaluated along with the effect of antioxidants in the prevention and treatment of this disease. The present study included 90 female patients with PCOS and 90 healthy women represented the control group. Patients with PCOS were further divided into two subgroups. The patients included in subgroup 1a were treated with antioxidant and hormonal therapy while patients included in subgroup 1b were treated with hormonal therapy only. ABCA1gene polymorphism and oxidative stress parameters were investigated in all groups. The level of the oxidant marker; MDA was higher in PCOS patients when compared to controls. In addition, the levels of GSH, vitamin E, ascorbic acid, and selenium were significantly decreased, while SOD and GPx activities were increased in PCOS patients when compared to controls. The response to treatment among PCOS patients was better in group 1a than group 1b. The frequency of ABCA1 AA genotype was higher in PCOS patients than the control group (32.2% and 11.1% respectively). It was concluded that oxidative stress may lead to PCOS which raises the possibility of using antioxidants for the prevention and control of PCOS. In addition, the polymorphism in ABCA1 gene may be associated with genetic susceptibility for PCOS.

Expression and Clinical Significance of ATP-Binding Cassette Transporter 1 in Serum and Placental Tissue in Chinese Patients with Preeclampsia

Aim: To investigate the expression and clinical significance of ATP-binding cassette transporter 1 (ABCA1) in pregnant women with preeclampsia (PE). Methods: 52 pregnant women with PE who were admitted for delivery were enrolled in the study, while 30 normal pregnant inpatients were chosen as controls. Blood lipid and serum ABCA1 concentrations were assayed by enzymatic analysis and ELISA, respectively, and the expression of the ABCA1 gene and its encoded protein were detected and quantified by RT-PCR and Western blotting. Results: In the study group, blood lipid levels were significantly higher than those in the control group (p < 0.01), while the ABCA1 gene and its encoded protein expression in both serum and placental tissue were lower than that of controls. These differences were highly correlated with disease severity (p < 0.05). In PE patients, serum ABCA1 concentration was positively correlated with ABCA1 protein expression in placental tissue (r = 0.384, p < 0.01) and high-density lipoprotein level (r = 0.318, p < 0.05), but negatively correlated with low-density lipoprotein level (r = -0.279, p < 0.05). Conclusion: In PE women, expression of ABCA1 was decreased, suggesting that ABCA1 may play an important role in onset of PE by altering blood lipid metabolism.

A NOVEL POLYMORPHISMS IN THE ABCA1 GENE M233V IN MONGOLIA POPULATION

ObjectivesTo investigate whether ATP-binding cassette transporter 1 (ABCA1) M233V genetic variation is correlated with blood lipids in Mongolian population and the association of this polymorphism with coronary heart disease (CHD).MethodsThe...

A novel mutation in the ABCA1 gene causing an atypical phenotype of Tangier disease

Tangier disease is a rare autosomal-recessive disorder caused by mutation in the ATP binding cassette transporter 1 (ABCA1) gene. Typically, Tangier disease manifests with symptoms and signs resulting from the deposition of cholesteryl esters in nonadipose tissues; chiefly, in peripheral nerves leading to neuropathy and in reticulo-endothelial organs, such as liver, spleen, lymph nodes, and tonsils, causing their enlargement and discoloration. An association with early cardiovascular disease can be variable. We describe a patient with a unique phenotype of Tangier disease from a novel splice site mutation in the ABCA1 gene that is associated with a central nervous system presentation resembling multiple sclerosis, and the presence of premature atherosclerosis.

Effect of fenofibrate therapy and ABCA1 polymorphisms on high-density lipoprotein subclasses in the Genetics of Lipid Lowering Drugs and Diet Network

Previous studies have shown that ATP-binding cassette transporter 1 (ABCA1) polymorphisms associated with increased ABCA1 expression result in increased small HDL (high-density lipoprotein) subclass particle concentration. This study examines the effect of treatment with fenofibrate, a drug known to bind peroxisome proliferator-activated receptor alpha (PPARalpha) which increases the expression of ABCA1 gene, on lipoprotein subclass profiles of individuals stratified by ABCA1 genotypes. Participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) were treated with fenofibrate over a three week period. We analyzed six ABCA1 polymorphisms in 287 GOLDN participants with triglyceride concentrations >or=150mg/dL and studied their associations with HDL subclass particle concentrations, as measured by nuclear magnetic resonance spectroscopy, before and after treatment. Fenofibrate treatment did not result in significant changes in small HDL subclass particle concentration. When changes in HDL subclasses were stratified by ABCA1 polymorphism genotypes, there were no statistically significant associations between ABCA1 genotypes and small HDL subclasses before fenofibrate treatment. However, after fenofibrate treatment the KK genotype of R1587K (mean 4.40micromol/L; p=0.004) and the RK genotype of R219K (mean 1.60micromol/L; p=0.02) polymorphisms were associated with significantly increased small HDL. The R1587KKK genotype (mean 4.80micromol/L; p=0.0002) and the R219K KK genotype (mean 2.50micromol/L; p=0.02) were also associated with increased HDL particle concentrations. There is a synergistic effect between ABCA1 polymorphisms and fenofibrate. Thus, our study indirectly confirms the role of fenofibrate and genotype in increasing cholesterol efflux, as evidenced by increased small HDL particles.

A novel haplotype in ABCA1 gene effects plasma HDL-C concentration

Background and objectives ATP-binding cassette transporter 1 ( ABCA1) is a trans-membrane protein responsible for the efflux of cholesterol and phospholipids across the cell membrane, an essential step in the reverse cholesterol transport system. This study investigates the effect of five non-synonymous SNPs of ABCA1 gene on plasma HDL-C levels in Pakistani individuals free of ischemic heart disease and stroke. Methods Five non-synonymous SNPs were selected after sequencing ABCA1 gene in patients of Hypoalphalipoproteinemia. The presence of these SNPs was then checked in 200 individuals by using PCR-RFLP. Plasma glucose and lipid fractions were measured in fasting state. Ethical approval was obtained from the Ethical Review Committee, Aga Khan University and informed consent was obtained from all subjects. Results LL genotype of V825L polymorphism was associated with decreased levels of HDL-C [− 0.17 (− 0.32 to − 0.19); P = 0.02] and P774 allele showed a significant increase in HDL-C levels as compared to T774 allele [− 0.15 (− 0.18 to − 0.02); P = 0.01]. R219K, A399V and V771M polymorphisms did not show any association with levels of HDL-C, LDL-C, cholesterol and triglycerides. Haplotype analysis between R219K and V825L polymorphisms showed a unique interaction between R219 allele and L825 allele. The RL haplotype was found to be associated with decreased levels of HDL-C [− 0.12 (− 0.22 to − 0.03); P = 0.001]. Conclusions ABCA1 polymorphisms are associated with varying levels of HDL-C in Pakistani individuals. These results warrant further investigations as ABCA1 polymorphisms may have a major role in the high incidence of cardiovascular disorders in South Asians.

Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by a complex interaction of genetic and environmental factors. Increasing evidence highlights a potential role for cholesterol in the pathophysiology of AD. The ABCA1 gene, located in close vicinity to the 9q linkage peaks identified by genome-wide AD linkage studies, plays an important role in cellular cholesterol efflux, and is likely a good candidate gene. However, results from published genetic association studies between ABCA1 and AD are ambiguous. In the present study, we examined the role of two ABCA1 polymorphisms, R219K (rs2230806) and G-17C (rs2740483) in modifying the risk of late-onset AD (LOAD) in a large American white cohort of 992 AD cases and 699 controls. We observed significant gender×R219K interaction (p=0.00008). Female carriers of the 219K allele showed a 1.75-fold increased risk of developing AD compared to non-219K carrier females (95% CI 1.34–2.29; p=0.00004). The overall two-site haplotype distribution was also significant between female AD cases and controls (p=0.017). The risk associated with the R219K polymorphism was independent of the recently reported significant association in the ubiquilin (UBQLN1) gene in this region on chromosome 9q. Our data suggest a gender-specific and APOE and UBQLN1 independent association between the ABCA1/R219K polymorphism and LOAD.

ABCA1, ApoA-I and type II DM

The ATP-binding cassette transporter 1 ( ABCA1) is a trans-membrane peptide that is involved in the lipidification of ApoA-I. ABCA1 gene was initially implicated in Tangier disease and familial hypoalphalipoproteinemia and has been shown to be associated with coronary artery disease and atherosclerosis as well. Recently, a haplotype in ABCA1 gene was associated with increased risk of type II diabetes mellitus (DM). In this report, a relationship between ApoA-I, DM and ABCA1 has been emphasized.

MTE04-IS-001 Atherosclerosis of arteries other than carotides and those of lower extremities

The ATP-binding cassette transporter 1 (ABCA1) is a trans-membrane peptide that is involved in the lipidification of ApoA-I. ABCA1 gene was initially implicated in Tangier disease and familial hypoalphalipoproteinemia and has been shown to be associated with coronary artery disease and atherosclerosis as well. Recently, a haplotype in ABCA1 gene was associated with increased risk of type II diabetes mellitus (DM). In this report, a relationship between ApoA-I, DM and ABCA1 has been emphasized.

Association of the ABCA1 gene polymorphisms with type 2 DM in a Japanese population

To examine the association of the ATP-binding cassette transporter 1 (ABCA1) gene with type 2 diabetes (DM), we studied genetic polymorphisms of the ABCA1 gene including its linkage disequilibrium (LD) and haplotype analyses using a Japanese population. A sample set (DM:72, IGT:75, and NGT:227) was genotyped with 34 SNPs distributed from the promoter region to the last exon of the ABCA1 gene. LD between SNPs was assessed in pairwise manner. Among 13 LD blocks constructed, an LD block at the 5′-region showed a significant difference in the haplotype distribution between the study groups (NGT vs. IGT + DM: overall p = 0.0180; NGT vs. DM: 0.0001). Fisher’s exact probability test (NGT vs. DM) showed a significant association of the haplotype 2 of the LD block ( p = 0.0001), with an odds ratio (OR) of 2.53 (95%CI:1.62–4.12). Diplotype analysis also showed a significant association of the diplotypes with the haplotype 2 (OR:2.59, 95%CI:1.48–4.54, p = 0.0013).

The association of the R219K polymorphism in the ATP-binding cassette transporter 1 ( ABCA1) gene with coronary heart disease and hyperlipidaemia.

The R219K polymorphism in the ATP-binding cassette transporter 1 gene ( ABCA1) has been associated with reduced severity of atherosclerosis, fewer coronary events, decreased triglycerides and a trend to increased HDL in men with coronary heart disease (CHD). This study examined the frequency and the effect on CHD and plasma lipids of the polymorphism in patients of both sexes attending a lipid out-patient clinic. The overall frequency of the K allele was 0.26. It was lower in patients with CHD (0.21) than in those without (0.27) but this was not statistically significant. Amongst patients with elevated Lp(a) the frequency of the K allele was significantly lower in those with CHD (0.16) than in those without (0.29). There were no statistically significant differences in total cholesterol, LDL, HDL, apoB or apoAI between carriers and non-carriers. When patients with probable secondary hypertriglyceridaemia (triglycerides >1000 mg/dl), type 2 diabetes and carriers of lipoprotein lipase polymorphisms associated with hypertriglyceridaemia were excluded, the K allele was significantly associated with reduced triglycerides but only in patients with apoE 3/3 genotype. In conclusion, we provide additional evidence that the R219K polymorphism in the ABCA1 gene either directly or as a result of linkage disequilibrium with additional functional variant(s), has a protective effect against CHD and is associated with lower plasma triglycerides in sub-groups of patients with hyperlipidaemia.

A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common autosomal codominant hereditary disease caused by defects in the LDL receptor (LDLR) gene, and one of the most common characteristics of affected subjects is...

Novel mutations in ABCA1 gene in Japanese patients with Tangier disease and familial high density lipoprotein deficiency with coronary heart disease

Mutations in the ATP-binding cassette transporter 1 (ABCA1) gene have been recently identified as the molecular defect in Tangier disease (TD) and familial high density lipoprotein deficiency (FHA). We here report novel mutations in the ABCA1 gene in two sisters from a Japanese family with TD who have been described previously (S. Ohtaki, H. Nakagawa, N. Kida, H. Nakamura, K. Tsuda, S. Yokoyama, T. Yamamura, S. Tajima, A. Yamamoto, Atherosclerosis 49 (1983)) and a family with FHA. Both probands of TD and FHA developed coronary heart disease. Sequence analysis of the ABCA1 gene from the patients with TD revealed a homozygous G to A transition at nucleotide 3805 of the cDNA resulting in the substitution of Asp 1229 with Asn in exon 27, and a C to T at nucleotide 6181 resulting in the substitution of Arg 2021 with Trp in exon 47. Sequence analysis of the ABCA1 gene from the FHA patient revealed a homozygous 4 bp CGCC deletion from nucleotide 3787 to 3790 resulting in premature termination by frameshift at codon 1224. These mutations were confirmed by restriction digestion analysis, and were not found in 141 control subjects. Our findings indicate that mutations in the ABCA1 gene are associated with TD as well as FHA.