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Genetic variants of angiopoietin-like protein 3 (ANGPTL3) are associated with serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) concentration in GWASs. ANGPTL3 deficiency causes declined TG, total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) serum concentration, a phenotype defined as familial combined hypolipidaemia (FHBL2). Our aim is to establish whether ANGPTL3 serum protein concentration correlates with lipoproteins and lipids in hyper- or hypolipidaemic subjects, and whether ANGPTL3 sequence variants are associated with untypical lipid profiles. Additionally, 10 subjects with very low lipoprotein concentrations were sequenced for ANGPTL3 for possible loss-of-function (LOF) variants. Study subjects were selected from Finnish FINRISK and Health 2000 surveys. ANGPTL protein concentrations were measured by ELISA method. As a result, ANGPTL3 serum concentration correlated positively with age, phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) activities, but not with any of the lipid or lifestyle attributes. No ANGPTL3 variants were found among sequenced samples. Subjects who carried ANGPTL3 sequence variants rs12563308 (n = 4) and rs199772471 (n = 1) had abnormally high TC and LDL-C concentrations. Whole exome sequencing data of these five subjects were further analyzed for rare and deleterious missense variants in genes associated with cholesterol metabolism. In conclusion, ANGPTL3 serum protein concentration did not predict lipid concentrations, unlike apolipoprotein C-III (apoC-III) which positively correlated with most of the lipid attributes. ANGPTL3 variant screen yielded five carriers with abnormally high TC concentration; the actual genetic causality, however, could not be verified. Show less

Fetal growth restriction (GR) is associated with perinatal mortality and subsequent metabolic disorders in adulthood. Until now, there is little information regarding changes in the properties of lipoproteins from growth-restricted fetuses and their maternal sera. To identify unique lipoprotein biomarkers for fetal GR in maternal and cord sera from small neonates, we analyzed lipoprotein compositions and functions. Lipoprotein compositions and functions were compared between cord blood and maternal blood among small for gestational age neonates (SGA; n = 15, 2589 ± 50 g) and appropriate for gestational age neonates (AGA; n = 15) in Korea. Cord blood from the SGA group showed 2-fold higher triglyceride (TG) and TG/high-density lipoprotein cholesterol levels than the AGA group as well as significantly lower (up to 20%) paraoxonase activity and apolipoprotein (apo) A-I content. The SGA group showed the highest cholesteryl ester transfer protein activities in both cord and maternal sera. SGA neonates showed elevated apo-B content in very low-density lipoprotein, 52% reduction of apo A-I content in high-density lipoprotein, and 30% increased glycation (P < .001) compared with AGA neonates. Especially, low-density lipoprotein from the SGA group showed 1.9-fold higher sensitivity to oxidation as well as 3-fold greater uptake into macrophages, suggesting stronger proatherosclerotic properties. Lipoproteins from maternal serum of SGA neonates showed greater oxidation along with TG enrichment and loss of antioxidant ability. On microinjection of cord serum (50 nL) into zebrafish embryos, the SGA group showed the most severe embryonic damage. Lipoproteins from cord and maternal sera of SGA neonates resulted in severe impairment of functional and structural correlations accompanied by greater pro-oxidant and proatherosclerotic properties. Show less

Atherosclerosis is a pathology leading to cardiovascular diseases with high epidemiologic impact; thus, new therapies are required to fight this global health issue. Immunotherapy is a feasible approach to treat atherosclerosis and given that genetically engineered plants are attractive hosts for vaccine development; we previously proved that the plant cell is able to synthesize a chimeric protein called CTB:p210:CETPe, which is composed of the cholera toxin B subunit (CTB) as immunogenic carrier and target epitopes from the cholesteryl ester transfer protein (CETP Show less

Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-β HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established. Show less

Cardiovascular morbidity and mortality are of increasing concern, not only to patients but also to the health care profession and service providers. The preventative benefit of treatment of dyslipidaemia is unquestioned but there is a large, so far unmet need to improve clinical outcome. There are exciting new discoveries of targets that may translate into improved clinical outcome. Areas covered: This review highlights some new pathways in cholesterol and triglyceride metabolism and examines new targets, new drugs and new molecules. The review includes the results of recent trials of relatively new drugs that have shown benefit in cardiovascular endpoint outcomes, drugs that have been licenced without endpoint trials yet available and new drugs that have not yet been licenced but have produced exciting results in animal studies and some in early phase 2 human studies. Expert opinion: The new areas that have been discovered as the cause of dyslipidaemia have opened up a host of new targets for new drugs including antisense RNA's, microRNA's and human monoclonal antibodies. The plethora of new targets and new drugs has made it an extraordinarily exciting time in the development of therapeutics to combat atherosclerosis. Show less

The polymorphisms/mutations of genes encoding proteins and enzymes involved in lipoprotein metabolism play important roles in the development of diabetic dyslipidemia. The aim of our study was to investigate the effects of LPL (rs320), LIPC (rs2070895), SCARB1 (rs5888), LCAT (rs2292318), CETP (rs708272), ADIPOQ (rs1501299), RETN (rs3745367), PON1 (rs662), and MNSOD (rs4880) gene polymorphisms on lipid metabolism and diabetic dyslipidemia. This case-control study included 217 patients with diabetic dyslipidemia and 212 healthy age- and gender-matched individuals. Genomic DNA isolation was performed from blood samples, and genotype analysis was performed using melting curve analysis on a LightCycler® 480 Instrument. The chi-square test was used to compare genotype distribution and allele frequencies between the groups. Significant associations were observed between LPL (rs320) (p<0.001), LIPC (rs2070895) (p<0.001), SCARB1 (rs5888) (p<0.001), LCAT (rs2292318) (p<0.001), CETP (rs708272) (p<0.001), ADIPOQ (rs1501299) (p=0.01), RETN (rs3745367) (p<0.001), and MNSOD (rs4880) (p<0.001) polymorphisms and diabetic dyslipidemia. However, no association was observed between PON1 (rs662) polymorphisms and diabetic dyslipidemia (p=0.611). LPL (rs320), LIPC (rs2070895), SCARB1 (rs5888), LCAT (rs2292318), CETP (rs708272), ADIPOQ (rs1501299), RETN (rs3745367), and MNSOD (rs4880) polymorphisms play an important role in basic molecular metabolism in diabetic dyslipidemia. Therefore, these polymorphisms may be used as a predictive marker for diabetic dyslipidemia in high-risk patients. Show less

Disturbance in lipid metabolism has been suggested as a major pathogenic factor for age-related macular degeneration (AMD). Conventional lipid measures have been inconsistently associated with AMD. Other factors that can alter lipid metabolism include lipoprotein phenotype and genetic mutations. We performed a case-control study to examine the association between lipoprotein profile and neovascular AMD (nAMD) and whether the cholesterylester transfer protein ( Show less

High-density lipoproteins (HDL) are involved in reverse cholesterol transport. Results from randomized trials of HDL-targeting therapies, including cholesteryl ester transfer protein (CETP) inhibitors, have shown a lack of benefit in unsegmented populations. These observations could be explained by inter-individual variability of clinical responses to such agents depending on the patients' genotypes. In parallel, although lowering of LDL cholesterol (LDL-c) with statin therapy reduces the risk of vascular events in a wide range of individuals, inter-individual variability exists with regard to LDL-c-lowering response as well as efficacy in reducing major cardiovascular events. Pharmacogenomic analyses were performed in the dal-OUTCOMES and dal-PLAQUE-2 studies. Beneficial and concordant results were observed in patients with the favorable genotype when treated with the CETP inhibitor dalcetrapib. Similarly, previous studies revealed genetic variants associated with differential LDL-c response to statin therapy. In this review, we discuss the pharmacogenetic determinants of HDL-targeting and statin therapy responses in light of the latest available published data, and their potential therapeutic applications. Show less

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; Show less

Hepatitis C virus (HCV) is a leading cause of chronic liver diseases and the most common indication for liver transplantation in the United States. HCV particles in the blood of infected patients are characterized by heterogeneous buoyant densities, likely owing to HCV association with lipoproteins. However, clinical isolates are not infectious in vitro and the relative infectivity of the particles with respect to their buoyant density therefore cannot be determined, pointing to the need for better in vivo model systems. To analyze the evolution of the buoyant density of in vivo-derived infectious HCV particles over time, we infected immunodeficient human liver chimeric fumaryl acetoacetate hydrolase Similar to the severe combined immunodeficiency disease/Albumin-urokinase plasminogen activator human liver chimeric mouse model, density fractionation of infectious mouse serum showed higher infectivity in the low-density fractions early after infection. However, over the course of the infection, viral particle heterogeneity increased and the overall in vitro infectivity diminished without loss of the human liver graft over time. In mice provided with a sucrose-rich diet we observed a minor shift in HCV infectivity toward lower density that correlated with a redistribution of triglycerides and cholesterol among lipoproteins. Our work indicates that the heterogeneity in buoyant density of infectious HCV particles evolves over the course of infection and can be influenced by diet. Show less

To determine the frequency of the genotypes of single nucleotide polymorphisms (SNPs) in the gene encoding cholesteryl ester transfer protein (CETP) and their associations with age-related macular degeneration (AMD) in the Lithuanian population. A total of 1264 subjects were examined: 251 patients with early AMD, 206 patients with exudative AMD, and 807 healthy controls. The genotyping of CETP (rs5882, rs708272, rs3764261, rs1800775, rs2303790) was carried out using the RT-PCR. Binomial logistic regression analysis revealed that each copy of rs5882 allele A was associated with a 1.3-fold increased risk of exudative AMD (p=0.046). The G/A and A/A genotypes of the rs708272 polymorphism were associated with 1.5-fold and 1.7-fold increased risks of exudative AMD (p=0.049 and p=0.021, respectively). Combination of two genotypes (G/A+A/A) under the dominant model were associated with a 1.5-fold increased risk of exudative AMD (p=0.021). Analysis of rs708272 revealed that the G/A and A/A genotypes under the co-dominant model were associated with 1.5-fold and 1.7-fold increased risks of exudative AMD, respectively (OR=1.450, 95% CI=1.002-2.098; p=0.049 and OR=1.710, 95% CI=1.064-2.156; p=0.021, respectively). Both genotypes (G/A+A/A) under the dominant model were associated with the 1.5-fold increased risk of exudative AMD, as well (OR=1.514, 95% CI=1.064-2.156; p=0.021) and each additional copy A allele was associated with a 1.3-fold increased risk of exudative AMD (OR=1.316, 95% CI=1.051-1.646; p=0.016). The rs3764261 polymorphism was identified to be protective: the C/A genotype and the combination of two genotypes (C/A+A/A) were associated with 1.8-fold and 1.5-fold decreased risks of exudative AMD (p=0.001 and p=0.015, respectively). Our study identified two polymorphisms with a higher risk of AMD development (rs5882 and rs708272) and a protective polymorphism for AMD (rs3764261). Show less

It is well-known that policosanol can improve serum lipid profiles, although the physiological mechanism is still unknown. Here, we investigated functional and structural changes in lipoproteins after consumption of policosanol. To investigate the physiological effect of policosanol, we analyzed serum parameters in young non-smoker (YN; n=7, 24.0±2.4 years), young smoker (YS; n=7, 26.3±1.5 years), and middle-aged subjects (MN; n=11, 52.5±9.8 years) who consumed policosanol daily (10 mg/day) for 8 weeks. After 8 weeks, systolic blood pressure was significantly lowered to 4% (7 mmHg, p=0.022) from initial levels in the YS and MN groups. Moisture content of facial skin increased up to 38 and 18% from initial levels in the YS and MN groups, respectively. Serum triglyceride (TG) levels decreased to 28 and 26% from initial levels in the YN and MN groups, respectively. The percentage of high-density lipoprotein-cholesterol (HDL-C) in total cholesterol was elevated in all subjects (YN, 36%; YS, 35%; MN, 8%) after 8 weeks of policosanol consumption. All groups showed a reduction in serum glucose and uric acid levels. Serum cholesteryl ester transfer protein (CETP) activity was significantly diminished up to 21 and 32% from initial levels in the YN and MN groups, respectively. After 8 weeks, oxidation of the low-density lipoprotein fraction was markedly reduced accompanied by decreased apolipoprotein B (apoB) fragmentation. In the HDL fraction, paraoxonase activity was elevated by 17% along with elevation of apoA-I and cholesterol contents. Electron microscopy revealed that the size and number of HDL particles increased after 8 weeks, and the YS group showed a 2-fold increase in particle size. Daily consumption of policosanol for 8 weeks resulted in lowered blood pressure, reduced serum TG level and CETP activity, and elevated HDL-C contents. These functional enhancements of HDL can prevent and/or attenuate aging-related diseases, hypertension, diabetes and coronary heart disease. Show less

Cholesteryl ester transfer protein (CETP) inhibitors are a new class of therapeutics for dyslipidemia that simultaneously improve two major cardiovascular disease (CVD) risk factors: elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. However, the detailed molecular mechanisms underlying their efficacy are poorly understood, as are any potential mechanistic differences among the drugs in this class. Herein, we used electron microscopy (EM) to investigate the effects of three of these agents (Torcetrapib, Dalcetrapib and Anacetrapib) on CETP structure, CETP-lipoprotein complex formation and CETP-mediated cholesteryl ester (CE) transfer. We found that although none of these inhibitors altered the structure of CETP or the conformation of CETP-lipoprotein binary complexes, all inhibitors, especially Torcetrapib and Anacetrapib, increased the binding ratios of the binary complexes (e.g., HDL-CETP and LDL-CETP) and decreased the binding ratios of the HDL-CETP-LDL ternary complexes. The findings of more binary complexes and fewer ternary complexes reflect a new mechanism of inhibition: one distal end of CETP bound to the first lipoprotein would trigger a conformational change at the other distal end, thus resulting in a decreased binding ratio to the second lipoprotein and a degraded CE transfer rate among lipoproteins. Thus, we suggest a new inhibitor design that should decrease the formation of both binary and ternary complexes. Decreased concentrations of the binary complex may prevent the inhibitor was induced into cell by the tight binding of binary complexes during lipoprotein metabolism in the treatment of CVD. Show less

Genetic and environmental (behavior, clinical, and demographic) factors are associated with increased risks of both myocardial infarction (MI) and high cholesterol (HC). It is known that HC is major risk factor that may cause MI. However, whether there are common single nucleotide polymorphism (SNPs) associated with both MI and HC is not firmly established, and whether there are modulate and modified effects (interactions of genetic and known environmental factors) on either HC or MI, and whether these joint effects improve the predictions of MI, is understudied.The purpose of this study is to identify novel shared SNPs and modifiable environmental factors on MI and HC. We assess whether SNPs from a metabolic pathway related to MI may relate to HC; whether there are moderate effects among SNPs, lifestyle (smoke and drinking), HC, and MI after controlling other factors [gender, body mass index (BMI), and hypertension (HTN)]; and evaluate prediction power of the joint and modulate genetic and environmental factors influencing the MI and HC.This is a retrospective study with residents of Erie and Niagara counties in New York with a history of MI or with no history of MI. The data set includes environmental variables (demographic, clinical, lifestyle). Thirty-one tagSNPs from a metabolic pathway related to MI are genotyped. Generalized linear models (GLMs) with imputation-based analysis are conducted for examining the common effects of tagSNPs and environmental exposures and their interactions on having a history of HC or MI.MI, BMI, and HTN are significant risk factors for HC. HC shows the strongest effect on risk of MI in addition to HTN; gender and smoking status while drinking status shows protective effect on MI. rs16944 (gene IL-1β) and rs17222772 (gene ALOX) increase the risks of HC, while rs17231896 (gene CETP) has protective effects on HC either with or without the clinical, behavioral, demographic factors with different effect sizes that may indicate the existence of moderate or modifiable effects. Further analysis with the inclusions of gene-gene and gene-environmental interactions shows interactions between rs17231896 (CETP) and rs17222772 (ALOX); rs17231896 (CETP) and gender. rs17237890 (CETP) and rs2070744 (NOS3) are found to be significantly associated with risks of MI adjusted by both SNPs and environmental factors. After multiple testing adjustments, these effects diminished as expected. In addition, an interaction between drinking and smoking status is significant. Overall, the prediction power in successfully classifying MI status is increased to 80% with inclusions of all significant tagSNPs and environmental factors and their interactions compared with environmental factors only (72%).Having a history of either HC or MI has significant effects on each other in both directions, in addition to HTN and gender. Genes/SNPs identified from this analysis that are associated with HC may be potentially linked to MI, which could be further examined and validated through haplotype-pairs analysis with appropriate population stratification corrections, and function/pathway regulation analysis to eliminate the limitations of the current analysis. Show less

Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function. Show less

The objective of this study was to observe the infection of human cytomegalovirus (HCMV) to human umbilical vein endothelial cells, and its effect on the expression of single-stranded DNA-binding protein (SSBP1) and on lipid metabolism in endothelial cells. We screened the differential expression of mRNAs after HCMV infection by suppression subtractive hybridization and the expression levels of SSBP1 mRNA and protein after HCMV infection by real-time PCR and western blot. After verification of successful infection by indirect immunofluorescent staining and RT-PCR, we found a differential expression of lipid metabolism-related genes including LDLR, SCARB, CETP, HMGCR, ApoB and LPL induced by HCMV infection. The expression levels of SSBP1 mRNA and protein after HCMV infection were significantly down-regulated. Furthermore, we found that upregulation of SSBP1 inhibited the expression of atherosclerosis-associated LDLR, SCARB, HMGCR, CETP as well as the accumulation of lipids in the cells. The results showed that the inhibition of SSBP1 by HCMV infection promotes lipid accumulation in the cells. Show less

Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has been recently studied as a cholesterol modifying agent to reduce cardiovascular risk and mortality in high risk cardiovascular disease patients. Evacetrapib acts to decrease lipid exchange through CETP inhibition. CETP acts to transfer cholesteryl esters from high-density lipoprotein-cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoprotein (VLDL-C). HDL-C is involved in reverse cholesterol transport and its blood levels have been shown to be inversely correlated with cardiovascular risk. Thus, a pharmacologic agent that can elevate HDL-C has been seen as an exciting area of research. In recent studies, evacetrapib was shown to be safe and efficacious. It produced an increase in HDL-C up to 128% and a 35% decrease in LDL-C, in comparison to placebo. In addition, evacetrapib was also shown to be more potent than previous CETP inhibitors. HDL-C particles treated with evacetrapib remained functional and had improved cholesterol efflux. A previously studied CETP inhibitor, torcetrapib, exhibited side effects of hyperaldosteronism, manifesting in electrolyte disturbances, and hypertension. These detrimental effects were not seen with evacetrapib. Recently, the results of evacetrapib's phase III ACCELERATE trial showed no significant reduction in major adverse cardiovascular events or mortality, and the drug will not be marketed. Although beneficial cholesterol effects were seen with this drug, more needs to be known to understand what role, if any, evacetrapib has in the reduction of cardiovascular risk. Show less

The mechanism of cholesteryl ester transfer protein (CETP) in lipid metabolism is still unclear. Furthermore, the relationship of CETP and atherosclerosis (AS) has been controversial. As pigs are a good model for both lipid and AS research, we investigated the lipid metabolism of human CETP (hCETP) transgenic pigs and explored the mechanism of CETP in lipid modulation. Plasmids expressing the hCETP gene were designed, successfully constructed, and transfected into porcine fetal fibroblasts by liposomes. Using somatic cell nuclear transfer technology and embryonic transfer, hCETP transgenic pigs were generated. After the DNA, RNA, and protein levels were identified, positive hCETP transgenic pigs were selected. Blood samples were collected at different ages to evaluate the phenotypes of biochemical markers, and the metabolomes of plasma samples were analyzed by liquid mass spectrometry. Eight positive hCETP transgenic pigs and five negative cloned pigs were generated by transgenic technology. Finally, five hCETP transgenic and five cloned pigs were grown healthily. After feeding with a normal diet, hCETP transgenic pigs compared with unmodified pigs had no significant differences in body weight, liver function, kidney function, or plasma ions, while total cholesterol and low-density lipoprotein were higher than in unmodified pigs, and high-density lipoprotein was significantly decreased. Metabolomics analysis showed that there were differences in metabolic components between hCETP transgenic pigs, cloned pigs, and unmodified pigs. In this study, we created hCETP transgenic pigs that could serve as an excellent model for lipid disorders and atherosclerosis. Show less

The contribution of polymorphisms associated with adult lipids in early life is unknown. We studied 158 adult lipid polymorphisms in 1440 participants (544 children, 544 mothers and 324 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) birth cohort. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) measurements were collected at birth, 3 and 5 years of age. Polymorphisms were genotyped using the Illumina Cardio-Metabochip array. Genotype scores (GS) were calculated for TC, HDL-C, LDL-C and TG. Linear and mixed-effects regressions adjusted for sex, age and population stratification were performed. The GS was associated with LDL-C level at 3 and 5 years (β = 0.017 ± 0.003, P = 2.9 × 10 Show less

To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD. Show less

Xanthohumol, a prominent prenyl flavonoid from the hop plant (Humulus lupulus L.), is suggested to be antiatherogenic since it reportedly increases high-density lipoprotein (HDL) cholesterol levels. It is not clear whether xanthohumol promotes reverse cholesterol transport (RCT), the most important antiatherogenic property of HDL; therefore, we investigated the effects of xanthohumol on macrophage-to-feces RCT using a hamster model as a CETP-expressing species. In vivo RCT experiments showed that xanthohumol significantly increased fecal appearance of the tracer derived from intraperitoneally injected [ Show less

To investigate the effect of apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP) and proprotein convertase subtilisin kexin type 9 (PCSK9) polymorphisms on the lipid-lowering response to simvastatin therapy in Thai hypercholesterolemic patients. Two hundred and twenty-five hypercholesterolemic patients in southern Thailand were enrolled and treated with simvastatin 20 or 40 mg per day for 3 months. Serum lipids were measured before and after the therapy. APOE, CETP TaqIB, and PCSK9 (R46L, I474V, and E670G) polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). After 3 months of simvastatin therapy, subjects with APOE2 (Total cholesterol [TC]: -30.89% vs-13.56%, P < .05, LDL-C: -45.00% vs -17.73%, P < .05) and APOE3 carriers (TC: -26.22% vs -13.56%, P < .05, LDL-C: -37.14% vs -17.73%, P < .05) had greater TC and LDL-C reduction compared to APOE4 carriers, whereas CETP TaqIB B2B2 genotype showed lower TC (-16.37% vs -24.92%, P = .016) and LDL-C (-22.54% vs -35.19%, P = .028) reduction compared to CETP TaqIB B1 carriers. In addition, PCSK9 474IV carriers showed greater LDL-C (-50.57% vs -32.99%) reduction compared to PCSK9 474II carriers. Combined effect analyses showed that individuals carrying more risk alleles tended to have lower TC and LDL-C (P for trend = .000 and .000, respectively) reduction in response to simvastatin therapy. APOE4 carriers and the CETP TaqIB B2B2 genotype were associated with a decreased response, but PCSK9 474IV carriers tended to be associated with an increased response to simvastatin therapy in Thai hypercholesterolemic patients. Show less

Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .). Show less

Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Odds ratio (OR) for major cardiovascular events. The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles. Show less

Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neovascular AMD (tAMD). We aim to examine the extent to which common genetic variants are shared between these two subtypes. We performed the meta-analysis of association in a total of 1062 PCV patients, 1157 tAMD patients and 5275 controls of East Asian descent from the Genetics of AMD in Asians Consortium at the 34 known AMD loci. A total of eight loci were significantly associated with PCV, including age-related maculopathy susceptibility 2 (ARMS2)-HtrA serine peptidase 1 (HTRA1), complement factor H (CFH), C2-CFB-SKIV2L, CETP, VEGFA, ADAMTS9-AS2 and TGFBR1 (P<5 × 10 Show less