Biomedical subjects
Publications and source records attributed to R M Krauss.
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Comparison of genomic DNA sequences from human and mouse revealed a new apolipoprotein (APO) gene (APOAV) located proximal to the well-characterized APOAI/CIII/AIV gene cluster on human 11q23. Mice expressing a human APOAV transgene showed a decrease in plasma triglyceride concentrations to one-third of those in control mice; conversely, knockout mice lacking Apoav had four times as much plasma triglycerides as controls. In humans, single nucleotide polymorphisms (SNPs) across the APOAV locus were found to be significantly associated with plasma triglyceride levels in two independent studies. These findings indicate that APOAV is an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease.
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PURPOSE: Elevated plasma concentrations of low-density lipoproteins (LDL) increase risk for coronary heart disease. However, lipoprotein profiles rich in small, dense LDL particles confer greater risk than those that mainly consist of large, buoyant LDL. This may be due, in part, to the greater oxidative susceptibility of small, dense LDL. In the current studies, we tested whether differences in the oxidative behavior of buoyant and dense LDL arise from differences in their immediate metabolic precursors, intermediate-density lipoproteins. SUBJECTS AND METHODS: We compared the properties of intermediate-density lipoproteins and buoyant and dense LDL subfractions in 9 subjects with the large, buoyant LDL phenotype versus 6 with the small, dense LDL phenotype. Oxidative susceptibility was evaluated based on conjugated diene formation and parinaric acid oxidation induced by copper. Antioxidants (ubiquinol-10 and alpha-tocopherol) were measured by high-performance liquid chromatography. RESULTS: Oxidative susceptibility was increased and antioxidant concentrations were decreased with increasing lipoprotein density (intermediate intermediate-density lipoproteins to buoyant LDL to dense LDL). Intermediate-density lipoproteins from subjects with the small, dense LDL phenotype had a greater oxidative susceptibility (by the parinaric acid test) and lower antioxidant concentrations than corresponding particles from subjects with the large, buoyant LDL phenotype. CONCLUSIONS: Differences in oxidative susceptibility between large, buoyant and small, dense LDL particles are apparent in their lipoprotein precursors. These results suggest that lipoprotein oxidative susceptibility may be metabolically programmed and that intermediate-density lipoproteins may contribute to the increased risk associated with the small, dense LDL phenotype.
BACKGROUND: Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents. METHODS: This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable. RESULTS: Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein. CONCLUSION: Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.
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Studies employing analysis of LDL subclasses have demonstrated heterogeneity of the LDL response to low fat, high carbohydrate diets in healthy nonobese subjects. In individuals with a genetically influenced atherogenic lipoprotein phenotype, characterized by a predominance of small dense LDL (LDL subclass pattern B), lowering of plasma LDL cholesterol levels by diets with < or =24% fat has been found to represent a reduction in numbers of circulating mid-sized and small LDL particles, and hence an expected lowering of cardiovascular disease risk. In contrast, in the majority of healthy individuals with larger LDL (pattern A, found in approximately 70% of men and a larger percentage of women), a significant proportion of the low fat diet-induced reduction in plasma LDL cholesterol is made by depletion of the cholesterol content of LDL particles. This change in LDL composition is accompanied by a shift from larger to smaller LDL particle diameters. Moreover, with progressive reduction of dietary fat and isocaloric substitution of carbohydrate, an increasing number of subjects with pattern A convert to the pattern B phenotype. Studies in families have indicated that susceptibility to induction of pattern B by low fat diets is under genetic influence. Thus, diet-gene interactions affecting LDL subclass patterns may contribute to substantial interindividual variability in the effects of low fat diets on coronary heart disease risk.
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We have tested whether differences in distribution and dietary responsiveness of low-density lipoprotein (LDL) subclasses contribute to the variability in the magnitude of LDL-cholesterol reduction induced by diets low in total and saturated fat and high in carbohydrate. Our studies have focused on a common, genetically influenced metabolic profile, characterized by a predominance of small, dense LDL particles (subclass pattern B), that is associated with a two- to threefold increase in risk for coronary artery disease. We have found that healthy normolipidemic individuals with this trait show a greater reduction in LDL cholesterol and particle number in response to low-fat, high-carbohydrate diets than do unaffected individuals (subclass pattern A). Moreover, such diets result in reduced LDL particle size, with induction of pattern B in a substantial proportion of pattern A men. Recent studies have indicated that this response is under genetic influence. Future identification of the specific genes involved may lead to improved targeting of dietary therapies aimed at reducing cardiovascular disease risk.
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The insulin resistance syndrome (IRS) is characterized by a combination of interrelated coronary heart disease risk factors, including low high-density lipoprotein cholesterol (HDLC) levels, obesity and increases in triglyceride (TG), systolic and diastolic blood pressure (BP), small low-density lipoprotein particles (LDL-size), and fasting and postload plasma insulin and glucose. Using factor analysis, we previously identified multivariate factors based on data from women participating in the Kaiser Permanente Women Twins Study: 1) Weight/Fat, 2) Insulin/Glucose, 3) Lipids, and 4) BP. The purpose of this study is to evaluate evidence for genetic linkage between the multivariate factors and candidate genes. Quantitative sib-pair analysis based on the factor scores with markers for 9 candidate genes was carried out based on data from 126 pairs of dizygotic (DZ) women twins from the second exam of the Kaiser Permanente Women Twins study. Suggestive evidence for linkage was found for the Weight/fat factor and the Apo E gene (p = 0.01), and stronger evidence for linkage with the Lipid factor and the cholesterol ester transfer protein (p = 0.002) gene. Therefore, the CETP gene appears to influence covariation in LDL size, TG, and HDL, and may account for a portion of the well-established statistical and metabolic associations observed between these risk factors.
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To accelerate the biological annotation of novel genes discovered in sequenced regions of mammalian genomes, we are creating large deletions in the mouse genome targeted to include clusters of such genes. Here we describe the targeted deletion of a 450-kb region on mouse chromosome 11, which, based on computational analysis of the deleted murine sequences and human 5q orthologous sequences, codes for nine putative genes. Mice homozygous for the deletion had a variety of abnormalities, including severe hypertriglyceridemia, hepatic and cardiac enlargement, growth retardation, and premature mortality. Analysis of triglyceride metabolism in these animals demonstrated a several-fold increase in hepatic very-low density lipoprotein triglyceride secretion, the most prevalent mechanism responsible for hypertriglyceridemia in humans. A series of mouse BAC and human YAC transgenes covering different intervals of the 450-kb deleted region were assessed for their ability to complement the deletion induced abnormalities. These studies revealed that OCTN2, a gene recently shown to play a role in carnitine transport, was able to correct the triglyceride abnormalities. The discovery of this previously unappreciated relationship between OCTN2, carnitine, and hepatic triglyceride production is of particular importance because of the clinical consequence of hypertriglyceridemia and the paucity of genes known to modulate triglyceride secretion.
Earlier work has shown that increasing concentration of palmitic acid at the sn-2 position of a fat enhances the atherogenic properties of that fat. This effect has been observed with lard, tallow, cottonseed oil, and palm oil. In the experiment reported here, we have studied the atherogenic effects of four synthetic fats fed to rabbits as 58% (w/w) of the total fat (15%) (w/w) of a semipurified diet containing 0.05% cholesterol. The fats being tested were: 1,3-stearoyl-2-oleoylglycerol (SOS); 1,2-stearoyl-3-oleoylglycerol (SSO); 1,3-palmitoyl-2-oleoylglycerol (POP); and 1,2-palmitoyl-3-oleoylglycerol (PPO). After 20 wk on diet there were no differences among the groups in weight gain, liver weight, serum, or liver lipids. These data are consistent with our previous findings. There were significant differences in atherosclerosis. The most severe atherosclerosis was observed in group PPO and the least in groups SSO and POP. Severity of atherosclerosis was graded visually on a 0-4 scale. The average atherosclerosis [(aortic arch and thoracic aorta) divided by 2] was: SOS--1.35; SSO--0.97; POP--0.83; and PPO--1.80. Fecal fat excretion (an indicator of fat absorption) was higher in the two groups fed the stearic acid-rich fats and lower in groups fed the palmitic acid-rich fats. There were no differences in low density lipoprotein particle size. The results confirm previous findings concerning the increased atherogenicity of fats bearing palmitic acid at the sn-2 position. The mechanism underlying these observations is moot but may, in part, reflect greater absorption of the atherogenic fat.
OBJECTIVES: To test the hypothesis that a garlic supplement alters plasma lipoproteins, postprandial lipemia, low-density lipoprotein (LDL) size and high-density lipoprotein (HDL) subclass distribution differently in 50 moderately hypercholesterolemic subjects classified as LDL subclass pattern A or B. BACKGROUND: Garlic has been variably reported to reduce or not affect plasma cholesterol values. Low-density lipoprotein pattern B is a common inherited disorder of lipoprotein metabolism that has been shown to have a significantly greater response to several lipid lowering treatments including low fat diet when compared with LDL pattern A individuals. METHODS: A double blind, randomized, placebo controlled trial in an outpatient lipid research clinic was performed and included fifty moderately hypercholesterolemic subjects (mean LDL cholesterol = 166 +/- 22 mg/dl) classified as LDL subclass pattern A (predominantly large LDL, n = 22) or B (predominantly small LDL, n = 28). Following a two-month stabilization period, subjects were randomly assigned to a placebo or 300 mg three times a day of a standardized garlic tablet for three months. RESULTS: For all subjects, LDL pattern A and B subjects combined, garlic treatment for three months resulted in no significant change in total cholesterol, LDL cholesterol, HDL cholesterol, HDL subclass distribution, postprandial triglycerides, apolipoprotein B, lipoprotein (a) (Lp[a]), LDL peak particle diameter or LDL subclass distribution. There was no significant difference in response for the same parameters among subjects classified as LDL pattern A or B with the exception of significantly greater (p = 0.01) reduction in mean peak particle diameter in pattern A subjects treated with either garlic or placebo. There was no significant change in LDL subclass distribution. CONCLUSIONS: This investigation confirms that garlic therapy has no effect on major plasma lipoproteins and further, that it has no impact on HDL subclasses, Lp(a), apolipoprotein B, postprandial triglycerides or LDL subclass distribution. Garlic may have a greater effect on LDL particle diameter in LDL pattern A compared with pattern B subjects. This difference was not reflected in other plasma lipid measurements.
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BACKGROUND: A genetically influenced atherogenic lipoprotein phenotype characterized by a predominance of small, dense LDL particles (subclass pattern B) can be induced by low-fat diets in healthy subjects with large LDL particles (pattern A). OBJECTIVE: The aim of this study was to test whether genetic predisposition to subclass pattern B contributes to susceptibility to induction of this trait by a low-fat diet. DESIGN: The prevalence of pattern B in children is relatively low compared with that in older individuals, but genetic susceptibility to this trait in offspring can be inferred by its presence in their parents. Plasma lipoproteins were analyzed 10 d after a change from a usual diet to a very-low-fat (10% fat), high-carbohydrate diet in offspring (mean age: 14 y; range: 7-28 y) of 22 families according to parental LDL-subclass patterns when consuming a low-fat diet: AxA mating (9 families with 19 children), AxB mating (5 families with 10 children), and BxB mating (8 families with 21 children). RESULTS: The very-low-fat, high-carbohydrate diet produced significantly greater decreases in LDL particle size in offspring of BxB parents (f1.gif" BORDER="0"> +/- SE: -0.55 +/- 0.16 nm) and AxB parents (-0.48 +/- 0.19 nm) than in offspring of AxA parents (0.14 +/- 0.20 nm). The number of children expressing pattern B with the 10%-fat diet and the proportion of children converting from pattern A to pattern B was significantly greater in offspring of BxB parents than in those with 1 or 2 pattern A parents. CONCLUSION: A very-low-fat, high-carbohydrate diet can induce expression of LDL-subclass pattern B in genetically predisposed children with low expression of the trait while consuming their usual diets.