👤 J D Otvos

Familial dysbetalipoproteinemia (FDB) is a genetic lipoprotein disorder that can develop in patients homozygous for the APOE2 genotype (ε2/ε2). It is associated with decreased clearance of remnant lipoproteins and increased atherosclerotic cardiovascular disease (ASCVD) risk disproportionate to their level of LDL-C. A goal of this study was to develop a screening test for the ε2/ε2 genotype based on routinely available lipid tests and to determine those at most risk for ASCVD. After assembly of a primary prevention cohort from the UK Biobank (n= 269,895), gene array and exome data was utilized to classify patients as being ε2/ε2 genotype positive or negative. Lipid profiles and APOB levels were extracted and the number of ASCVD events was tabulated during a 15-year follow-up period. Using a newly developed equation for estimating APOB (eAPOB) with lipid panel test results, the ratio of measured APOB to eAPOB was better than any other individual lipid test or ratio for identifying patients with the ε2/ε2 genotype (AUC: APOB/eAPOB: 0.990 (0.986-0.994), nonHDL-C/APOB: 0.961 (0.952-0.970), APOB: 0.955 (0.949-0.961), VLDL/TG: 0.788 (0.771-0.804)). The majority of ε2/ε2 patients could be identified with the APOB/eAPOB ratio even before they expressed the FDB phenotype with elevated TG and nonHDL-C. The PCE or PREVENT risk equations were the most accurate method for identifying higher risk patients (AUC: PREVENT: 0.690 (0.637-0.742), PCE: 0.697 (0.645-0.749)). The APOB/eAPOB ratio can be used to accurately identify the ε2/ε2 genotype and conventional risk equations are the best method for determining those at risk for ASCVD. Show less

Atherogenic lipoprotein exposure during young adulthood increases the risk of atherosclerotic cardiovascular disease (ASCVD) later in life. The relationships between cumulative and usual yearly apolipoprotein B (apoB), low-density lipoprotein particle (LDL-P), and triglyceride-rich lipoprotein particle (TRL-P) exposure in early adult life and incident ASCVD was quantified. Follow-up data of young adults aged 18 to <40 years from the longitudinal population-based Coronary Artery Risk Development in Young Adults (CARDIA) cohort were used. Cumulative early adult exposure of apoB, LDL-P, and TRL-P were defined over a 22-year exposure period (18 to <40 years). 'Usual' exposure to atherogenic lipid particles was calculated by dividing the cumulative exposure to apoB, LDL-P, and TRL-P by 22 years, and the hazard ratio was calculated between a 1 SD higher cumulative lipoprotein exposure with incident ASCVD after age 40 using adjusted Cox regression models. Among 4366 CARDIA participants, there were 241 ASCVD events after age 40 (mean follow-up of 19.3 years). A 1 SD higher cumulative exposure to apoB, LDL-P, and TRL-P was associated with unadjusted HRs of 1.53 [95% confidence interval (CI) 1.36-1.72], 1.54 (95% CI 1.36-1.75), and 1.48 (95% CI 1.30-1.68) for incident ASCVD after age 40, respectively. Adjustment for covariates yielded HRs for each measure of approximately 1.30. The hazard ratio for ASCVD increased after a usual apoB exposure of approximately 75 mg/dL/year from age 18 to <40. Cumulative exposure to atherogenic lipid particles in young adulthood increases the risk for incident ASCVD later in life. Apolipoprotein B concentration <75 mg/dL may represent a goal to maintain low risk in young adults. Show less

Aortic valve calcification (AVC) shares pathological features with atherosclerosis. Lipoprotein components have been detected in aortic valve tissue, including HDL (high-density lipoprotein). HDL measures have inverse associations with cardiovascular disease, but relationships with long-term AVC progression are unclear. We investigated associations of HDL cholesterol, HDL-particle number and size, apoC3-defined HDL subtypes, and, secondarily, CETP (cholesteryl ester transfer protein) mass and activity, with long-term incidence and progression of AVC. We used linear mixed-effects models to evaluate the associations of baseline HDL indices with AVC. AVC was quantified by Agatston scoring of up to 3 serial computed tomography scans over a median of 8.9 (maximum 11.2) years of follow-up in the Multi-Ethnic Study of Atherosclerosis (n=6784). After adjustment, higher concentrations of HDL-C (high-density lipoprotein cholesterol), HDL-P (HDL particles), large HDL-P, and apoC3-lacking HDL-C were significantly associated with lower incidence/progression of AVC. Neither small or medium HDL-P nor apoC3-containing HDL-C was significantly associated with AVC incidence/progression. When included together, a significant association was observed only for HDL-C, but not for HDL-P. Secondary analyses showed an inverse relationship between CETP mass, but not activity, and AVC incidence/progression. In exploratory assessments, inverse associations for HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL with AVC incidence/progression were more pronounced for older, male, and White participants. ApoC3-containing HDL-C only showed a positive association with AVC in these subgroups. In a multiethnic population, HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL-C were inversely associated with long-term incidence and progression of AVC. Further investigation of HDL composition and mechanisms could be useful in understanding pathways that slow AVC. Show less

Lipoprotein particles with abnormal compositions, such as lipoprotein X (LP-X) and lipoprotein Z (LP-Z), have been described in cases of obstructive jaundice and cholestasis. The study objectives were to: (1) develop an NMR-based assay for quantification of plasma/serum LP-Z particles, (2) evaluate the assay performance, (3) isolate LP-Z particles and characterize them by lipidomic and proteomic analysis, and (4) quantify LP-Z in subjects with various liver diseases. Assay performance was assessed for linearity, sensitivity, and precision. Mass spectroscopy was used to characterize the protein and lipid content of isolated LP-Z particles. The assay showed good linearity and precision (2.5-6.3%). Lipid analyses revealed that LP-Z particles exhibit lower cholesteryl esters and higher free cholesterol, bile acids, acylcarnitines, diacylglycerides, dihexosylceramides, lysophosphatidylcholines, phosphatidylcholines, triacylglycerides, and fatty acids than low-density lipoprotein (LDL) particles. A proteomic analysis revealed that LP-Z have one copy of apolipoprotein B per particle such as LDL, but less apolipoprotein (apo)A-I, apoC3, apoA-IV and apoC2 and more complement C3. LP-Z were not detected in healthy volunteers or subjects with primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, or type 2 diabetes. LP-Z were detected in some, but not all, subjects with hypertriglyceridemia, and were high in some subjects with alcoholic liver disease. LP-Z differ significantly in their lipid and protein content from LDL. Further studies are needed to fully understand the pathophysiological reason for the enhanced presence of LP-Z particles in patients with cholestasis and alcoholic liver disease. Show less

The effect of genetic variation on plasma lipoproteins and their subfraction distribution was examined. Forty Hispanic men and 223 women and 42 non-Hispanic white men and 53 women participated in the study. Genotypes for cholesteryl ester transfer protein (CETP TaqIB), hepatic lipase (LIPC -480 C > T), lipoprotein lipase (LPL S447X), and apolipoprotein CIII (APOC3--455T > C) were determined by polymerase chain reaction. Lipoprotein particle size distribution was determined by nuclear magnetic resonance. For all but APOC3, genotype effects were homogeneous in the ethnic/racial groups and men and women. Effects were seen primarily in the women. Compared to women carriers of the common CETP B1 allele, B2B2 women had significantly higher plasma levels of high-density lipoprotein cholesterol (HDL-C) (16.4.0%, p = 0.001), reflected in the level of larger HDL particles (21.9%, p = 0.001), and larger mean particle size of HDL (2.3%, p = 0.01) and low-density lipoproteins (LDL) (1.3%, p = 0.02). Compared to LPL 447S homozygous women carriers of the LPL 447X allele had significantly lower levels of very-low-density lipoprotein-triglyceride (VLDL-TG) (21.0%, p = 0.02). For APOC3, there was significant gender:genotype interaction with the genotype differences seen only in the men. Compared to men homozygous for the -455T allele, carriers of -455C had higher levels of VLDL-TG (71.4%, p = 0.0001), reflected in a larger mean VLDL particle size (13.7%, p = 0.009). LIPC genotype was not associated with significant effects on any of these traits. These data confirm the role of genetic variants of CETP, LPL and APOC3 in determining the relationship between VLDL, LDL and HDL particles. Show less

Apolipoprotein (apo) CIII participates in the regulation of the metabolism of triglyceride-rich lipoproteins and it is a major component of chylomicrons and VLDL. The APOC3 gene is on chromosome 11q23 and is highly polymorphic. The less common allele (S2) of the SstI polymorphism on the 3' untranslated region of the APOC3 gene has been previously associated with increased triglycerides, total cholesterol (TC), and apoCIII levels and cardiovascular risk on several, but not all, studies. The aim of this study was to examine the association of this polymorphism with plasma lipid levels, lipoprotein subfractions and coronary heart disease (CHD) risk in a population-based study: The Framingham Offspring Study. The frequency of the S2 allele was 0.086, consistent with previous reports in Caucasian populations. In men, the S2 allele was associated with lower concentrations of high-density lipoprotein cholesterol (HDL-C; P<0.04) and HDL2-C (P<0.02) and a significant increase in apoCIII non-HDL (P<0.05). TG levels were higher in men carriers of the S2 allele, but this association did not reach statistical significance (P=0.30). Conversely, in women, the S2 allele was associated with increased TC (P<0.03), low-density lipoprotein cholesterol (LDL-C; P<0.03), and ApoB levels (P<0.04). Lipoproteins subfractions were also examined using nuclear magnetic resonance (NMR) spectroscopy. S2 male carriers had significantly lower concentrations of large LDL and a significant reduction in LDL particle size (P<0.04). In women, there was a significant increase in intermediate LDL particles (P<0.05) with no significant effect on lipoprotein diameters. We also examined the associations between the S2 allele and biochemical markers of glucose metabolism. In men, the S2 allele was associated with elevated fasting insulin concentrations (P<0.04), whereas no significant associations were observed in women. Despite the described associations with lipid and glucose metabolism related risk factors, we did not find any significant increase in CHD risk associated with the S2 allele in this population. Show less