Lipoprotein Metabolism Gene Research Articles

Blood lipid profiles, fatty acid deposition and expression of hepatic lipid and lipoprotein metabolism genes in laying hens fed palm oils, palm kernel oil, and soybean oil.

The palm oil, palm kernel oil and soybean oil have unique and distinctive fatty acid chain length and saturation profiles, and how they affect lipid peroxidation, fatty acid intake and metabolism is worth exploring in poultry. This study elucidated the influence the dietary oils on lipid peroxidation, blood lipid profiles, fatty acid deposition of liver, serum and yolk and the expression of liver genes related to lipid and lipoprotein metabolism in laying hens. About 150 Hisex brown laying hens were fed diets containing crude palm oil (CPO), red palm oil (RPO), refined palm oil (RBD), palm kernel oil (PKO) or soybean oil (SBO) for 16 weeks. Serum, liver and yolk lipid peroxidation were not different between dietary oils. The PKO increased liver, serum and yolk medium-chain fatty acids (MCFA). There was no difference in liver saturated fatty acids (SFA). The CPO and RPO reduced serum SFA, but the PKO increased yolk SFA. The SBO increased polyunsaturated fatty acids (PUFA) in liver serum and yolk. No difference in liver elaidic acid (C18:1-trans), but SBO lowered elaidic acid (C18:1-trans) in serum. Higher very-low density lipoprotein (VLDL) in CPO than RPO and SBO and greater serum lipase in CPO, RBD and PKO than SBO. There was no difference in sterol regulatory element-binding protein 2 (SREBP-II) between oils. Apolipoprotein VLDL-II (APOVLDL2) was upregulated in palm oils and apolipoprotein B-100 (APOB) in RBD. Downregulation in peroxisome proliferator-activated receptor-alpha (PPAR-α), peroxisome proliferator-activated receptor gamma (PPAR-γ) and low-density lipoprotein receptor (LDLR) was observed in palm oils and PKO. In conclusion, different dietary oils greatly influence several aspects of fatty acid metabolism, deposition and lipoprotein profiles but have no influence on reducing lipid peroxidation.

Antioxidant Enzyme System Modulation by Dietary Palm Oils, Palm Kernel Oil and Soybean Oil in Laying Hens.

Palm-based oils (palm oil and kernel oil) and soybean oil have unique fatty acid and antioxidant profiles based on the compounds present in them. Hence, this study elucidated the antioxidant properties of crude palm oil (CPO), red palm oil (RPO), refined palm oil (RBD), palm kernel oil (PKO) and soybean oil (SBO) and the influence of dietary oils on blood lipid profiles, tissue fatty acid deposition and the expression of hepatic lipid and lipoprotein metabolism genes in laying hens. The oils were analyzed for color, beta-carotene, free fatty acid and acid value, phenolic content and lipid peroxidation. In an in vivo trial, 150 laying hens were allotted into five groups and supplemented with either CPO, RPO, RBD, PKO or SBO for 16 weeks. High antioxidant compounds present in palm oils help reduce the oxidation of oils. Dietary supplementation with palm oils, particularly CPO and RPO, contributed to the lower liver, serum and jejunal mucosal antioxidant enzyme activities. The antioxidant enzyme genes in the jejunal mucosa were downregulated in palm oils and PKO, but there was no difference between oils in antioxidant enzyme genes in the liver. In conclusion, dietary supplementation with oils with high antioxidant content contributed to protection against oxidation and was associated with a lower requirement for producing antioxidant enzymes.

Hypermethylation and reduced expression of lipoprotein metabolism genes ABCG1, LIPC and PLTP in Obese and Diabetic subjects: Potential risk factors for Coronary artery disease

Hypermethylation and reduced expression of lipoprotein metabolism genes ABCG1, LIPC and PLTP in Obese and Diabetic subjects: Potential risk factors for Coronary artery disease

PPAR control of metabolism and cardiovascular functions.

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.

Fenofibrate Regulates Visceral Obesity and Nonalcoholic Steatohepatitis in Obese Female Ovariectomized C57BL/6J Mice.

Fibrates, including fenofibrate, are a class of hypolipidemic drugs that activate peroxisome proliferator-activated receptor α (PPARα), which in-turn regulates the expression of lipid and lipoprotein metabolism genes. We investigated whether fenofibrate can reduce visceral obesity and nonalcoholic fatty liver disease via adipose tissue PPARα activation in female ovariectomized (OVX) C57BL/6J mice fed a high-fat diet (HFD), a mouse model of obese postmenopausal women. Fenofibrate reduced body weight gain (−38%, p < 0.05), visceral adipose tissue mass (−46%, p < 0.05), and visceral adipocyte size (−20%, p < 0.05) in HFD-fed obese OVX mice. In addition, plasma levels of alanine aminotransferase and aspartate aminotransferase, as well as free fatty acids, triglycerides, and total cholesterol, were decreased. Fenofibrate also inhibited hepatic lipid accumulation (−69%, p < 0.05) and infiltration of macrophages (−72%, p < 0.05), while concomitantly upregulating the expression of fatty acid β-oxidation genes targeted by PPARα and decreasing macrophage infiltration and mRNA expression of inflammatory factors in visceral adipose tissue. These results suggest that fenofibrate inhibits visceral obesity, as well as hepatic steatosis and inflammation, in part through visceral adipose tissue PPARα activation in obese female OVX mice.

Disruption of Lipid Profile and Alteration of Hepatic Lipoprotein Metabolism Gene Expression in Anaemia-induced Rat

Background and Objective: Iron metabolism in animals is altered by haemolytic anaemia induced by phenylhydrazine (PHZ), however, its effects on lipid metabolism remains elusive. The aim of this study was to examine the impact of anaemia on lipid profiles and lipoprotein metabolism gene expression in rats. Materials and Methods: Fourteen adult male Wistar rats were randomly classified into normal control and anaemia‐induced group (n = 7), respectively. Anaemia was induced in rats by daily administration of PHZ at 10 mg kg–1 for 8 consecutive days, after which blood was collected and liver excised. Lipid profiles of plasma and liver were determined spectrophotometrically while the expression of genes associated with lipid and lipoprotein metabolism was assayed by reverse transcriptase polymerase chain reaction. Results: The induced‐anaemia resulted in hypotriglyceridemia and hypophospholipidosis, with concurrent hypercholesteromia compared to control, respectively. Liver triglycerides, phospholipids, cholesterol were observed to be up‐regulated. Anaemic rats showed a significant (p<0. 05) up‐regulation of the relative expression of hepatic lecithin‐cholesterol acyltransferase (Lcat), paraoxonase‐1 (Pon‐1), aryl hydrocarbon receptor (Ahr), 3‐hydroxy‐3‐ methylglutaryl‐CoA reductase (Hmgcr) and down‐regulation of Scavenger Receptor Class B Type I (Scarb1). Conclusion: The induced‐anaemia alter the expression of lipoprotein metabolizing genes which might be the underlying mechanism of anaemia to disrupt lipid metabolism.

Prevalence of Pathogenic Variants of Lipoprotein Metabolism Genes in a Single Lipidology Clinic*

Prevalence of Pathogenic Variants of Lipoprotein Metabolism Genes in a Single Lipidology Clinic*

A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR

We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes PCSK9, APOB, and LDLR. Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 PCSK9, 730 APOB, and 720 LDLR variants were filtered by imputation quality (r2 > 0.4), minor allele frequency (>1%), linkage disequilibrium (r2 < 0.3), and association with LDL-C levels, yielding a set of two PCSK9, three APOB, and five LDLR variants in EA but no variants in AA. Cases and controls were defined for each phecode using the PheWAS package in R. Logistic regression assuming an additive genetic model was used with adjustment for age, sex, and the first two principal components. Significant associations were tested in additional cohorts from Vanderbilt University (n = 29,713), the Marshfield Clinic Personalized Medicine Research Project (n = 9562), and UK Biobank (n = 408,455). We identified one PCSK9, two APOB, and two LDLR variants significantly associated with an examined phecode. Only one of the variants was associated with a non-lipid disease phecode, (“myopia”) but this association was not significant in the replication cohorts. In this large-scale PheWAS we did not find LDL-C-related variants in PCSK9, APOB, and LDLR to be associated with non-lipid-related phenotypes including diabetes, neurocognitive disorders, or cataracts.

Epipolymorphisms within lipoprotein genes contribute independently to plasma lipid levels in familial hypercholesterolemia

Gene polymorphisms associated so far with plasma lipid concentrations explain only a fraction of their heritability, which can reach up to 60%. Recent studies suggest that epigenetic modifications (DNA methylation) could contribute to explain part of this missing heritability. We therefore assessed whether the DNA methylation of key lipoprotein metabolism genes is associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels in patients with familial hypercholesterolemia (FH). Untreated FH patients (61 men and 37 women) were recruited for the measurement of blood DNA methylation levels at the ABCG1, LIPC, PLTP and SCARB1 gene loci using bisulfite pyrosequencing. ABCG1, LIPC and PLTP DNA methylation was significantly associated with HDL-C, LDL-C and triglyceride levels in a sex-specific manner (all P < 0.05). FH subjects with previous history of coronary artery disease (CAD) had higher LIPC DNA methylation levels compared with FH subjects without CAD (P = 0.02). Sex-specific multivariable linear regression models showed that new and previously reported epipolymorphisms (ABCG1-CpGC3, LIPC-CpGA2, mean PLTP-CpGC, LPL-CpGA3, CETP-CpGA2, and CETP-CpGB2) significantly contribute to variations in plasma lipid levels (all P < 0.001 in men and P < 0.02 in women), independently of traditional predictors such as age, waist circumference, blood pressure, fasting plasma lipids and glucose levels. These results suggest that epigenetic perturbations of key lipoprotein metabolism genes are associated with plasma lipid levels, contribute to the interindividual variability and might partially explain the missing heritability of plasma lipid levels, at least in FH.

Adeno-Associated Virus-Based Transgene Delivery for Treating of Progressive Vascular Diseases

There has been much progress in the clinical treatment of Progressive Vascular Diseases (PVD) since the introduction of statins, calcium channel blockers, and other relevant drugs. Yet long term PVD still plagues much of our aged population. The use of gene therapy, delivering therapeutic transgenes, should provide both long-term and safe treatment, as well as more physiologically relevant treatments. Adeno-associated Virus (AAV) can provide long term and safe gene delivery, very appropriate for long term PVD. In regards to therapeutic transgenes for the treatment of PVD, there is the choice of several gene categories, all of which may provide a significant level of efficacy yet have different metabolic modes of action. As examples there are anti-inflammatory cytokine genes, blood lipoproteinmetabolism genes, and anti-oxidant genes.

Modulation of cardiometabolic pathways in skin and serum from patients with psoriasis

BackgroundModerate-to-severe psoriasis is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD); however, the link is poorly understood.MethodsSkin and serum from patients with psoriasis were evaluated to understand if there was evidence of dysregulation in a targeted group of inflammatory and lipid genes related to ASCVD. Microarray analyses of expression of targeted ASCVD genes from skin in 89 patients with moderate-to-severe psoriasis from the ACCEPT trial were compared with non-diseased skin from healthy controls (n = 25). Serum (n = 149) was tested at baseline for monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine (MDC), and apolipoprotein-A1 (Apo-A1) comparing to healthy controls (n=162).ResultsAn increase in skin gene expression for MCP-1 (7.98-fold) and MDC (6.66-fold) (p < 0.001 each) was observed in lesional versus healthy skin. Significant decreases in liver X receptor-alpha (LXR-α) (−5.94-fold), a protective lipoprotein metabolism gene, and in peroxisome proliferator-activated receptor-alpha (PPAR-α) (−7.58-fold), a protective anti-inflammatory and lipid modulating gene, were observed in lesional versus healthy skin (p < 0.001 each). Serum analyses revealed that MCP-1 (502 vs. 141 pg/mL) and MDC (1240 vs. 409 pg/mL) levels were significantly elevated in psoriasis compared with healthy controls (p < 0.001 each). Dysregulated lipid metabolism was also evident in the serum, as Apo-A1, a protein product related to PPAR-α activation, was significantly decreased in patients with psoriasis compared with healthy controls (25.2 vs. 38.9 mg/dL; p < 0.001).ConclusionsAnalyses of targeted genes and their products known to be associated with ASCVD revealed dysregulation of inflammatory (MCP-1 and MDC) and lipid metabolism (LXR-α, PPAR-α) genes in psoriasis. These findings provide evidence of a potential shared pathophysiology linking psoriasis to cardiometabolic diseases.

Regulators of blood lipids and lipoproteins? PPARδ and AMPK, induced by exercise, are correlated with lipids and lipoproteins in overweight/obese men and women

PPARδ is a transcription factor regulating the expression of genes involved in oxidative metabolism, which may regulate blood cholesterols through transcription of oxidative and lipoprotein metabolism genes. To determine the association of skeletal muscle PPARδ content with blood lipids and lipoproteins before and following exercise, overweight and obese men (n = 9) and women (n = 7) were recruited; age, BMI, body fat percentage, and Vo(2max) were (means ± SE) 45 ± 2.5 yr, 31.9 ± 1.4 kg/m(-2), 41.1 ± 1.5%, and 26.0 ± 1.3 mLO(2)·kg(-1)·min(-1), respectively. Subjects performed 12 wk of endurance exercise training (3 sessions/wk, progressing to 500 kcal/session). To assess the acute exercise response, subjects performed a single exercise session on a treadmill (70% Vo(2max), 400 kcal energy expenditure) before and after training. Muscle and blood samples were obtained prior to any exercise and 24 h after each acute exercise session. Muscle was analyzed for protein content of PPARδ, PPARα, PGC-1α, AMPKα, and the oxidative and lipoprotein markers FAT/CD36, CPT I, COX-IV, LPL, F(1) ATPase, ABCAI, and LDL receptor. Blood was assessed for lipids and lipoproteins. Repeated-measures ANOVA revealed no influence of sex on measured outcomes. PPARδ, PGC-1α, FAT/CD36, and LPL content were enhanced following acute exercise, whereas PPARα, AMPKα, CPT I, and COX-IV content were enhanced only after exercise training. PPARδ content negatively correlated with total and LDL cholesterol concentrations primarily in the untrained condition (r ≤ -0.4946, P < 0.05), whereas AMPKα was positively correlated with HDL cholesterol concentrations regardless of exercise (r ≥ 0.5543, P < 0.05). Our findings demonstrate exercise-induced expression of skeletal muscle PPARs and their target proteins, and this expression is associated with improved blood lipids and lipoproteins in obese adults.

Functional validation of new pathways in lipoprotein metabolism identified by human genetics

Recent genome-wide association studies (GWAS) have identified approximately 100 genomic loci that are associated with plasma lipid traits, two-thirds of which had never been previously associated with lipoprotein metabolism. Identification of the causal genes and variants, functional validation of these genes and biological pathways, and elucidation of molecular mechanisms is required and poses a daunting task. Human genetics have been used to recently 'validate' genes, such as LIPG, SCARB1 and ANGPTL3, which were previously implicated in lipoprotein metabolism through classical wet bench approaches. Additionally, many novel genes have been identified as associated with plasma lipid traits by GWAS, though only relatively few have been functionally validated through targeted sequencing and genetic manipulation in cells and animals. These types of studies have defined new roles in lipid metabolism for the novel lipid genes SORT1 and TRIB1. These examples demonstrate the ways in which human genetics can validate candidate genes, as well as provide a novel discovery that requires functional validation at the bench, and point towards a more complete understanding of the molecular physiology of lipoprotein metabolism. This review summarizes recent developments in the use of human genetics to validate candidate genes in lipoprotein metabolism as well as in the functional validation of novel GWAS loci associated with plasma lipid traits.

The androgen receptor drives the sex-specific expression of vascular cell adhesion molecule-1 in endothelial cells but not lipid metabolism genes in monocyte-derived macrophages.

Anecdotal evidence suggests that male sex hormones are proatherogenic. We hypothesized that the male sex hormone receptor, the androgen receptor (AR), acts as a molecular switch in sex-specific inflammatory signaling in vascular cells. AR expression in human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages (MDMs) or HeLa cells was modulated by transfection with AR siRNA or human AR cDNA expression vector. Activity and expression levels were measured by luciferase reporter assays, Western blotting or real-time PCR analysis. AR knockdown reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in genetically male HUVECs. Conversely, AR upregulation in genetically female HUVECs induced VCAM-1 expression and increased dihydrotestosterone-stimulated monocyte adhesion. Co-transfection of an AR expression vector with VCAM-1 or NF-κB-reporter vectors into phenotypically female, AR-negative HeLa cells confirmed AR regulation of VCAM-1 expression as well as AR activation of NF-κB. AR upregulation was not sufficient to increase ICAM-1 levels in female HUVECs or lipoprotein metabolism gene expression in female MDMs, despite AR knockdown limiting expression in their male counterparts. AR acts as a molecular switch to induce VCAM-1 expression. Low AR levels in female HUVECs limit NF-κB/VCAM-1 induction and monocyte adhesion and could contribute to the gender bias in cardiovascular disease. Unidentified factors in female cells limit induction of other proatherogenic genes not primarily regulated by NF-κB.

Interaction effects of high-density lipoprotein metabolism gene variation and alcohol consumption on coronary heart disease risk: the atherosclerosis risk in communities study.

Light to moderate alcohol consumption has been widely established to be protective against coronary heart disease (CHD), whereas heavy alcohol consumption has been shown to have a potential detrimental effect. The reduction in risk of CHD associated with light and moderate alcohol intake is generally attributed to the beneficial effects of alcohol on high-density lipoprotein (HDL) cholesterol levels. Previous research in the Atherosclerosis Risk in Communities (ARIC) study showed all levels of alcohol consumption to be protective against CHD in whites but to be associated with an increased risk of CHD in black men. We investigated the ARIC cohort to determine whether risk of incident CHD is influenced by an interaction effect between alcohol intake and genetic variation involved in the regulation of HDL cholesterol. Genes of interest included cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic lipase (HL), and paraoxonase-1 (PON1). Participants were selected from the ARIC study, a prospective investigation of atherosclerosis and its clinical sequelae, involving 15,792 individuals, ages 45-64 years at recruitment (1987-1989). Incident CHD was identified through annual telephone calls and hospital and death certificate surveillance. Because of ethnic differences in the alcohol-CHD relationship observed in the ARIC cohort and pattern of alcohol consumption differences, statistical analyses were evaluated separately for each race-gender stratum (white men/women, black men/women). Genotype modified the relationship between heavy drinking and CHD risk but did not modify this relationship for light or moderate drinking. Interaction analyses were significant for heavy alcohol intake and PON1 genotype (p=.02) in black men, with a suggested interaction for heavy alcohol intake and CETP genotype (p=.06) in black men. Heavy drinking was associated with an increased risk for CHD in black men with the PON1 QQ and CETP GG genotypes (PON1 hazard rate ratio [HRR]=17.3, 95% confidence interval [CI]: 1.76-170.2; CETP HRR=2.23, 95% CI: 1.01-4.91). Results from the current study suggest that interaction effects between alcohol consumption and HDL cholesterol metabolism gene variation influence the risk of incident CHD in black men. Additional studies are warranted to confirm these findings.

ASSOCIATION OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN −493G/T POLYMORPHISM WITH LIPID METABOLISM AND MICROVASCULAR COMPLICATIONS IN TYPE 2 DIABETIC PATIENTS.

Background Type 2 diabetes (T2D) affects over 15 million Americans, and the prevalence is rising precipitously. T2D patients are at risk for atherosclerosis and microvascular complications; identifying those at risk can lead to improved outcomes. Risk for complications due to dyslipidemia is modulated by genetic factors. Common variations in the microsomal triglyceride transfer protein (MTP −493G/T) and apolipoprotein B (apoB insertion/deletion [In/Del]) genes may modulate the risk for diabetic complications through their impact on lipid metabolism. Methods As part of a longitudinal case-control study of T2D in a French population (401 cases, 113 controls, mean age 59.5 years at baseline, and 4.2-year mean follow-up) we examined the relationship between MTP −493G/T, apoB In/Del, lipoprotein parameters, and the prevalence of diabetic complications. Results After adjusting for relevant covariates, MTP −493G/T was associated with T2D (p = .032), lower apoB concentrations (p = .024), triglycerides (p = .047), total cholesterol (p = .049), body mass index (p = .006), and creatinine levels (p = .007). Given the biochemical interaction of apoB and MTP proteins in the assembly of triglyceride-rich lipoproteins, we tested for their genetic interaction as a predictor of apoB concentration; T2D individuals with MTP T/T and apoB In/In had the highest apoB concentrations (p = .05). MTP −493G/T was associated with nephropathy at follow-up (p = .048), with G-allele homozygotes more likely to have nephropathy than T-allele carriers (odds ratio = 1.621, 95% confidence interval 1.004, 2.616). Conclusion MTP −493G/T is associated with T2D and impacts lipoprotein parameters associated with complications in T2D. Importantly, we contribute novel evidence that lipoprotein metabolism genes are risk factors for diabetic complications.

Evaluation of the role of lipoprotein metabolism genes in systemic cationic liposome-mediated gene transfer in vivo.

Germ line gene disruption and gene insertion are often used to study the function of selected genes in vivo. We used selected knockout and transgenic mouse models to attempt to identify lipoprotein-related genes and gene products that regulate the process of intravenous cationic liposome-DNA complex (CLDC)-based gene delivery. Several observations suggested that proteins involved in lipoprotein metabolism might be important in influencing the delivery and/or expression of CLDC. First, in vitro transfection of either K562 or CHO cells by CLDCs was enhanced by the presence of a functional low-density lipoprotein receptor (LDLR). Second, pretreatment of mice with 4-aminopyrazolopyrimidine (4APP), an agent that alters lipoprotein profiles in mice, significantly decreased expression of luciferase (luc) after intravenous injection of CLDC-luc complexes in mice. Therefore, we tested mouse model systems either deficient for, or overexpressing, selected genes involved in lipoprotein metabolism, for their potential to regulate intravenous, CLDC-based gene delivery. Although homozygous knockout mutation in the apoE gene caused a significant decrease in gene expression in many tissues of apoE-deficient mice, mice with homozygous deletion of both the apoE and LDLR genes showed wild-type levels of gene transfer efficiency. Thus, a secondary event, produced by homozygous deletion of apoE, but compensated for by the concomitant deletion of LDLR, and/or effects resulting from strain-related, genetic background differences, appeared to play a significant role in mediating intravenous, CLDC-based gene delivery. Secondary alterations resulting from germ line knockouts, as well as epigenetic effects produced by strain differences, may limit the ability to assign specific, gene transfer-related functions to the deleted gene.

Multiple Genetic Determinants of Variation of Plasma Lipoproteins in Alberta Hutterites

We hypothesized that variation of nine candidate genes in lipoprotein metabolism would be associated with variation in fasting plasma lipoprotein variables in 718 Alberta Hutterites, a genetic isolate. We measured plasma lipids, lipoproteins, and apolipoproteins and analyzed DNA for genotypes of apolipoprotein (apo) B (APOB), paraoxonase (PON), lipoprotein lipase (LPL), VLDL receptor (VLDLR), apo CIII (APOC3), LDL receptor-related protein (LRP), hepatic lipase (HL), LDL receptor (LDLR), and apo E (APOE). Using a multivariate analysis, we found that (1) genotypes of APOB, PON, LPL, LDLR, and APOE were significantly associated with variation of plasma apo B-related traits; (2) genotypes of PON, LPL, and APOC3 were significantly associated with variation in plasma triglycerides; and (3) genotypes of VLDLR, APOC3, LDLR, and APOE were significantly associated with variation in plasma apo AI and HDL cholesterol. Regression analysis showed that between 3.2% and 7.8% of the total variation in plasma lipoproteins was accounted for by variation in the candidate genes tested. The observations demonstrate a modest but significant genetic component of variation in plasma lipoprotein levels that is due to the candidate genes studied in this normolipemic human genetic isolate.