CETP gene polymorphisms and haplotypes are explanatory variables for HDL cholesterol level in sickle cell disease

Variations in lipid profile have been observed in sickle cell disease (SCD) and understanding their relationship with disease severity is crucial. This study aimed to investigate the association of polymorphisms of the CETP gene and laboratory markers of disease severity with lipid profile in a pediatric population with SCD. Biochemical and anthropometric analyses and CETP and alpha-thalassemia genotyping were performed. The study included 133 children and adolescents with sickle cell anemia (SCA) or hemoglobin SC disease (SCC), in steady-state. The SCA and no hydroxyurea (no HU) groups had higher values of ApoB, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) compared to the SCC and HU groups. However, there were no significant differences in ApoA1 and HDL-C levels between the groups based on genotype. Furthermore, the groups with altered levels of ApoA1, HDL-C, and the triglyceride/HDL ratio exhibited lower hemoglobin (Hb) levels and higher white blood cell counts. Hb level was associated to HDL-C levels. Analysis of CETP gene variants showed that the minor alleles of rs3764261 (C>A), rs247616 (C>T), and rs183130 (C>T), as well as the TTA haplotype, are explanatory variables for HDL-C levels. These findings suggested that dyslipidemia in SCD, specifically related to HDL-C levels, may be influenced by individual genetic background. Additionally, further investigation is needed to determine if clinical manifestations are impacted by CETP gene variants.

A STUDY TO EVALUATE THE IMPORTANCE OF FASTING LIPID PROFILE ESTIMATION AS THE PART OF INITIAL EVALUATION OF HIV POSITIVE PATIENTS BEFORE STARTING HAART

BACKGROUND:-There is evidence that ART is associated with lipodystrophy syndrome, a disturbance of lipid metabolism characterised by insulin resistance, dyslipidaemia, and fat maldistribution, metabolic bone disease (osteopenia and/or osteoporosis), and lactic acidosis. ART- associated dyslipidaemia is characterized by elevated serum concentrations of total cholesterol, triglycerides, low density lipoprotein 2(LDL-c), very low-density lipoprotein (VLDL), and Apo lipoprotein B (apoB) and low levels of high density lipoprotein (HDL-c) constituting an atherogenic lipid 1pro?le . In this study 143 young patients who were attending the Antiretroviral Therapy Plus MATERIAL AND METHODS:- Centre & Medicine Wards, ACSR GMC NELLORE were included randomly. 5ml Sample preparation and Biochemical assay :- of venous blood sample was collected by venipuncture from 12 hours overnight fast and centrifuged at 3000 cycles per minute and serum was separated for lipid pro?le measurement within one hour of blood collection. The serum levels of TC, HDL-C, LDL-C, VLDL and TG were measured using AU480 BECKMANS random access fully automated auto analyzer at Biochemistry laboratory, ACSR GMC, NELLORE. TC, LDL and TC/HDL lipid pro?les are signi?cant. F-Signi?cant values are RESULTS;- <0.05, reject null hypothesis. It means that the difference among the lipid pro?les of TC, LDL and TC/HDL in the study group is statistically signi?cant with respect to regimen groups. HDL, TG and VLDL lipid pro?les are not signi?cant. F-Signi?cant values are >0.05, no evidence to reject null hypothesis. It means that the no signi?cant difference among the lipid pro?les of HDL, TG, and VLDL in the study group is not statistically signi?cant with respect to regimen groups. Signi?cant CONCLUSIONS:- metabolic and morphological alterations occur in HIV infected patients especially in patients on HAART. The patients on HAART had an elevated Castelli Index I, indicating an increased risk for atherosclerotic cardiovascular disease in this population. There is need to assess lipid pro?les at baseline before initiation of HAART treatment and lipid pro?le monitoring during therapy to monitor any rising trends. New medications with more lipid friendly pro?les within existing drugs such as darunavir (PI), etravirine (NNRTI), new classes of drugs such as integrase inhibitors (raltegravir) and CCR5 inhibitors (maraviroc) can be used to avoid dyslipidaemia

Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Abstract Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC50 of 0.96 µM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors

Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

Fibrates are a class ofmedication that mainly lowers theblood triglyceride levels. Theyreduce the LDL andincrease the levels of HDL C, in the blood.Clofibrate,the first member to bediscovered in 1962, and introduced in USA in 1967, is withdrawnin 2002, due to unexplained hepatomegaly,hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular diseaseand diabeticretinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density LipoproteinCholesterol Intervention Trial) , FIELD trail. (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study,ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and BIP (Bezafibrate Infarction Prevention Study) trial andangiography trials, like LOCAT(LopidCoronary Angiography Trial) and BECLAIT(Bezafibrate Coronary Atherosclerosis Intervention Trial)demonstrated thebeneficial effects of gemfibrozil and fenofibrate.Their mechanism of action remained obscure for three decades,ie till 1990s, when theirmode of actionwas found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL)modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involvingthevariousenzymes like LCAT (Lecithin-cholesterol acyl transferase)andCYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochromeP450 7A1 (CYP7A1)) , transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP,OATP (Na+-dependent taurocholate transporter/ organic anion transporters) . These are the.) andnuclear factors like LXR, PPAR alfa etc. (liver orphan receptorα , and peroxisome proliferative nuclear factor) , in relation to the mechanismsof action of fibrates are discussed . Areas of current interests in literature are briefed.

CETP polymorphisms confer genetic contribution to centenarians of Hainan, south of China

OBJECTIVE@#In this paper, we will discuss if the CETP polymorphism contributes to the centenarians in Hainan island.@*METHODS@#We tested the TaqIB and I405V polymorphisms of CETP gene among 276 centenarians and 301 matched healthy individuals by AS-PCR and analyzed the data with SPSS software package (Version 19.0).@*RESULTS@#Our data indicated that allele B1 and V have the significant differences between centenarians and healthy control groups with P < 0.001. Further analysis implied that genotypes B1B1 (P < 0.001, OR = 0.148, 95% CI = 0.095-0.230) and VV (P < 0.001 and OR = 0.353, 95% CI = 0.237-0.525) were significantly different between centenarians and matched controls. The combination of B and V, such as B1B1-II (P < 0.001, OR = 0.128, 95% CI = 0.049-0.329), B1B1-IV (P < 0.001, OR = 0.115, 95% CI = 0.056-0.237), B1B2-VV (P < 0.05, OR = 0.534, 95% CI = 0.310-0.920), and B2B2-VV (P < 0.001, OR = 0.198, 95% CI = 0.086-0.453) have significant differences between centenarians and matched healthy individuals from Hainan.@*CONCLUSION@#Our results implied that allele B1B1 and VV, as well as the combination B1B1-II, B1B1-IV, B1B2-VV and B2B2-VV may contribute to the longevity in centenarians of Hainan, south of China.

CETP polymorphisms confer genetic contribution to centenarians of Hainan, south of China

Objective In this paper, we will discuss if the CETP polymorphism contributes to the centenarians in Hainan island. Methods We tested the TaqIB and I405V polymorphisms of CETP gene among 276 centenarians and 301 matched healthy individuals by AS-PCR and analyzed the data with SPSS software package (Version 19.0). Results Our data indicated that allele B1 and V have the significant differences between centenarians and healthy control groups with P < 0.001. Further analysis implied that genotypes B1B1 (P < 0.001, OR = 0.148, 95% CI = 0.095-0.230) and VV (P < 0.001 and OR = 0.353, 95% CI = 0.237-0.525) were significantly different between centenarians and matched controls. The combination of B and V, such as B1B1-II (P < 0.001, OR = 0.128, 95% CI = 0.049-0.329), B1B1-IV (P < 0.001, OR = 0.115, 95% CI = 0.056-0.237), B1B2-VV (P < 0.05, OR = 0.534, 95% CI = 0.310-0.920), and B2B2-VV (P < 0.001, OR = 0.198, 95% CI = 0.086-0.453) have significant differences between centenarians and matched healthy individuals from Hainan. Conclusion Our results implied that allele B1B1 and VV, as well as the combination B1B1-II, B1B1-IV, B1B2-VV and B2B2-VV may contribute to the longevity in centenarians of Hainan, south of China.

Status of HDL in Current Scenario.

Cardiovascular disease is a leading cause of death worldwide. Coronary heart disease (CHD) caused by atherosclerosis is the most common cause of morbidity and mortality. Prevention, stabilization and regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events. Low-density lipoprotein-cholesterol (LDL-C) lowering agents, primarily the statins, are the current mainstay in the pharmacologic management of dyslipidemia. Epidemiologic and observational studies have shown that high-density lipoprotein-cholesterol (HDL-C) is also a strong independent predictor of CHD, suggesting that raising HDL-C levels might afford clinical benefit in the reduction of cardiovascular risk. HDL particles have key atheroprotective functions—including the capacity to efflux cellular cholesterol—in addition to having antioxidative, anti-inflammatory, antiapoptotic, antithrombotic and vasodilatory actions. Therapeutic approaches to raise HDL-C levels can target one or more of several mechanisms, including the production of apolipoprotein A-I (apoA-I) or modification of intravascular remodeling of HDL particles. However, the landscape of HDL-raising therapies is now littered with failed therapies, including niacin and the negative results with the cholesteryl ester transfer protein (CETP) inhibitors. This is attributed to potential adverse effects of CETP inhibition such as the generation of HDL particles that have deficient biological activities and a deleterious impact on reverse cholesterol transport and steroid metabolism. Normalization of both defective HDL function and diminished HDL levels should, therefore, be the focus of pharmacological HDL-raising in future studies.

Simultaneous transfer of cholesterol, triglycerides, and phospholipids to high-density lipoprotein in aging subjects with or without coronary artery disease

OBJECTIVE: To verify whether the capacity of high-density lipoprotein (HDL) to simultaneously receive nonesterified cholesterol, triglycerides, cholesteryl esters, and phospholipids changes with aging and the presence of coronary artery disease. DESIGN: Cross-sectional study with biochemical analyses. SUBJECTS: Eleven elderly patients with coronary artery disease (74±5 years) were compared with the following groups of non-coronary artery disease subjects (referred to as "healthy"): 25 young (25±5 years), 25 middle-aged (42± years), and 25 elderly subjects (75±8 years). METHODS: Plasma samples were incubated with a nanoemulsion labeled with radioactive lipids; the transfer of the lipids from the nanoemulsion to the HDL was measured in chemically precipitated HDL. HDL size and paraoxonase-1 activity were also determined. RESULTS: The transfer of cholesteryl esters and phospholipids to high-density lipoprotein was significantly greater (p<0.001) in healthy elderly subjects than in the middle-aged and younger subjects. Non-esterified cholesterol and triglyceride transfer was not different among these three groups. The HDL size was significantly greater (p<0.001) in healthy elderly subjects than in the middle-aged and younger subjects. The paraoxonase-1 activity was similar among the groups. Compared with healthy elderly subjects, coronary artery disease elderly subjects had significantly less (p<0.05) transfer of non-esterified cholesterol, triglycerides, and cholesteryl esters to the HDL and a significantly smaller (p<0.05) HDL size. CONCLUSION: Because lipid transfer is enhanced in healthy elderly subjects but not in those with coronary artery disease, increasing lipid transfer to HDL may be a protective mechanism against the disease.

Negative impact of imflammation and insulin resistance on the biogenesis of HDL-c in Indonesian men with metabolic syndrome.

Aim To find out the relationship between inflammation and insulin resistance with impaired HDL biogenesis that cause low HDL-c concentration Methods Using a cross-sectional design, this study involved 163 adult men, aged 25-60 years old with metabolic syndrome (IDF criteria, 2005), without liver and kidney dysfunction. This study was undertaken in Jakarta in the year 2007-2009. Measured indicators were serum apolipoprotein A-1 (apoA-1), prebeta-1 HDL, cholesteryl ester transfer protein (CETP), HDL cholesterol (HDL-c), body weight, height, waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), and triglyceride. The apoA-1/HDL-c ratios were taken as indicator of HDL maturation, whereas CETP/HDL-c and CETP/TG ratios were indicated HDL catabolism. high-sensitivity CRP (hsCRP) and HOMA-IR were taken as indicator of inflammation and insulin resistance, respectively. Data were analyzed by using univariate, bivariate, and multivariate analysis. Results Positive correlations were found between hsCRP and CETP (rs= 0.200, p= 0.042), and CETP/HDL-c ratios (rs= 0.188, p= 0.013). HOMA-IR positively correlated with apoA-1/HDL-c ratios (rs= 0.190, p= 0.016) and negatively correlated with the CETP/TG ratios (rs= -0.162, p= 0.04). Results of general linear model analysis showed that serum hsCRP concentration had the highest contribution to CETP/HDL-c ratios, apoA-1, dan CETP (p= 0.009; 0.016; 0.054, respectively). Conclusions Inflammation and insulin resistance related to dysfunction of HDL biogenesis in men with metabolic syndrome. The inflammation correlated with increased HDL catabolism, whereas the insulin resistance correlated with decreased HDL maturation and increased HDL catabolism. These may lead to low HDL-c concentration. Inflammation had higher contribution to HDL biogenesis factors than insulin resistance.

TaqI B1/B2 and -629A/C cholesteryl ester transfer protein (CETP) gene polymorphisms and their association with CETP activity and high-density lipoprotein cholesterol levels in a Tehranian population. Part of the Tehran Lipid and Glucose Study (TLGS)

We examined the cholesteryl ester transfer protein (CETP) gene TaqI intron 1 B1/B2 polymorphism and the -629A/C CETP promoter polymorphism in respect to high-density lipoprotein cholesterol (HDL-C) in a healthy Iranian population taken from the Tehran Lipid and Glucose Study (TLGS). The relationship between CETP activity and HDL-C level was also determined along with body mass index, blood pressure and tobacco smoking status. PCR-RFLP used to amplify a segment of the CETP intron 1 TaqI (B2/B1) polymorphism from 1021 individuals and we selected 345 individuals from the lowest, middle and highest HDL-C deciles and investigated the -629A/C polymorphism. We also evaluated the CETP activity of 103 of these individuals, each with at least one homozygous allele. The presence of the TaqI B2 and -629A/C A alleles were significantly associated with increased HDL-C levels (B2B2 = 1.19 ± 0.31 mmolL-1 vs. B1B1 = 1.01 ± 0.2 mmol L-1 for p < 0.001; AA = 1.15 ± 0.41 mmol L-1 vs. CC = 0.95 ± 0.28 mmol L-1 for p < 0.001) and decreased the CETP activity (B1B1 = 67.8 ± 8.9 pmol L-1 vs. B2B2 = 62.6 ± 9.6 pmol L-1 for p < 0.01; CC = 68.6 ± 8.4 pmol L-1 vs. AA = 62.7 ± 9.7 pmol L-1 for p < 0.002). The frequencies were 0.382 for the TaqI B2 allele and 0.462 for the -629A/C A allele, with linkage disequilibrium analysis giving D = 0.0965 and D' = 0.4695. We demonstrated that the TaqI B1 and B2 alleles and the -629A/C A and C alleles were in linkage disequilibrium in our population and that there was a significant association between the B2 and A alleles and high HDL-C levels and low CETP activity. Linkage disequilibrium between the TaqI A and B2 alleles also detected.

The Correlation of the Polymorphisms of CETP Gene with the Natural Longevity in Uygur Population / 医学研究杂志

Objective To investigate the relation ship between two polymorphisms within the CETP gene,TaqIB and I4O5V,and natural longevity in the Uygur population.Methods 191 healthy individuals over 90 years old and 53 control individuals who died before their 75 years were recruited.The polymorphisms within CETP gene,TaqIB and I4O5V,were genotyped by PCR-RFLP and PCR-Sequencing.Results There were no difference in the genotypes and alleles distribution of two polymorphisms within the CETP gene between longevity group and control group.Conclusions There was no correlation between the polymorphisms within CETP gene,TaqIB and I4O5V,and natural longevity of Uygur population in Hetian.

The Correlation of the D442G Polymorphism of CETP Gene with the Natural Longevity in Uygur Population / 医学研究杂志

Objective To investigate the relationship between polymorphisms within the CETP gene, D442G,and natural longevity in the Uygur population. Methods 191 healthy individuals over 90 years old and 53 control individuals who died before their 75 years were recruited. The D442G polymorphism within CETP gene was genotyped by PCR-RFLP and PCR-Sequencing. Results There were no difference in the genotypes and alleles distribution of D442G polymorphisms within the CETP gene between longevity group and control group. Conclusions There were no the correlation between the D442G polymorphisms within CETP gene and natural longevity of Uygur population in Hetian. The difference of D442G polymorphism existed in not only races, but also regions where the same race dwelled.

Progress on the drugs for regulating high-density lipoprotein / 中国临床药理学与治疗学

Atherosclerosis (AS) is pathologically important basis of many kinds of coronary atherosclerosis disease (CAD). It can be substantially protected by raising high-density lipoprotein (HDL).In view of mechanism, drugs for raising HDL include: cholesterol ester transfer protein inhibitors, peroxisomal proliferator-activated receptor agonists, liver X-activated receptor agonists, farnesoid X receptor antagonists or agonists, lipoprotein lipase activators, niacin, and phenytoin and lecin : cholesterol acyltransferase activators, etc. This review aimed to the progress of drugs for regulating high-density lipoprotein and their mechanism, in view of clinical and preclinical aspects.

Association of Cholesteryl Ester Transfer Protein Gene Polymorphism with Serum Lipid Concentration and Coronary Artery Disease in Korean Men

BACKGROUND AND OBJECTIVES: Cholesteryl ester transfer protein (CETP) plays a key role in the reverse cholesterol transport pathway. The purpose of this study was to investigate the association of CETP gene polymorphism with the plasma lipid levels and coronary artery disease (CAD) in Korean men. SUBJECTS AND METHODS: Two hundred and sixteen healthy control subjects (46.8+/-10.6 y) and 95 patients with CAD (58.2+/-8.8 y) were examined. The genotypes of C-629A, Taq1B and I405V were determined by the SNP-IT assay. RESULTS: The allele frequencies of the C:A in the C-629A, B1:B2 in the Taq1B and I:V in the I405V in the control group were 0.51:0.49, 0.63:0.37 and 0.55:0.45, respectively. The genotype distributions of the C-629 A and Taq1B polymorphisms in the CAD patients did not differ from those in the control group. No variation in the CETP genotype was associated with disease progression in the CAD group. The HDL cholesterol in -629A homozygous and Taq1B B2 homozygous were higher than those of the other genotypes. The Taq1B B2 carrier was an independent determinant for HDL cholesterol in the control group. However, I405V polymorphism was not associated with HDL cholesterol. The V allele in the I405V polymorphism was associated with reduced CAD events after controlling the age, BMI and other risk factors (OR:0.4, p<0.01). CONCLUSION: The frequencies of Taq1B and C-629A variants between the healthy and CAD groups did not differ. The B2 carrier in the Taq1B polymorphism was associated with a higher HDL cholesterol concentration. The V variation in the I405V polymorphism had a protective effect against the development of CAD in Korean men.

A common mutation in cholesteryl ester transfer protein gene and plasma HDL cholesterol level before and after hormone replacement therapy in Korean postmenopausal women

BACKGROUND: Plasma cholesteryl ester transfer protein (CETP) functions to transfer cholesteryl ester from HDL to triglyceride-rich lipoproteins and regulates plasma HDL cholesterol level. A common mutation, the exon 15 A to G substitution at codon 442 (D442G) results in reduced plasma CETP activity and increased plasma HDL cholesterol level. Meanwhile, hormone replacement therapy (HRT) in postmenopausal women increases plasma HDL cholesterol level. METHODS: We investigated the frequency of D442G mutation and its effect on plasma HDL cholesterol level in Korean women. We also examined if the mutation has any effect on an increase in plasma HDL cholesterol level during HRT. RESULTS: Two hundred and twenty eight women aged over 40 years were recruited in this study. Of 228 women, 22 (9.6%) were identified as having the D442G mutation; 21 heterozygotes and 1 homozygote. The subjects with the mutation had higher plasma HDL cholesterol levels than those without the mutation (61.6 +/- 17.3 vs. 55.1 +/- 14.0 mg/dL, p < 0.05). After 12 month HRT, HDL cholesterol increased by 6.4% (3.6 +/- 13.2 mg/dL, p < 0.05) and D442G mutation did not have any significant effect on the change of plasma HDL cholesterol level. CONCLUSION: D442G mutation is common in Korean postmenopausal women and it is associated with increased plasma HDL cholesterol level. HRT for postmenopausal women increased plasma HDL cholesterol level in similar amounts regardless of the presence or absence of D442G mutation.

CETP(Cholesteryl Ester Transfer Protein) Deficiency Caused by Genetic Mutation in the CETP Gene in Normal Korean Population

BACKGROUND: CETP(Cholesteryl ester transfer Protein) is the essential protein for 'reverse cholesterol transport' which transfers cholesteryl ester from HDL particles to other lipoproteins. The subjects with CETP deficiency caused by genetic mutation in the CETP gene have very high HDL levels that CETP deficiency implies anti-atherogenic effect. A missense mutation in the exon 15(D442G) and a splicing defect in the intron 14(Int 14A) in the CETP gene are reported to be popular among Japanese population which overall prevalence of both mutations is up to 10%. METHODS: To identify the CETP mutaion such as D442G or Int 14A among Koreans, seven subjects who have high HDL level above 80mg/dl and 14 first-degree relatives of them were included in this study. RESULTS: Of 21 subjects in 7 familes, 5 subjects in 2 families were confirmed as D442G mutation of CETP gene, but Int 14A mutation is not found. Subjects with D442G mutation have high apo A-I levels as well as HDL levels. CONCLUSION: The D442G mutation of CETP gene is firstly confirmed in Koreans. The CETP deficiency caused by genetic mutation in the CETP gene seems to be prevalent among Korean population.