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Biomedical subjects

M A Austin

Publications and source records attributed to M A Austin.

At least 55 records · Page 3Linked to original sources
PubMed1996

Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes.

The role of small, dense LDL as a risk factor for coronary heart disease is becoming well established. Several atherogenic mechanisms have been proposed to explain this relationship, including the association of small, dense LDL with the insulin resistance syndrome. A variety of studies, including large epidemiologic investigations, have now demonstrated that a predominance of small, dense LDL is one of the constellation of interrelated risk factors that characterize the insulin resistance syndrome. Recent results using a multivariate factor analysis approach have also shown that this set of risk factors can be simplified into three or four uncorrelated components that may provide new insights into the mechanisms underlying the syndrome and its association with disease. Furthermore, a number of cross-sectional studies and one prospective study have shown that small, dense LDL is a risk factor for noninsulin-dependent diabetes itself, and that this association may also be attributable to the insulin resistance syndrome.

Diabetes Mellitus, Type 2↗
PubMed1996

Compositional differences of LDL particles in normal subjects with LDL subclass phenotype A and LDL subclass phenotype B.

A predominance of small LDL particles (subclass phenotype B), as determined by gradient-gel electrophoresis is found among patients with myocardial infarction. Despite physical differences in phenotype A and B particles, differences in lipid composition of particles in these phenotypes have yet to be reported in an unselected population of males and females. The present study used lipid/apoB ratios to analyze the amount of lipid per LDL particle, isolated by density-gradient ultracentrifugation, in 70 healthy subjects. Relative to apoB, the LDL particles from phenotype B subjects were found to contain less free cholesterol (0.391 +/- 0.05 versus 0.465 +/- 0.05; mean +/- SD; P < .001), phospholipid (1.26 +/- 0.2 versus 1.43 +/- 0.2; P < .001), and cholesteryl ester (1.97 +/- 0.1 versus 2.11 +/- 0.2; P < .001) than particles from phenotype A subjects. The amount of triglyceride per LDL particle did not differ between the two phenotypes (0.410 +/- 0.1 versus 0.406 +/- 0.1; P = NS) despite higher plasma triglyceride levels in the phenotype B subjects. LDL size and buoyancy were positively correlated with particle free cholesterol, phospholipid, and cholesteryl ester but not with particle triglyceride. These data suggest that the physical properties of LDL from subjects with phenotype A and B reflect their lipid composition. The compositional differences between LDL particles of the two phenotypes may provide new insight into the increased risk of myocardial infarction in subjects with small, dense LDL.

Adult↗
PubMed1996

Genetic epidemiology of dyslipidaemia and atherosclerosis.

The clinical relevance of the heterogeneity in the size and density of low-density lipoprotein (LDL) particles is now widely recognized. The evidence from epidemiological studies, family studies and twins studies demonstrates that small, dense LDL (LDL subclass phenotype B) is a common, genetically influenced risk factor for coronary heart disease (CHD). Several atherogenic mechanisms have been proposed to explain the association of small, dense LDL with CHD, including evidence that small, dense LDL is an integral feature of the insulin resistance syndrome. Furthermore, a recent study in elderly Finnish men and women has shown that phenotype B prospectively predicts non-insulin-dependent diabetes mellitus (NIDDM). In addition, ongoing studies of large Japanese-American kindreds will provide valuable data for evaluating small, dense LDL as a marker for genetic susceptibility to both CHD and NIDDM in a high-risk ethnic group.

Cholesterol, LDL↗
PubMed1996

Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.

OBJECTIVES: Despite nearly 40 years of research, the role of plasma triglyceride as a risk factor for cardiovascular disease remains elusive. The objectives of the present study were to quantify the magnitude of the association between triglyceride and cardiovascular disease in the general population, and to determine whether this relationship is independent of high-density lipoprotein (HDL) cholesterol, using the semi-quantitative techniques of metaanalysis. METHODS AND DESIGN: Seventeen studies were selected for the analysis based on published reports of population-based, prospective studies, including 46413 men and 10864 women. To insure comparability, only studies reporting the association between fasting triglyceride levels and incident cardiovascular endpoints were included. Using standard meta-analysis calculations, relative risks (RR) and 95% confidence intervals (CI) were calculated and standardized with respect to a 1 mmol/l increase in triglyceride. Multivariable-adjusted RRs were determined for the six studies in men and two studies in women that reported adjustments for HDL cholesterol. RESULTS: For men and women, the univariate RRs for triglyceride were 1.32 (95% Cl 1.26-1.39) and 1.76 (95% Cl 1.50-2.07), respectively, indicating an approximately 30% increased risk in men and a 75% increase in women. Adjustment of HDL cholesterol and other risk factors attenuated these RRs to 1.14 (95% Cl 1.05-1.28) and 1.37 (95% Cl 1.13-1.66), respectively, which were still statistically significant values. CONCLUSION: Based on combined data from prospective studies, triglyceride is a risk factor for cardiovascular disease for both men and women in the general population, independent of HDL cholesterol. These finding demonstrate the necessity for clinical trials to evaluate whether lowering plasma triglyceride decreases the risk of cardiovascular disease.

Adolescent↗
PubMed1995

Deletion of the entire NF1 gene detected by the FISH: four deletion patients associated with severe manifestations.

Genetic analysis of NF1 has indicated a wide diversity of mutations, including chromosome rearrangements, deletions, insertions, duplications, and point mutations. Recently, five severely affected individuals have been found by Kayes et Al. [1994] to have deletions encompassing the entire gene. These deletions were detected by quantitative Southern analysis. To simplify deletion detection, we have employed fluorescence in situ hybridization (FISH) using intragenic probes. Thirteen unrelated individuals with NF1 have been studied. Among six with severe manifestations, four have been found to have deletions detected by probes cFF13, cFB5D, cP5, yA43A9, yA113D7 and yD8F4. All four deletions patients have severe developmental delay, minor and major anomalies (including one with bilateral iris colobomas), and multiple cutaneous neurofibromas or plexiform neurofibromas which were present before age 5 years. FISH provides a simple and rapid means of identification of NF1 gene deletions and will allow more rigorous testing of the hypothesis that such deletions are associated with severe manifestations.

Abnormalities, Multiple↗
PubMed1995

Prospective study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women.

BACKGROUND: The excess risk of atherosclerosis among patients with non-insulin dependent diabetes mellitus (NIDDM) is well documented. However, the presence of conventional risk factors cannot fully account for this excess risk, and the underlying mechanism remains to be elucidated. The present study prospectively evaluated the role of small LDL, a known risk factor for coronary heart disease, as a risk factor for the development of NIDDM. METHODS AND RESULTS: The study was based on a nested case-control sample of 204 elderly men and women from Kuopio, Finland. LDL subclasses were characterized by size with 2% to 14% polyacrylamide gels produced by recently developed methods. Logistic regression analysis showed that subjects with a predominance of small LDL (LDL subclass phenotype B) had a greater than two fold increased risk for developing NIDDM over the 3.5-year follow-up period. This association was independent of age, sex, glucose intolerance, and body mass index but was not independent of fasting triglyceride or insulin levels. Further, an increase of 5A in LDL diameter was associated with a 16% decrease in risk of NIDDM, and a composite variable of LDL diameter and triglyceride and HDL cholesterol concentrations, identified by principal-components analysis, was also associated with NIDDM. These associations may be attributable to the role of small LDL as a marker for insulin resistance. CONCLUSIONS: This study is the first to demonstrate that a predominance of small LDL particles is a risk factor for the future development of NIDDM, and it implies that small LDL contributes to risk of coronary heart disease in prediabetics.

Aged↗
PubMed1995

Evidence for genetic influences on smoking in adult women twins.

The purpose of the present study was to examine genetic influences on smoking behavior in women twins, and to compare the results before and after adjusting for environmental covariates. Subjects were participants in the Kaiser Permanente Women Twins Study in Oakland, California. Exam 1 (1978-1979) included 434 pairs of women, and exam 2 (1989-1990) included 352 pairs of women. For comparison with a previous study in male twins, pairwise concordance ratios (OCR) for smoking status between monozygotic (MZ) and dizygotic (DZ) twins were calculated. Multivariate logistic regression analysis was also used to assess the association of smoking behaviors between co-twins, adjusting for age, education, and frequency of contact. At exam 1, OCR's were consistent with previous results in male twins, and supported genetic influences on smoking initiation (OCR = 1.6; 95% Confidence Interval (95% CI) = 1.0, 2.3) and maintenance (OCR = 1.8; 95% CI = 1.3, 2.4). In contrast to the males, however, no clear evidence for genetic influences on smoking intensity or never smoking were present. The adjusted logistic regression models appeared to confirm the findings from the pairwise comparisons. The results were similar for exam 2. These results are consistent with modest genetic influences on smoking initiation and maintenance. Differences between these results and those for the male twins suggest possible genetic-environmental interactions.

Adult↗
PubMed1995

LDL physical and chemical properties in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is characterized by elevations of triglyceride and/or cholesterol within families and an elevation in apoB. Although small dense LDL has been consistently associated with hypertriglyceridemia, small dense LDL persists despite reductions in triglyceride after treatment with gemfibrozil in FCHL. The current study evaluated potential differences in the distribution and chemical composition of LDL species in patients with FCHL and normolipidemic control subjects. LDL from FCHL patients was characterized by a relative abundance of a discrete LDL species with a mean peak analytic ultracentrifuge flotation rate (S0f) of 4.7 +/- 0.5 (SEM), a density of 1.041 +/- 0.001 g/mL, and a particle diameter of 250 +/- 1 A as assessed by gradient gel electrophoresis. The major LDL species in the control subjects had a higher mean S0f rate (6.3 +/- 0.4), was more buoyant (density, 1.037 +/- 0.001 g/mL), and was larger (diameter, 262 +/- 2 A). In addition, in a series of six LDL fractions separated by equilibrium density gradient ultracentrifugation, particle diameters were significantly smaller in all fractions from FCHL patients compared with those from control subjects. LDL particles from patients contained less free cholesterol, cholesteryl ester, and phospholipid than LDL from control subjects. The amount of triglyceride per LDL particle, however, did not differ between FCHL patients and control subjects. Differences in flotation rate and mass of the major LDL species between patients and control subjects could not be fully accounted for by differences in plasma triglyceride levels. Thus, LDL particles from FCHL patients are smaller and more dense with less cholesterol and phospholipid. Many of these differences appear to be independent of plasma triglyceride.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

LDL subclass phenotypes and the risk factors of the insulin resistance syndrome.

The insulin resistance syndrome is characterized by a constellation of risk factors including obesity, central body fat distribution, hypertension, glucose intolerance, elevated plasma insulin levels, increased triglyceride and decreased high-density lipoprotein (HDL) cholesterol. Similarly, low-density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, is associated with increased triglyceride and lower HDL cholesterol levels. Both the insulin resistance syndrome and phenotype B have also been related to increased risk of coronary heart disease. Using a sample of nearly 700 women who participated in the Kaiser Permanente Women Twins Study, we investigated the associations of LDL subclass phenotype B with the risk factors that characterize the insulin resistance syndrome. The results demonstrate that LDL subclass phenotype B was strongly associated with both age and diabetes status. Among nondiabetic women, phenotype B was more prevalent in those with higher body mass index and in those with higher waist-hip ratio. In addition to the expected associations with triglyceride and HDL cholesterol, mean values of both systolic and diastolic blood pressure were higher in women with phenotype B. Finally, fasting and post-load insulin levels and post-load glucose levels were higher in those with phenotype B. In general, these relationships persisted in multivariate statistical analyses. Therefore, a predominance of small, dense LDL particles appears to be an integral feature of the risk factors that characterize the insulin resistance syndrome.

Adult↗
PubMed1994

Genetic influences on age-related change in total cholesterol, low density lipoprotein-cholesterol, and triglyceride levels: longitudinal apolipoprotein E genotype effects.

This study addressed the possible influence of apolipoprotein E (apo E) genotype on age-related changes in total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), and triglyceride (TG) levels in older males. Apo E is a component of LDL, is a ligand for the LDL receptor, and apo E genotype has been consistently associated with variation in mean levels of TC and LDL-C, and also appears to influence TG levels. Using male twins followed longitudinally between mean ages of 48 and 63 years, the change in TC, LDL-C, and TG over time for individuals with the epsilon 3 epsilon 3 and the epsilon 3 epsilon 4 genotypes was contrasted. At exam 1 mean TC and LDL-C levels were lower in the epsilon 3 epsilon 3 group than in the epsilon 3 epsilon 4 group, but at exam 3 mean TC and LDL-C levels were significantly higher in the epsilon 3 epsilon 3 group than in the epsilon 3 epsilon 4 group. The rate of change in TC and LDL-C with age differed significantly between epsilon 3 epsilon 3 and epsilon 3 epsilon 4 groups. Results for TG were not statistically significantly. These findings suggest that the apo E genotype effects on risk of coronary artery disease may be age-dependent. This study demonstrates the value of longitudinal studies in refining models for genetic risk factors for disease.

Adult↗
PubMed1994

Environmental and behavioral influences on plasma lipoprotein(a) concentration in women twins.

BACKGROUND: Genetic factors are firmly established as determinants of plasma lipoprotein(a) [Lp(a)] concentration. This study focused on behavioral or environmental factors that might also explain some of the variation in levels of this cardiovascular disease risk factor. METHODS: The study considers the 644 women twins (597 whites, 47 blacks; ages 30-91 years) who participated in the second examination of the Kaiser Permanente Women Twins Study. Cross-sectional associations of behaviors and environmental factors with Lp(a) concentration were studied before and after removing genetic influences on Lp(a) levels. RESULTS: Lp(a) levels were substantially higher among blacks than whites (P < 0.0001). The distribution of apo(a) size phenotypes also differed between blacks and whites, but this variation did not explain the difference in Lp(a) levels. A positive association of Lp(a) concentration with age was noted among blacks (P = 0.06) but not among whites (P = 0.86). No evidence was found for associations of Lp(a) with menopausal status, cigarette smoking, alcohol consumption, total or heavy recreational physical activity, 11-year weight gain, use of several antihypertensive medications, or diabetes status in either race. Among postmenopausal women, however, estrogen replacement therapy was associated with lower Lp(a) levels among whites (7.9 vs 9.9 mg/dl, P = 0.05). Removing genetic variation in Lp(a) concentration by matching 171 monozygotic (MZ) twins to their genetically identical co-twins did not alter these findings. CONCLUSION: The plasma concentration of Lp(a), unlike other lipoprotein risk factors for heart disease, has few behavioral or environmental correlates, at least among white women. Neither behavioral or environmental factors nor variation in the apo(a) size phenotype appeared to explain the higher mean Lp(a) levels among black compared with white women; further study seems warranted in larger samples of black women.

Adult↗
PubMed1994

Small, dense low-density lipoprotein as a risk factor for coronary heart disease.

Data from case-control and cross-sectional studies uniformly demonstrate an association between small, dense low-density lipoprotein and risk of coronary heart disease. This relationship may be attributable to the association of small, dense low-density lipoprotein with other atherogenic lipoproteins, the presence of the insulin resistance syndrome in subjects with small low-density lipoprotein, and/or the increased oxidative susceptibility of small, dense low-density lipoprotein particles. Furthermore, because small low-density lipoprotein appears to be a common trait in the general population, more than one of these atherogenic mechanisms may be operating simultaneously to increase risk of coronary heart disease.

Adult↗
PubMed1994

Variations in high-density lipoprotein subclasses during the menstrual cycle.

In a study of 41 healthy premenopausal women, plasma high-density lipoprotein-2a (HDL2a) levels (ie, HDL of diameter 8.8 to 9.7 nm) were significantly higher during the luteal phase than during the follicular phase of the cycle. There was no significant variation in HDL2b or any of the HDL3 subclasses.

Adolescent↗
PubMed1994

Epidemiology of triglycerides, small dense low-density lipoprotein, and lipoprotein(a) as risk factors for coronary heart disease.

In addition to LDL cholesterol, triglyceride; small, dense LDL (LDL subclass phenotype B); and lipoprotein(a) are emerging as important risk factors for CHD. Elevated plasma levels of each of these risk factors have consistently been associated with increased risk of CHD in case-control studies of white patients. In prospective studies, however, the association between triglycerides and CHD is generally not independent of HDL cholesterol in multivariate statistical analyses. Although the data are scarce, studies in women show that triglycerides are a stronger risk factor for CHD in women than in men. Although no prospective studies of LDL subclass phenotype B have been reported, a number of potential atherogenic mechanisms may be responsible for the association with CHD seen in the case-control studies. Similarly, few prospective studies of lipoprotein(a) have been published, all in Scandinavian men. The observational studies generally show an association between elevated lipoprotein(a) and CHD in whites but not in blacks. Each of these risk factors also has a genetic component. Of the two familial forms of hypertriglyceridemia, FCH has been associated with familial CHD in two cross-sectional studies. LDL subclass phenotype B is inherited consistent with a single major gene effect, and candidate gene linkage studies are in progress to map the chromosomal location of this proposed gene. Finally, lipoprotein(a) levels are largely attributable to variation at the apo(a) locus on chromosome 6. Whether other genetic variations explain the lack of reported associations between lipoprotein(a) and CHD in black populations remains to be determined. Understanding of these "non-LDL" lipoprotein-related risk factors will provide important information for the development of new, effective intervention strategies for the prevention of CHD.

Arteriosclerosis↗
PubMed1994

Characterization of low-density lipoprotein subclasses: methodologic approaches and clinical relevance.

Emerging evidence suggests that subclasses of LDL, characterized by variations in density, size, and chemical composition of LDL particles, are of important clinical significance. Accumulating case-control studies demonstrate that a predominance of small, dense LDL particles (LDL subclass phenotype B) is associated with an increased risk of coronary heart disease, and several potential atherogenic mechanisms have been proposed. New studies also demonstrate that LDL subclass phenotype B is an integral feature of the insulin resistance syndrome. In addition to the well-documented genetic influences on LDL subclass distributions, lipid-altering drugs, diet, and exercise all appear to affect LDL subclasses. A better understanding of this combination of genetic and environmental influences could lead to the development of effective intervention strategies for the prevention of coronary heart disease.

Case-Control Studies↗
PubMed1994

Genetic and environmental influences on LDL subclass phenotypes.

There is accumulating evidence that subclasses of low-density lipoproteins (LDL) are important in atherosclerosis. Several case-control studies have demonstrated that a predominance of small, dense LDL (LDL subclass phenotype B) is associated with increased risk of coronary heart disease (CHD). Phenotype B is also consistently characterized by an atherogenic lipoprotein phenotype, including increased levels of plasma triglyceride and decreased high-density lipoprotein cholesterol. Family studies and genetic linkage studies demonstrate that LDL subclasses are influenced by a single major gene effect, although this locus (or loci) remain to be definitively mapped. Twin studies confirm the presence of genetic effects, but also show that non-genetic influences are important. Hypolipidemic drugs, beta-blockers, diet and exercise, in particular, appear to influence the expression of LDL subclass phenotypes. This combination of genetic and environmental influences may provide opportunities to develop targeted intervention strategies to reduce CHD risk among genetically susceptible individuals.

Arteriosclerosis↗
PubMed1994

Genetic predictors of FCHL in four large pedigrees. Influence of ApoB level major locus predicted genotype and LDL subclass phenotype.

The genetic basis of familial combined hyperlipidemia (FCHL) has eluded investigators for 20 years, despite the apparent segregation of FCHL as an autosomal dominant disorder affecting 1% to 2% of individuals. Etiologic heterogeneity and additive effects of traits controlled by other genetic loci have been suggested. Two traits have been implicated in FCHL. The first is the predominance of a small, dense low-density lipoprotein (LDL), LDL subclass phenotype B, which segregates as a mendelian trait. The second is a mendelian locus with large effects on apolipoprotein (apo) B levels that is defined by complex segregation analysis (predicted apoB level genotype). This study shows that these factors appear to be separate genetic effects, both of which aid in the prediction of FCHL in four large pedigrees. The results suggest that FCHL may be best predicted by a threshold model in which apoB level genotype and LDL subclass phenotype each act to increase the risk of FCHL. Heterogeneity in the transmission of apoB levels among families is suggested, supporting the etiologic heterogeneity of FCHL. These results emphasize the advantages inherent in the study of large pedigrees when disease heterogeneity is suspected.

Adult↗