Single nucleotide polymorphism haplotypes in the cholesteryl-ester transfer protein (CETP) gene and lipid phenotypes

We studied the association between high (HDL) and low-density (LDL) cholesterol concentrations and family-derived haplotypes based on six common SNPs in the cholesteryl-ester transfer protein (CETP) gene. We based our analysis on 201 founders from families recruited throughout Germany. The analysis revealed one subhaplotype block with complete, pairwise, linkage disequilibrium between 5 SNPs located in the promoter and intron 1. The sixth SNP was the well known 1405V polymorphism in exon 14, close to the 3' end of the gene. Four haplotypes accounted for 86% of the entire sample. We found that haplotype associations with HDL, LDL, and the LDL/HDL ratio were more robust than associations with individual SNPs. Moreover, the associations were robust for men, but not for women. Our data suggest an interaction between gender and genetic variation within the CETP gene.     

A gene score of nine LDL and HDL regulating genes is associated with fluvastatin-induced cholesterol changes in women

While conventional pharmacogenetic studies have considered single gene effects, we tested if a genetic score of nine LDL- and HDL-associated single nucleotide polymorphisms, previously shown to predict cardiovascular disease, is related to fluvastatin-induced lipid change. In patients with asymptomatic plaque in the right carotid artery, thus candidates for statin therapy, we related score LDL [APOB(rs693), APOE(rs4420638), HMGCR(rs12654264), LDLR(rs1529729), and PCSK9(rs11591147)] and score HDL [ABCA1(rs3890182), CETP(rs1800775), LIPC(rs1800588), and LPL(rs328)] as well as the combined score LDL+HDL to fluvastatin-induced LDL reduction (± metoprolol) (n = 395) and HDL increase (n = 187) following 1 year of fluvastatin treatment. In women, an increasing number of unfavorable alleles (i.e., alleles conferring higher LDL and lower HDL) of score LDL+HDL (P = 0.037) and of score LDL (P = 0.023) was associated with less pronounced fluvastatin-induced LDL reduction. Furthermore, in women, both score LDL+HDL (P = 0.001) and score HDL (P = 0.022) were directly correlated with more pronounced fluvastatin-induced HDL increase, explaining 5.9–11.6% of the variance in treatment response in women. There were no such associations in men. This suggests that a gene score based on variation in nine different LDL- and HDL-associated genes is of importance for the magnitude of fluvastatin HDL increase in women with asymptomatic plaque in the carotid artery.     

Influence of dietary fatty acid composition on the relationship between CETP activity and plasma lipoproteins in monkeys.

CETP activity, measured as transfer of cholesteryl ester from exogenous HDL to exogenous VLDL and LDL, reflecting CETP mass as determined by ELISA, was documented in three groups of St. Kitts vervet monkeys fed diets enriched in saturated (Sat), monounsaturated (Mono), or n-6 polyunsaturated (Poly) fatty acids. CETP activity was not different when comparing the three dietary fats. However, CETP activity was significantly higher when cholesterol was added to each of the diets. Significant positive associations between CETP activity and VLDL and LDL cholesterol concentrations were found whereas significant negative associations were seen between CETP activity and HDL cholesterol in each of the diet groups. The strength of these associations was highest in the Sat group. Cholesteryl ester (CE) fatty acid composition of lipoproteins varied widely among diet groups, with the more polyunsaturated CE of the Poly group being associated with a higher rate of CE transfer to endogenous acceptor apolipoprotein B-containing lipoproteins. Finally, only the Sat diet group showed significant positive correlations of CETP activity with LDL particle diameter (r = 0.76), cholesteryl ester percentage (r = 0.67), and a strong negative correlation (r = -0.86) with LDL receptor function, estimated as the difference between native and methylated LDL turnover rates. We speculate that strong associations between CETP and LDL metabolism may explain, at least in part, the increased atherogenicity of dietary saturated fat.     

Cholesterol ester transfer protein gene is associated with high-density lipoprotein cholesterol levels in Korean population

High-density lipoprotein (HDL) cholesterol levels are associated with decreased risk of coronary artery disease. Several genome-wide association studies (GWAS) for HDL cholesterol levels have implicated cholesterol ester transfer protein (CETP) as possibly causal. We tested for the association between single nucleotide polymorphisms (SNPs) in CETP gene and HDL cholesterol levels in Korean population. A total of 979 subjects in Seoul City were genotyped using a genome-wide marker panel for a discovery study. Another 2,277 subjects in Bundang-Gu in Korea were used for a replication study with selected markers. In the discovery phase, the top SNP associated with mean HDL cholesterol levels was rs6499861 in the CETP gene on chromosome 16 (p=1.18×10^?6 in the Seoul City sample, p=8.91×10^?3 in the Bundang-Gu sample). Another SNP (rs6499863) in the CETP gene was also among the top five SNPs associated with HDL cholesterol levels (p=3.83×10^?5 in the Seoul City sample, p=3.29×10^?3 in the Bundang-Gu sample). SNP rs1800775 was also associated with HDL cholesterol levels (p=4.86×10^?4 in meta-analysis results of 3256 samples). This study clearly demonstrates that genetic variants in CETP influence HDL cholesterol levels in Korean adults.     

Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol (HDL-C) and lowers LDL cholesterol in dyslipidemic patients; however, the effects of ANA on cholesterol/lipoprotein metabolism in a dyslipidemic hamster model have not been demonstrated. To test whether ANA (60 mg/kg/day, 2 weeks) promoted reverse cholesterol transport (RCT), 3H-cholesterol-loaded macrophages were injected and (3)H-tracer levels were measured in HDL, liver, and feces. Compared to controls, ANA inhibited CETP (94%) and increased HDL-C (47%). 3H-tracer in HDL increased by 69% in hamsters treated with ANA, suggesting increased cholesterol efflux from macrophages to HDL. 3H-tracer in fecal cholesterol and bile acids increased by 90% and 57%, respectively, indicating increased macrophage-to-feces RCT. Mass spectrometry analysis of HDL from ANA-treated hamsters revealed an increase in free unlabeled cholesterol and CE. Furthermore, bulk cholesterol and cholic acid were increased in feces from ANA-treated hamsters. Using two independent approaches to assess cholesterol metabolism, the current study demonstrates that CETP inhibition with ANA promotes macrophage-to-feces RCT and results in increased fecal cholesterol/bile acid excretion, further supporting its development as a novel lipid therapy for the treatment of dyslipidemia and atherosclerotic vascular disease.     

Postprandial chylomicrons: potent vehicles for transporting cholesterol from endogenous LDL+HDL and cell membranes to the liver via LCAT and CETP

We examined whether postprandial (PP) chylomicrons (CMs) can serve as vehicles for transporting cholesterol from endogenous cholesterol-rich lipoprotein (LDL+HDL) fractions and cell membranes to the liver via lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. During incubation of fresh fasting and PP plasma containing [(3)H]cholesteryl ester (CE)-labeled LDL+HDL, both CMs and VLDL served as acceptors of [(3)H]CE or cholesterol from LDL+HDL. The presence of CMs in PP plasma suppressed the ability of VLDL to accept [(3)H]CE from LDL+HDL. In reconstituted plasma containing an equivalent amount of triglycerides from isolated VLDL or CMs, a CM particle was about 40 times more potent than a VLDL particle in accepting [(3)H]CE or cholesterol from LDL+HDLs. When incubated with red blood cells (RBCs) as a source for cell membrane cholesterol, the cholesterol content of CMs, VLDL, LDL, and HDL in PP plasma increased by 485%, 74%, 13%, and 30%, respectively, via LCAT and CETP activities. The presence of CMs in plasma suppressed the ability of endogenous lipoproteins to accept cholesterol from RBCs. Our data suggest that PP CMs may play an important role in promoting reverse cholesterol transport in vivo by serving as the preferred ultimate vehicle for transporting cholesterol released from cell membranes to the liver via LCAT and CETP.     

I405V and TaqIB polymorphisms of the cholesteryl ester transfer protein and their relation to serum lipid and lipoprotein levels in a Turkish population

Cholesteryl ester transfer protein (CETP) plays a central role in high‐density lipoprotein (HDL) metabolism. Genetic polymorphisms of the CETP gene can influence levels of serum lipoproteins. It has been reported that mean HDL‐cholesterol (HDL‐C) concentrations are low in Turkish population. Thus, we investigated the frequencies of the common I405V and TaqIB polymorphisms of the CETP gene and their relation to serum lipid and lipoprotein levels in a Turkish population. The variant allele frequencies of I405V and TaqIB polymorphisms of the CETP gene were found to be 0.38 and 0.46, respectively and similar to some of the European populations. Subjects for the VV genotype of I405V polymorphism had higher HDL‐C levels than did II subjects. The covariance analysis showed that gender and triglyceride (TG) levels have an effect on the association of HDL‐C and I405V polymorphism. In conclusion, our results indicate that I405V polymorphism may affect the HDL‐C levels in Turkish population. The association of this polymorphism and HDL‐C levels could be modified by other factors, such as gender and TG levels. Copyright © 2009 John Wiley & Sons, Ltd.     

Association Between Lipids, Lipoproteins Composition of HDL Particles and Triglyceride-Rich Lipoproteins, and LCAT and CETP Activity in Post-renal Transplant Patients

High-density lipoprotein (HDL) remodeling within the plasma compartment and the association between lecithin-cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activity, and lipid, lipoprotein concentrations and composition were investigated. The aim was to examine the high sensitivity of C-reactive protein (hsCRP), lipid, apolipoprotein B (apoB), apoAI, total apoAII, apoAIInonB, apoB-containing apoAII (apoB:AII), total apoCIII, apoCIIInonB, apoB-containing apoCIII (apoB:CIII) concentration and LCAT and CETP activity to gain an insight into the association between them and LCAT and CETP, 57 post-renal transplant (Tx) patients with and without statin therapy and in 15 healthy subjects. Tx patients had moderate hypertriglyceridemia, hypercholesterolemia, and dyslipoproteinemia, disturbed triglyceride-rich lipoproteins (TRLs) and HDL composition, decreased LCAT, and slightly increased hsCRP but no CETP activity. Spearman’s correlation test showed the association between lipids and lipoproteins and LCAT or CETP, and multiple ridge stepwise forward regression showed that immunosuppressive therapy in Tx patients can disturb HDL and TRLs composition. The results suggest that inhibition or activation of LCAT is due, in part, to HDL-associated lipoprotein. Lipoprotein composition of apoAI, apoAIInonB, and apoCIIInonB in HDL particle and apoB:AII TRLs can contribute to decrease LCAT mass in Tx patients. Tx patients without statin and with lower triglycerides but higher HDL cholesterol concentration and disturbed lipoprotein composition of ApoAI and apoAII in HDL particle can decrease LCAT, increase LDL cholesterol, aggravate renal graft, and accelerate atherosclerosis and chronic heart diseases.     

Can novel Apo A-I polymorphisms be responsible for low HDL in South Asian immigrants?

Coronary artery disease (CAD) is the leading cause of death in the world. Even though its rates have decreased worldwide over the past 30 years, event rates are still high in South Asians. South Asians are known to have low high-density lipoprotein (HDL) levels. The objective of this study was to identify Apolipoprotein A-I (Apo A-I) polymorphisms, the main protein component of HDL and explore its association with low HDL levels in South Asians. A pilot study on 30 South Asians was conducted and 12-h fasting samples for C-reactive protein, total cholesterol, HDL, low-density lipoprotein (LDL), triglycerides, Lipoprotein (a), Insulin, glucose levels, DNA extraction, and sequencing of Apo A-I gene were done. DNA sequencing revealed six novel Apo A-I single nucleotide polymorphisms (SNPs) in South Asians, one of which (rs 35293760, C938T) was significantly associated with low (<40 mg/dl) HDL levels (P = 0.004). The association was also seen with total cholesterol (P = 0.026) and LDL levels (P = 0.032). This pilot work has highlighted some of the gene-environment associations that could be responsible for low HDL and may be excess CAD in South Asians. Further larger studies are required to explore and uncover these associations that could be responsible for excess CAD risk in South Asians.     

Lipid transfer inhibitor protein defines the participation of high density lipoprotein subfractions in lipid transfer reactions mediated by cholesterol ester transfer protein (CETP)

Cholesterol ester transfer protein (CETP) moves triglyceride (TG) and cholesteryl ester (CE) between lipoproteins. CETP has no apparent preference for high (HDL) or low (LDL) density lipoprotein as lipid donor to very low density lipoprotein (VLDL), and the preference for HDL observed in plasma is due to suppression of LDL transfers by lipid transfer inhibitor protein (LTIP). Given the heterogeneity of HDL, and a demonstrated ability of HDL subfractions to bind LTIP, we examined whether LTIP might also control CETP-facilitated lipid flux among HDL subfractions. CETP-mediated CE transfers from [3H]CE VLDL to various lipoproteins, combined on an equal phospholipid basis, ranged 2-fold and followed the order: HDL3 > LDL > HDL2. LTIP inhibited VLDL to HDL2 transfer at one-half the rate of VLDL to LDL. In contrast, VLDL to HDL3 transfer was stimulated, resulting in a CETP preference for HDL3 that was 3-fold greater than that for LDL or HDL2. Long-term mass transfer experiments confirmed these findings and further established that the previously observed stimulation of CETP activity on HDL by LTIP is due solely to its stimulation of transfer activity on HDL3. TG enrichment of HDL2, which occurs during the HDL cycle, inhibited CETP activity by approximately 2-fold and LTIP activity was blocked almost completely. This suggests that LTIP keeps lipid transfer activity on HDL2 low and constant regardless of its TG enrichment status. Overall, these results show that LTIP tailors CETP-mediated remodeling of HDL3 and HDL2 particles in subclass-specific ways, strongly implicating LTIP as a regulator of HDL metabolism.     

In vivo effects of anacetrapib on preβ HDL: improvement in HDL remodeling without effects on cholesterol absorption

Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased preβ HDL-dependent cholesterol efflux via ABCA1 in vitro. However, the effects of ANA on in vivo preβ HDL have not been characterized. In vitro, ANA inhibited the formation of preβ, however in ANA-treated dyslipidemic hamsters, preβ HDL levels (measured by two-dimensional gel electrophoresis) were increased, in contrast to in vitro findings. Because changes in plasma preβ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamsters. ANA treatment of hamsters (on either dyslipidemic or normal diet) had no effect on cholesterol absorption, while dalcetrapib-treated hamsters displayed an increase in cholesterol absorption. Taken together, these data support the notion that ANA promotes preβ HDL functionality in vivo, with no effects on cholesterol absorption.     

Structural and biophysical insight into cholesteryl ester-transfer protein

CETP (cholesteryl ester-transfer protein) is essential for neutral lipid transfer between HDL (high-density lipoprotein) and LDL (low-density lipoprotein) and plays a critical role in the reverse cholesterol transfer pathway. In clinical trials, CETP inhibitors increase HDL levels and reduce LDL levels, and therefore may be used as a potential treatment for atherosclerosis. In this review, we cover the analysis of CETP structure and provide insights into CETP-mediated lipid transfer based on a collection of structural and biophysical data.     

Polymorphisms of the gene encoding cholesterol ester transfer protein and serum lipoprotein levels in subjects with and without coronary heart disease

Summary We determined TaqI-A, TaqI-B and EcoNI genotypes at the cholesteryl ester transfer protein (CETP) locus in 111 healthy volunteers and in 187 hyperlipidemic men of whom 72 had suffered a myocardial infarction. There were no significant differences in the allele distributions at these polymorphic loci either between the population sample and the hyperlipidemic subjects, or between patients with and without previous myocardial infarction. To detect the associations between the CETP polymorphisms and serum lipid and apoprotein levels, we determined the serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL)-cholesterol, apoA-I, apoA-II and apoB in the subjects studied and correlated them to the 3 RFLPs. No significant differences were observed in the serum levels of apoproteins and lipid parameters between subjects with different genotypes in any of these polymorphic CETP loci, either in the population sample or in hyperlipidemic men. Multivariate analyses did not reveal a significant independent role for any of the 3 polymorphisms in determining serum HDL-cholesterol or apoA-I levels after adjusting for triglyceride and low density lipoprotein cholesterol concentrations. This was evident for the group of healthy volunteers and for hyperlipidemic subjects, including those who had survived a myocardial infarction. We conclude that, in Finns, the CETP RFLPs are not useful markers for the risk of coronary heart disease.     

HDL and reverse cholesterol transport. Role of cholesterol ester transfer protein]

As most of peripheral cells are not able to catabolize cholesterol, the transport of cholesterol excess from peripheral tissues back to the liver, namely "reverse cholesterol transport", is the only way by which cholesterol homeostasis is maintained in vivo. Reverse cholesterol transport pathway can be divided in three major steps: 1) uptake of cellular cholesterol by the high density lipoproteins (HDL), 2) esterification of HDL cholesterol by the lecithin: cholesterol acyltransferase and 3) captation of HDL cholesteryl esters by the liver where cholesterol can be metabolized and excreted in the bile. In several species, including man, cholesteryl esters in HDL can also follow an alternative pathway which consists in their transfer from HDL to very low density (VLDL) and low density (LDL) lipoproteins. The transfer of cholesteryl esters to LDL, catalyzed by the Cholesteryl Ester Transfer Protein (CETP), might affect either favorably or unfavorably the reverse cholesterol transport pathway, depending on whether LDL are finally taken up by the liver or by peripheral tissues, respectively. In order to understand precisely the implication of CETP in reverse cholesterol transport, it is essential to determine its role in HDL metabolism, to know the potential regulation of its activity and to identify the mechanism by which it interacts with lipoprotein substrates. Results from recent studies have demonstrated that CETP can promote the size redistribution of HDL particles. This may be an important process in the reverse cholesterol transport pathway as HDL particles with various sizes have been shown to differ in their ability to promote cholesterol efflux from peripheral cells and to interact with lecithin: cholesterol acyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monitoring of peripheral blood cytotoxic T-cells under fluvastatin treatment in renal transplant recipients

Flow cytometric T-cell analysis is capable of adding valuable information for balancing immunosuppression in transplant recipients as it can take into account individual effects of immunosuppressive drugs on each patient as well as effects of other drugs which may modify the overall immunosuppression. Studies suggest that HMG-CoA-reductase-inhibitors (statins) reduce the frequency of organ rejection, although the precise mechanism of this effect is unknown. We therefore evaluated the effect of fluvastatin on size and activation of T-cell subpopulations and NK-cell activity in renal transplant recipients. At baseline, the population size of activated (HLA-DR+) T-cells was negatively correlated to serum HDL cholesterol suggesting an increased T-cell activation at low HDL levels. Fluvastatin treatment of a hypercholesterolemic group of patients for two months significantly decreased the LDL cholesterol. A longitudinal analysis revealed a relative increase in non-MHC restricted cytotoxic T-cells (CD3+/CD16+ or CD56+) over time which was significantly attenuated in fluvastatin treated patients but not in normocholesterolemic controls. Moreover, a relative decrease of activated MHC class I-restricted cytotoxic CD8+ T-cells was only observed upon fluvastatin treatment. NK-cell number and activity did not differ between groups. In summary, fluvastatin treatment of hypercholesterolemic renal transplant recipients is associated with a specific modulation of T-cells exerting cytotoxic effector functions.     

Effect of CETP on the plasma lipoprotein profile in four strains of transgenic mouse

The plasma cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport. There are conflicting views regarding whether or not excessive CETP activity is one of the risk factors of atherosclerosis. To study how much effect CETP can have on the profiles of plasma lipoproteins in vivo, we produced four strains of transgenic mouse that expressed different levels of human CETP gene. We analyzed seven groups of mice that had different levels of CETP expression. The cholesterol level of HDL, chylomicron (CM) and VLDL, intermediate density lipoprotein (IDL) and LDL were proportionally changed in association with plasma CETP concentrations (2.9 +/- 0.6 to 37.4 +/- 1.7 microg/ml) in an allelic dose-dependent manner. We further characterized one of the transgenic strains, CETP-4, by optimizing the experimental condition for the mouse model of atherosclerosis, and found that it would be useful for the development of therapeutics against atherosclerosis.     

CETP does not affect triglyceride production or clearance in APOE*3-Leiden mice

The cholesteryl ester transfer protein (CETP) facilitates the bidirectional transfer of cholesteryl esters and triglycerides (TG) between HDL and (V)LDL. By shifting cholesterol in plasma from HDL to (V)LDL in exchange for VLDL-TG, CETP aggravates atherosclerosis in hyperlipidemic APOE*3-Leiden (E3L) mice. The aim of this study was to investigate the role of CETP in TG metabolism and high-fat diet-induced obesity by using E3L mice with and without the expression of the human CETP gene. On chow, plasma lipid levels were comparable between both male and female E3L and E3L.CETP mice. Further mechanistic studies were performed using male mice. CETP expression increased the level of TG in HDL. CETP did not affect the postprandial plasma TG response or the hepatic VLDL-TG and VLDL-apolipoprotein B production rate. Moreover, CETP did not affect the plasma TG clearance rate or organ-specific TG uptake after infusion of VLDL-like emulsion particles. In line with the absence of an effect of CETP on tissue-specific TG uptake, CETP also did not affect weight gain in response to a high-fat diet. In conclusion, the CETP-induced increase of TG in the HDL fraction of E3L mice is not associated with changes in the production of TG or with tissue-specific clearance of TG from the plasma.     

HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease – Insights from randomized clinical trials and human genetics

Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies.     

Association between Expression Quantitative Trait Loci and Metabolic Traits in Two Korean Populations

Most genome-wide association studies consider genes that are located closest to single nucleotide polymorphisms (SNPs) that are highly significant for those studies. However, the significance of the associations between SNPs and candidate genes has not been fully determined. An alternative approach that used SNPs in expression quantitative trait loci (eQTL) was reported previously for Crohn’s disease; it was shown that eQTL-based preselection for follow-up studies was a useful approach for identifying risk loci from the results of moderately sized GWAS. In this study, we propose an approach that uses eQTL SNPs to support the functional relationships between an SNP and a candidate gene in a genome-wide association study. The genome-wide SNP genotypes and 10 biochemical measures (fasting glucose levels, BUN, serum albumin levels, AST, ALT, gamma GTP, total cholesterol, HDL cholesterol, triglycerides, and LDL cholesterol) were obtained from the Korean Association Resource (KARE) consortium. The eQTL SNPs were isolated from the SNP dataset based on the RegulomeDB eQTL-SNP data from the ENCODE projects and two recent eQTL reports. A total of 25,658 eQTL SNPs were tested for their association with the 10 metabolic traits in 2 Korean populations (Ansung and Ansan). The proportion of phenotypic variance explained by eQTL and non-eQTL SNPs showed that eQTL SNPs were more likely to be associated with the metabolic traits genetically compared with non-eQTL SNPs. Finally, via a meta-analysis of the two Korean populations, we identified 14 eQTL SNPs that were significantly associated with metabolic traits. These results suggest that our approach can be expanded to other genome-wide association studies.     

Familial cholesteryl ester transfer protein deficiency is associated with triglyceride-rich low density lipoproteins containing cholesteryl esters of probable intracellular origin

The net transfer of core lipids between lipoproteins is facilitated by cholesteryl ester transfer protein (CETP). We have recently documented CETP deficiency in a family with hyperalphalipoproteinemia, due to a CETP gene splicing defect. The purpose of the present study was to characterize the plasma lipoproteins within the low density lipoprotein (LDL) density range and also the cholesteryl ester fatty acid distribution amongst lipoproteins in CETP-deficient subjects. In CETP deficiency, the conventional LDL density range contained both an apoE-rich enlarged high density lipoprotein (HDL) (resembling HDLc), and also apoB-containing lipoproteins. Native gradient gel electrophoresis revealed clear speciation of LDL subclasses, including a distinct population larger in size than normal LDL. Anti-apoB affinity-purified LDL from the CETP-deficient subjects were shown to contain an elevated triglyceride to cholesteryl ester ratio, and also a high ratio of cholesteryl oleate to cholesteryl linoleate, compared to their own HDL or to LDL from normal subjects. Addition of purified CETP to CETP-deficient plasma results in equilibration of very low density lipoprotein (VLDL) cholesteryl esters with those of HDL. These data suggest that, in CETP-deficient humans, the cholesteryl esters of VLDL and its catabolic product, LDL, originate predominantly from intracellular acyl-CoA:cholesterol acyltransferase (ACAT). The CETP plays a role in the normal formation of LDL, removing triglyceride and transferring LCAT-derived cholesteryl esters into LDL precursors.