Cholesteryl Ester Transfer Protein Deficiency Research Articles

A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Māori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236mmol/L and lower LDL-C by 0.133mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.

HDL Receptor in Schistosoma japonicum Mediating Egg Embryonation: Potential Molecular Basis for High Prevalence of Cholesteryl Ester Transfer Protein Deficiency in East Asia.

Schistosomiasis is a life-threatening parasitic disease caused by blood flukes, Schistosomes. In its intestinal type, the parasites reside in visceral/portal veins of the human hosts and lay eggs to excrete in feces via intestinal tracts, and some of the aberrant eggs plug into the liver via the portal blood flow. Ectopic growth of these eggs causes fatal granulomatosis and cirrhosis of the liver. The parasites ingest nutrients from the host blood plasma by using nonspecific and specific transport via their body surface and alimentary tracts. It is especially important for the female adults to obtain lipid molecules because they synthesize neither fatty acids nor sterols and yet produce egg yolk. Low-density lipoprotein receptors have been identified in the body of the Schistosomes but their functions in the parasite life cycle have not clearly been characterized. On the other hand, CD36-related protein was identified in the body and the eggs of Asian blood fluke, Schistosoma japonicum, and characterized as a molecule that mediates selective uptake of cholesteryl ester from the host plasma high-density lipoproteins (HDLs). This reaction was shown crucial for their eggs to grow to miracidia. Interestingly, abnormal large HDL generated in lack of cholesteryl ester transfer protein (CETP) is a poor substrate for this reaction, and, therefore, CETP deficiency resists pathogenic ectopic growth of the aberrant parasite eggs in the liver. This genetic mutation is exclusively found in East Asia, overlapping with the current and historic regions of Schistosoma japonicum epidemic, so that this infection could be related to high prevalence of CETP deficiency in East Asia.

Long-term Benefits and Harms Associated With Genetic Cholesteryl Ester Transfer Protein Deficiency in the General Population

The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown. To assess the relative benefits and harms associated with genetic CETP deficiency. This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018. Weighted CETP allele scores. Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non-high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency. Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol. This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD.

Development and Clinical Application of an Enzyme-Linked Immunosorbent Assay for Oxidized High-Density Lipoprotein.

Aims: HDL particles have various anti-atherogenic functions, whereas HDL from atherosclerotic patients was demonstrated to be dysfunctional. One possible mechanism for the formation of dysfunctional HDL is the oxidation of its components. However, oxidized HDLs (Ox-HDLs) remain to be well investigated due to lack of reliable assay systems. Methods: We have developed a novel sandwich enzyme-linked immunosorbent assay (ELISA) for Ox-HDL by using the FOH1a/DLH3 antibody, which can specifically recognize oxidized phosphatidylcholine, a major component of HDL phospholipid (HDL-PL). We defined forced oxidation of 1 mg/L HDL-PL as 1 U/L Ox-HDL. We assessed serum Ox-HDL levels of normolipidemic healthy subjects ( n =94) and dyslipidemic patients ( n =177). Results: The coefficients of variation of within-run and between-run assays were 12.5% and 13.5%. In healthy subjects, serum Ox-HDL levels were 28.5±5.0 (mean±SD) U/L. As Ox-HDL levels were moderately correlated with HDL-PL (r=0.59), we also evaluated the Ox-HDL/HDL-PL ratio, which represents the proportion of oxidized phospholipids in HDL particles. In dyslipidemic patients, Ox-HDL levels were highly variable and ranged from 7.2 to 62.1U/L, and were extremely high (50.4±13.3U/L) especially in patients with hyperalphalipoproteinemia due to cholesteryl ester transfer protein deficiency. Regarding patients with familial hypercholesterolemia, those treated with probucol, which is a potent anti-oxidative and anti-hyperlipidemic drug, showed significantly lower Ox-HDL (16.2±5.8 vs. 30.2±5.4, p ＜0.001) and Ox-HDL/HDL-PL ratios (0.200±0.035 vs. 0.229±0.031, p =0.015) than those without probucol. Conclusion: We have established a novel sandwich ELISA for Ox-HDL, which might be a useful and easy strategy to evaluate HDL functionality, although the comparison study between this Ox-HDL ELISA and the assay of HDL cholesterol efflux capacity remains to be done. Our results indicated that probucol treatment may be associated with lower Ox-HDL levels.

Shotgun proteomic analysis reveals proteome alterations in HDL of patients with cholesteryl ester transfer protein deficiency

We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions. This study aimed to investigate the protein composition of HDL particles in patients with CETP-D. Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL. We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3±6.9 vs 43.7±2.5, P<.001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9±5.3 vs 27.1±3.7, 2.3±1.1 vs 0.4±1.1, respectively; P<.01). We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D.

A15333 Relationship of Human CETP Deficiency Variant, HDL and Acute Myocardial Infarction in Chinese Population

A15333 Relationship of Human CETP Deficiency Variant, HDL and Acute Myocardial Infarction in Chinese Population

Abstract 180: Missense Mutations in ABCA1 and CETP Associate with Changes in the HDL Proteome in Primate Half-Sibs Discordant for HDL Cholesterol Levels

HDL protein composition and corresponding function may impact cardiovascular disease risk. Identifying genetic variation that influences the HDL proteome may reveal modifiable HDL functions that impact this risk. We studied genetic determinants of the HDL proteome in a cohort of rhesus macaques enriched for extreme HDL cholesterol levels (HDL-c). We selected macaques from 2 distinct paternal half-sibships, each comprising 8 half-sib pairs matched for age-class and sex, but with large differences in HDL-c (N=22 genomes). HDL was isolated by ultracentrifugation and the protein cargo analyzed by mass spectrometry. Identified peptide sequences were compared to a Swiss-Prot canonical human protein database using BLAST to determine ortholog matches. Among the proteins identified, 64 are among the 229 reported in similar human studies, and 45 of these 64 are among the 95 highest-confidence HDL proteins tracked by the HDL Proteome Watch. We performed deep exome sequencing, and assessed predicted function for all genetic variants in macaques, among 23 genes associated with HDL disorders or variation in HDL-c in humans. We focused on the higher-impact variants most likely to have conserved effects between macaques and humans by proximity (i.e., &lt;10 bp) to known human mutations. This produced a set of 3 missense variants in ABCA1 associated with Tangier disease and HDL deficiency, and 4 missense variants in CETP associated with CETP deficiency, reduced CETP activity, and hyper- and hypoalphalipoproteinemias. Using a measured genotype approach, we tested for association of all 7 variants with adjusted spectral counts, while accounting for age and sex, and applied a false discovery rate (FDR) of 20% to all nominally significant results. After controlling for FDR, 3 missense variants in ABCA1 were significantly associated with spectral counts for VCAM1 , ITGA2 , and ITGB1 (nominal P-values 0.0005-0.0026), and 4 missense variants in CETP were significantly associated with spectral counts for APOA2 , APOC3 , C4BPA , and PLTP (nominal P-values 0.0002-0.0038). While our results require replication, these proteins suggest that changes in HDL-c in macaques are associated with changes in HDL that modulate vascular inflammation, immune response, and particle remodeling.

Particle number analysis of lipoprotein subclasses by gel permeation HPLC in patients with cholesteryl ester transfer protein deficiency.

ObjectiveWe previously reported that patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) have a higher prevalence of atherosclerotic cardiovascular disease, in spite of increased HDL-C levels. However, characterization of HDL in CETP-D has not been well described. Therefore, we examined HDL particle number (PN) rather than HDL-C level.Approach and resultsNine patients with CETP-D and 9 normolipidemic subjects were enrolled. We performed gel permeation high-performance liquid chromatography (GP-HPLC) analysis, determined the cholesterol and triglyceride composition of all lipoprotein subclasses, and calculated the PN of each subclass, which consisted of 3 VLDL (large, medium, and small), 4 LDL (large, medium, small, and very small), and 5 HDL (very large, large, medium, small, and very small) subclasses. The PNs of large and medium LDL were significantly lower in CETP-D than that in healthy subjects (0.66- and 0.63-fold decrease, respectively; p<0.001), whereas the PN of very small LDL, which is known to be atherogenic, was significantly higher (1.36-fold increase, p = 0.016). The PNs of very large and large HDL in CETP-D were markedly higher than that in healthy subjects (19.9- and 4.5-fold increase, respectively; p<0.001), whereas the PNs of small and very small HDL, which have more potent anti-atherogenic functions, were significantly lower (0.76- and 0.61-fold decrease, respectively; p<0.001).ConclusionWe have assessed the PNs of detailed subclasses of patients with CETP-D for the first time. The PN of larger HDL was markedly increased, that of smaller HDL was decreased, and that of very small LDL was increased, suggesting that CETP-D has pro-atherogenic lipoprotein properties.

Shotgun proteomics analysis characterizes HDL proteome in patients with cholesteryl ester transfer protein deficiency

Shotgun proteomics analysis characterizes HDL proteome in patients with cholesteryl ester transfer protein deficiency

P 227 - The role of cholesteryl ester transfer protein expression on endothelial cells: oxidative stress and vascular dysfunction

High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with development of atherosclerotic coronary heart disease and studies demonstrate that cholesteryl ester transfer protein (CETP) deficiency is associated with markedly increased HDL levels. HDL may exert atheroprotective activity by preventing endothelial dysfunction, a key step in the development of atherosclerosis. However, the CETP effects per se on endothelial function needs to be clarified. This study evaluates the role of CETP in the setting of early atherosclerosis and its contribution to endothelial dysfunction. In vitro, knockdown of Human Aortic Endothelial Cells (HAECs) with siCETP, prevented expression of adhesion molecules. Notably, eNOS activity was augmented in aortas of CETP-transgenic mice and correlated with decreased levels of inhibitory interaction with caveolin-1. Furthermore, the presence of CETP in aortas coincided with an increase in vascular production of reactive oxygen species evidenced by augmented oxidized to reduced glutathione ratio (GSSG/GSH), increased superoxide and hydrogen peroxide production and a marked decrease in endothelium-dependent vasorelaxation. Together, these findings suggest a role for CETP in promoting endothelial dysfunction and highlight the role in promoting oxidative stress.

Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation.

To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events. However, outcome studies of three CETP inhibitors (torcetrapib, dalcetrapib and evacetrapib) were prematurely terminated because of increased mortality or futility despite marked increases in HDL-cholesterol and decreases in LDL-cholesterol except for dalcetrapib. Patients with CETP deficiency show remarkable changes in HDL and LDL and are sometimes accompanied by atherosclerotic cardiovascular diseases. Recent prospective epidemiological studies demonstrated atheroprotective roles of CETP. CETP inhibition induces formation of small dense LDL and possibly dysfunctional HDL and downregulates hepatic scavenger receptor class B type I (SR-BI). Therefore, CETP inhibitors may interrupt LDL receptor and SR-BI-mediated cholesterol delivery back to the liver. For future drug development, the opposite strategy, namely enhancers of RCT via CETP and SR-BI activation as well as the inducers of apolipoprotein A-I or HDL production might be a better approach rather than delaying HDL metabolism by inhibiting a main stream of RCT in vivo.

High-performance gel permeation chromatography analysis demonstrates atherogenic properties of lipoproteins in patients with cholesteryl ester transfer protein deficiency

Objectives: Recent studies have shown that the elevation of serum HDL-cholesterol (HDL-C) levels by CETP inhibitors was not associated with reduced incidence of cardiovascular diseases. Therefore, we should take other parameters beyond HDL-C levels into account. Here, we developed a novel methodology using high-performance gel permeation chromatography (HPLC) to evaluate particle numbers of each lipoprotein subclass.

Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated.

Abstract 395: High-performance Gel Permeation Chromatography Analysis Characterizes Lipoprotein Profiles in Patients with Cholesteryl Ester Transfer Protein Deficiency

Introduction: Recent studies have suggested that HDL efflux capacity could be a potentially beneficial assay to predict the risk of cardiovascular diseases (CVDs), compared to HDL cholesterol (HDL-C) levels. Recently, we developed a novel methodology using high-performance gel permeation chromatography (HPLC) to evaluate lipoprotein particle number of each subclass. In this study, we investigated CETP-deficient (CETP-D) patients, who are elevated in HDL-C levels, but not likely to be protected from atherosclerosis as we reported previously. Hypothesis: To evaluate lipoprotein particle number of each subclass may be also useful to predict the risk of CVDs. Methods: Nine CETP-D patients, whose serum CETP mass was less than 0.1μg/mL, were compared with 9 normolipidemic controls. Free cholesterol, cholesteryl ester, triglyceride and phospholipid levels in each 20 lipoprotein subclass were determined by computer-assisted HPLC. Furthermore, we calculated the particle number of each subclass by using HPLC data and serum apolipoprotein levels, which is newly-developed LipoSEARCH® system (Skylight Biotech Inc, Akita). Results: As we reported previously, serum HDL-C levels were markedly elevated in CETP-D patients compared with controls. The number of very large and large HDL particles in CETP-D patients was markedly higher than that in controls (4237.3±2353.4nM vs 213.4±55.7nM, 7672.2±1368.3nM vs 1720.2±536.6nM, respectively; p&lt;0.001), while the number of small and very small HDL, which have anti-atherogenic function, was significantly lower (4339.1±937.4nM vs 5690.3±467.8nM, 1999.4±514.8nM vs 3256.5±294.0nM, respectively; p&lt;0.001). The number of large and medium LDL was significantly lower in CETP-D patients than that in controls (158.3±36.4nM vs 240.6±51.1nM, 349.1±69.9nM vs 557.3±94.8nM, respectively; p&lt;0.001), whereas the number of very small LDL, which is known to be atherogenic, was significantly higher (233.2±64.8nM vs 171.4±22.1nM, p=0.016). Conclusions: We have investigated particle numbers of each lipoprotein subclass in CETP-D patients. Our data might indicate that CETP deficiency leads to pro-atherogenic lipoprotein profile.

Abstract 132: CETP Deficiency in Rabbits Protects High Fat High Cholesterol Diet Induced Atherosclerosis

CETP has been suggested as an effective and promising target for further reducing cardiovascular events through elevation of the HDL-C levels. The failure of Pfizer’s torcetrapib and Roche’s dalcetrapib raised the question whether increased HDL from pharmacological inhibition of CETP are cardioprotective. Because mice lack CETP naturally, we generated CETP knockout (KO) rabbits by Zinc-finger nucleases (ZFN) to gain insights onto CETP and HDL biology in CVD. The ZFN pairs target on exon 3 of rabbit CETP gene. By microinjection of ZFN mRNA into rabbit embryos, we generated 5 CETP knockout (CETPko) founder rabbits. The founder used for this study contained 4 nucleotides deletion in exon 3 that results in a premature stop codon. Western blot confirms that there is no detectable CETP protein in the homozygous CETPko rabbit plasma and liver. No CETP activity was detected in the CETPko rabbit plasma, consistent with their genotype. At the normal chow fed conditions, there is no significant difference between wild type and CETPko male rabbits in plasma HDLc and total cholesterol (TC) level; whereas female CETPko rabbits show 40 to 100% increase in both HDLc and TC levels compared to wild type ones. By sequential ultracentrifugation method to separate plasma lipoproteins, we found that there is much higher HDL3 component in female CETPko rabbits, but not in male CETPko ones, comparing to their WT age matched control. At the HFHC (3% soy bean oil and 0.3% cholesterol) diet fed conditions, both male and female CETPko rabbits show significantly lower level of TC and LDLc compared to wild type rabbits. At the same time, the HDLc levels are significantly higher in the CETPko rabbits. In addition, apoB depleted plasma from CETPko rabbit showed 2-fold increase in cholesterol efflux tested in human THP1 cells. Furthermore, we measured the atherosclerotic plaque in the rabbit aorta after 16 weeks HFHC diet treatment. The total gross lesion areas in CETPko rabbits were only one-third of those in the wild type rabbits. In conclusion, our study shows that genetic deficiency of CETP in rabbits has beneficial effects on enhancing HDL function and reducing atherosclerosis. Our work sheds light on CETP and HDL biology, and provides valuable information to the development of CETP drugs.

Unique features of high-density lipoproteins in the Japanese: in population and in genetic factors.

Despite its gradual increase in the past several decades, the prevalence of atherosclerotic vascular disease is low in Japan. This is largely attributed to difference in lifestyle, especially food and dietary habits, and it may be reflected in certain clinical parameters. Plasma high-density lipoprotein (HDL) levels, a strong counter risk for atherosclerosis, are indeed high among the Japanese. Accordingly, lower HDL seems to contribute more to the development of coronary heart disease (CHD) than an increase in non-HDL lipoproteins at a population level in Japan. Interestingly, average HDL levels in Japan have increased further in the past two decades, and are markedly higher than in Western populations. The reasons and consequences for public health of this increase are still unknown. Simulation for the efficacy of raising HDL cholesterol predicts a decrease in CHD of 70% in Japan, greater than the extent by reducing low-density lipoprotein cholesterol predicted by simulation or achieved in a statin trial. On the other hand, a substantial portion of hyperalphalipoproteinemic population in Japan is accounted for by genetic deficiency of cholesteryl ester transfer protein (CETP), which is also commonly unique in East Asian populations. It is still controversial whether CETP mutations are antiatherogenic. Hepatic Schistosomiasis is proposed as a potential screening factor for historic accumulation of CETP deficiency in East Asia.

Prevention of fatal hepatic complication in schistosomiasis by inhibition of CETP.

Schistosoma japonicum, once endemic all the East Asia, remains as a serious public health problem in certain regions. Ectopic egg embryonation in the liver causes granulomatosis and eventually fatal cirrhosis, so that prevention of this process is one of the keys to reduce its mortality. The embryonation requires cholesteryl ester from HDL of the host blood for egg yolk formation, and this reaction is impaired from the abnormal large HDL in genetic cholesteryl ester transfer protein (CETP) deficiency. When CETP was expressed in mice that otherwise lack this protein, granulomatosis of the liver was shown increased compared to the wild type upon infection of Schistosoma japonicum. The CETP deficiencies accumulated exclusively in East Asia, from Indochina to Siberia, so that Shistosomiasis can be a screening factor for this accumulation. CD36 related protein (CD36RP) was identified as a protein for this reaction, cloned from the cDNA library of Schistosoma japonicum with 1880-bp encoding 506 amino acids. The antibody against the extracellular loop of CD36RP inhibited cholesteryl ester uptake from HDL and suppressed egg embryonation in culture. Therefore, inhibition of CETP is a potential approach to prevent liver granulomatosis and thereby fatal liver cirrhosis in the infection of Schistosoma japonicum.

Abstract 20674: Genetic CETP Deficiency Associated With Higher eGFR and Lower Coronary Stenosis Index in Dyslipdemic Patients in Japan

Background: It is still controversial whether lower CETP is anti-atherogenic or not. Genetic deficiency should have greater impact on clinical course because its lifetime long effect. We evaluated impact of CETP deficiency on coronary atherosclerosis among dyslipidemic patients with non-familial hypercholesterolemia (non-FH) and with FH in Japanese population that include approximately 10% of heterozygous CETP deficiency. Methods: 374 non-FH dyslipidemic patients (170 males, mean age of 58 ± 14) including 201 subjects coronary angiography (CAG) assessed, and 235 genetically confirmed FH heterozygotes (121 males, mean age of 47 ± 17) including 61 CAG assessed were enrolled. Two common CETP variant, intron 14 G(+1)-to-A transition and D442G missense mutation in exon 15, were genotyped. Fasting lipid profiles without lipid drugs were analysed. Subgroup with LDL-C ≥140mg/dL (52% of non-FH) was defined as “hyper-LDL” in this study. Estimated Glomerular Filtration Rate (eGFR) and other conventional coronary risk factors were also analyzed. Results: Heterozygotes of CETP mutations were identified in 12% in non-FH group, and 8% in FH group. There were no differences in age or sex. In non-FH group, CETP mutations showed higher HDL-C (56 ± 22 vs. 50 ± 15 mg/dL, p &lt;0.05), lower non-HDL-C (172 ± 39 vs. 188 ± 48 mg/dL, p &lt;0.05), lower plasma CETP (2.1 ± 0.8 vs. 2.5 ± 0.7 μg/mL, p &lt;0.05), higher eGFR (83.6 ± 18 vs. 78.1 ± 21 ml/min/1.73m 2 , p &lt;0.05), and lower coronary stenosis index (CSI) (7.0 ± 7 vs. 11.1 ± 11, p &lt;0.05) in CAG. Plasma CETP showed strong positive correlation with LDL-C ( p &lt;0.0001, R 2 13%). In non-FH subgroup, CETP mutation showed lower CSI in hyper-LDL group (5.7 ± 8 vs. 12.6 ± 11, p &lt;0.05), but no difference in normal-LDL group (8.0 ± 7 vs. 10.2 ± 11, ns ). In FH group, CETP mutations showed higher HDL-C (58 ± 19 vs. 48 ± 14 mg/dL, p &lt;0.005), tendency of lower LDL-C (258 ± 51 vs. 275 ± 102 mg/dL, ns ) and higher eGFR (92.4 ± 27 vs. 83.1 ± 21 ml/min/1.73m 2 , ns ), but no difference in CSI (16.2 ± 15 vs. 19.2 ± 11, ns ). High HDL may have favorable effect also on kidney function, but further study will be required for the mechanism. Conclusion: CETP deficiency carriers showed favourable lipid profiles, eGFR, and CSI in non-FH dyslipidemic group especially with high LDL-C.

Cholesteryl ester transfer protein (CETP) deficiency and CETP inhibitors.

Epidemiologic studies have shown that low-density lipoprotein cholesterol (LDL-C) is a strong risk factor, whilst high-density lipoprotein cholesterol (HDL-C) reduces the risk of coronary heart disease (CHD). Therefore, strategies to manage dyslipidemia in an effort to prevent or treat CHD have primarily attempted at decreasing LDL-C and raising HDL-C levels. Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL and LDL. We have published the first report indicating that a group of Japanese patients who were lacking CETP had extremely high HDL-C levels, low LDL-C levels and a low incidence of CHD. Animal studies, as well as clinical and epidemiologic evidences, have suggested that inhibition of CETP provides an effective strategy to raise HDL-C and reduce LDL-C levels. Four CETP inhibitors have substantially increased HDL-C levels in dyslipidemic patients. This review will discuss the current status and future prospects of CETP inhibitors in the treatment of CHD. At present anacetrapib by Merck and evacetrapib by Eli Lilly are under development. By 100mg of anacetrapib HDL-C increased by 138%, and LDL-C decreased by 40%. Evacetrapib 500 mg also showed dramatic 132% increase of HDL-C, while LDL-C decreased by 40%. If larger, long-term, randomized, clinical end point trials could corroborate other findings in reducing atherosclerosis, CETP inhibitors could have a significant impact in the management of dyslipidemic CHD patients. Inhibition of CETP synthesis by antisense oligonucleotide or small molecules will produce more similar conditions to human CETP deficiency and may be effective in reducing atherosclerosis and cardiovascular events. We are expecting the final data of prospective clinical trials by CETP inhibitors in 2015.

Genetic cetp deficiency associated with lower coronary stenosis index in dyslipdemic patients in japan

Genetic cetp deficiency associated with lower coronary stenosis index in dyslipdemic patients in japan