Biomedical subjects

K L Edwards

Publications and source records attributed to K L Edwards.

At least 19 recordsLinked to original sources

PubMed2006

Functional variants of the lipoprotein lipase gene and the risk of preeclampsia among non-Hispanic Caucasian women.

Hypertriglyceridemia is an important pathophysiologic feature of preeclampsia, a common vascular disorder of pregnancy. Three well-documented functional variants (N291S, S447X, and D9N) of the lipoprotein lipase gene were related to hypertriglyceridemia. Results from the only two studies concerning the relationship between these variants and preeclampsia risk have been inconsistent. We investigated this relationship in a case-control study including 144 preeclamptic and 290 normotensive pregnant women (all non-Hispanic Caucasians). We estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for maternal age, pre-pregnancy body mass index, and parity. After adjusting for covariates, women with the 291 N/S or S/S genotype had significantly increased risk of preeclampsia (OR 6.9, 95% CI 1.9-25.4) compared with women with the common 291N/N genotype. The 447 S/X or X/X genotype was not significantly associated with preeclampsia risk. The frequency of the 9N variant allele was 1.8% in controls, while this allele was not observed among cases. Haplotype 9D/291S/447S was strongly associated with higher risk of preeclampsia as compared with the most common haplotype 9D/291N/447S (adjusted OR 6.6, 95% CI 1.7-25.0). Results from our study support the thesis that abnormal lipid metabolism is important in the pathogenesis of preeclampsia.

Adult↗

PubMed2004

Heritability of C-reactive protein and association with apolipoprotein E genotypes in Japanese Americans.

Numerous studies have demonstrated that increased C-reactive protein (CRP) levels predict coronary heart disease, stroke, peripheral vascular disease, and diabetes, and are associated with features of the metabolic syndrome. Only three previous studies have investigated the heritability of CRP levels, primarily in samples of Caucasian families. The purpose of the present study was to estimate the magnitude of genetic influences on CRP levels, and to examine potential associations between variation in the APOE gene and CRP levels, using a sample of 562 individual Japanese Americans from 68 extended kindreds. In general, correlation coefficients between first-degree relatives for CRP were approximately 0.2, and spouse correlations did not differ from zero, consistent with genetic influences. Heritability estimates were approximately 0.3 (p < 0.01), even with adjustment for factors known to influence CRP levels. A significant relationship was seen between unadjusted CRP levels and APOE genotypes (p = 0.02), with the highest mean CRP level among epsilon2 carriers (1.20 mg/L), and nearly the same mean levels among epsilon3/epsilon3 subjects and epsilon4 carriers (0.72 and 0.74 mg/L, respectively). However, this relationship was diminished with adjustment for covariates (p = 0.07). These results demonstrate the presence of both genetic and environmental effects on CRP levels among Asian Americans, and additional studies are needed to determine if the APOE gene contributes to these genetic influences.

Adult↗

PubMed2001

Complex effects of molecular chaperones on the aggregation and refolding of fibroblast growth factor-1.

Fibroblast growth factor one (FGF-1) exists in a molten globule (MG)-like state under physiological conditions (neutral pH, 37 degrees C). It has been proposed that this form of the protein may be involved in its atypical membrane transport properties. Macromolecular chaperones have been shown to bind to MG states of proteins as well as to be involved in protein membrane transport. We have therefore examined the effect of such proteins on the aggregation and refolding of FGF-1 to evaluate whether they might play a role in FGF-1 transport. The proposed chaperone alpha-crystallin was found to strongly inhibit the aggregation of the MG state of FGF-1. Curiously, two other proteins of similar size and charge (thyroglobulin and a monoclonal IgM immunoglobulin) with no previously reported chaperone properties were also found to have a related effect. In contrast, the chaperone GroEL/ES induced further aggregation of MG-like FGF-1 but had no effect on the native conformation. Both chaperones stimulated refolding to the native state (25 degrees C) but had no detectable effect when FGF-1 was refolded to the MG state (37 degrees C). This suggests that disordered intermediates are present in the folding pathways of the native and MG-like FGF conformations which differ from the MG-like state induced under physiological conditions. FGF-1 does, therefore, interact with molecular chaperones, although this may involve both the MG and the native states of the protein.

Adenosine Triphosphate↗

PubMed2001

Low density lipoprotein particle size and risk of early-onset myocardial infarction in women.

Previous studies of middle-aged men have shown a univariate association between low density lipoprotein (LDL) particle diameter (size) and coronary heart disease, but this association has yet to be examined in younger women. Using a subsample from a population-based case-control study of women living in western Washington State, the authors examined the association between LDL particle size and risk of early-onset myocardial infarction (MI) in 1992-1995. Gradient gel electrophoresis was used to characterize LDL subclasses in nonfasting blood samples from 72 MI cases and 159 controls aged 20-44 years. Mean LDL particle size in cases was significantly smaller compared with controls (26.4 vs. 26.9 nm, p < 0.001), with an odds ratio of 2.3 (p < 0.0001) for a 1-nm smaller LDL particle size. These results were independent of age, menopausal status, smoking, diabetes, hypertension, and LDL cholesterol (odds ratios = 1.9-2.3 for a 1-nm smaller LDL particle size, all p < 0.02) but were not independent of body mass index, high density lipoprotein cholesterol, or triglyceride (odds ratios = 1.4, 1.4, and 1.1, respectively; all p > 0.05). Therefore, in age-adjusted analyses, smaller LDL particle size was associated with MI in young women, but the risk was attenuated after adjustments for metabolic factors related to both LDL particle size and MI.

Adult↗

PubMed2001

Conformational origin of the aggregation of recombinant human factor VIII.

Aggregation of proteins is a major problem in their use as drugs and is also involved in a variety of pathological diseases. In this study, biophysical techniques were employed to investigate aggregate formation in the pharmaceutically important protein, recombinant human factor VIII (rhFVIII). Recombinant human factor VIII incubated in solution at 37 degrees C formed soluble aggregates as detected by molecular sieve chromatography and dynamic light scattering. This resulted in a corresponding loss of biological activity. Fluorescence and CD spectra of the thermally stressed rhFVIII samples did not, however, suggest significant differences in protein conformation. To identify conformational changes in rhFVIII that may be involved in rhFVIII aggregation, temperature and solutes were used to perturb the native structure of rhFVIII. Far-UV CD and FTIR studies of rhFVIII as a function of temperature revealed conformational changes corresponding to an increase in intermolecular beta-sheet content beginning at approximately 45 degrees C with significant aggregation observed above 60 degrees C. Fluorescence and DSC studies of rhFVIII also indicated conformational changes initiating between 45 and 50 degrees C. An increase in the exposure of hydrophobic surfaces was observed beginning at approximately 40 degrees C, as monitored by increased binding of the fluorescent probe, bis-anilinonaphthalene sulfonic acid (bis-ANS). Perturbation by various solutes produced several transitions prior to extensive unfolding of rhFVIII. In all cases, a common transition, characterized by an increase in the wavelength of the fluorescence emission maximum of rhFVIII from approximately 330 to 335 nm, was observed during thermal and solute perturbation of factor VIII. Moreover, this transition was correlated with an increased association of factor VIII upon incubation at 37 degrees C in the presence of various solutes. These results suggest that association of rhFVIII in solution was initiated by a small transition in the tertiary structure of the protein which produced a nucleating species that led to the formation of inactive soluble aggregates.

1-Propanol↗

PubMed2001

Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study.

In order to characterize the lipoprotein abnormalities in familial combined hyperlipidemia (FCHL) and to describe factors associated with the stability of the FCHL phenotype during 20-year follow-up, 287 individuals from 48 families with FCHL originally identified in the early 1970s (baseline) were studied. Hyperlipidemia was defined as lipid-lowering medication use, or > or =age- and sex-specific 90th percentile for triglycerides or cholesterol. Triglyceride, cholesterol and medical history data were obtained at baseline and 20-year follow-up. Additional follow-up measures included HDL-C, LDL-C, LDL particle size, lipoprotein(a), apolipoprotein (apo) A-I, apoB, and apoE polymorphism. Longitudinally, two-thirds of relatives were consistently normolipidemic or hyperlipidemic, and one third were discordant for hyperlipidemic status at baseline and 20-year follow-up. Individuals with hyperlipidemia at baseline and/or follow-up had higher apoB levels than those with consistently normal lipids (P<0.05), whereas small LDL size was associated with concurrent hyperlipidemia. Among individuals who were normolipidemic at baseline, the following variables were independently associated with development of hyperlipidemia over 20 years: older age at baseline, male sex, greater increase in BMI during follow-up, and apoE alleles epsilon 2 or epsilon 4. In conclusion, apoB is associated with hyperlipidemia and apoE polymorphism is associated with later onset of hyperlipidemia in FCHL.

Adult↗

PubMed2001

Lipoprotein(a) as a risk factor for maternal cardiovascular disease mortality in kindreds with familial combined hyperlipidemia or familial hypertriglyceridemia.

Most but not all epidemiologic studies have shown that lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD). Lp(a) levels are also strongly genetically influenced. The purpose of this study was to evaluate the association between Lp(a) levels in adult offspring and parental CVD mortality in 61 kindreds with familial forms of hyperlipidemia. The study sample consisted of offspring-parent pairs in which offspring had fasting Lp(a) measurements and parents had 20-year vital status data and standardized cause-of-death classification if deceased. Linear regression analyses, using a robust variance estimator, were performed separately for 241 offspring with known maternal history (114 mothers) and 194 offspring with known paternal history (93 fathers). Maternal history of CVD mortality was significantly (p=0.004) associated with 2.4-fold higher median Lp(a) levels in offspring compared with those with no maternal history, independent of diabetes, lipid-lowering medications and hormone use. No association was observed between paternal CVD mortality and offspring Lp(a) levels (p=0.505). Adjusting for apolipoprotein(a) kringle 4 number did not alter these parent-specific associations. In conclusion, Lp(a) levels in offspring may be associated with maternal but not paternal history of CVD mortality. This parent-specific finding needs to be confirmed in other samples of high-risk families.

Adolescent↗

PubMed2001

Lipoprotein candidate genes for multivariate factors of the insulin resistance syndrome: a sib-pair linkage analysis in women twins.

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.

Blood Pressure↗

PubMed2000

Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men.

Decreased low-density lipoprotein (LDL) particle size is associated with coronary heart disease (CHD) risk among middle-aged Caucasian populations, and has been consistently correlated with increased plasma levels of triglyceride and decreased levels of high-density lipoprotein (HDL) cholesterol. This study examines whether these risk factors predict CHD among older Japanese-American men. With use of the Honolulu Heart Program Lipoprotein Exam 3 (1980 to 1982) as baseline, and 12-year follow-up for CHD events, a nested, case-control study was designed. One hundred forty-five incident CHD cases were identified and matched to 2 controls each. LDL particle diameter (size) was determined by gradient gel electrophoresis. A 10-angstrom (A) decrease in LDL size at baseline was associated with increased risk of incident CHD (relative risk 1.28, 95% confidence interval 1.01 to 1.63). After adjustment for baseline risk factors, the LDL size association was no longer statistically significant (relative risk 1.13, 95% confidence interval 0.86 to 1.49). When principal components analysis was used to define a composite variable for LDL size, triglycerides, and HDL cholesterol, this component predicted CHD independent of smoking, alcohol consumption, physical activity, body mass index, hypertension, diabetes, and beta-blocker use (p <0.01). Therefore, this prospective analysis of data from older, Japanese-American men demonstrated that decreased LDL size is a univariate predictor of incident CHD, and that a composite risk factor of LDL size, triglyceride, and HDL cholesterol was a risk factor for CHD independent of other risk factors.

Aged↗

PubMed2000

Cardiovascular disease mortality in familial forms of hypertriglyceridemia: A 20-year prospective study.

BACKGROUND: Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are 2 of the most common familial forms of hyperlipidemia. There is a paucity of prospective data concerning the risk of cardiovascular disease (CVD) in such families. The purposes of this study were to estimate 20-year total and CVD mortality risk among relatives in these families and to evaluate plasma triglyceride as a predictor of death. METHODS AND RESULTS: The study was based on lipid and medical history data from 101 families ascertained in 2 studies conducted in the early 1970s. Vital status and cause of death was determined during 1993 to 1997 for 685 family members, including first-degree relatives of the probands and spouse control subjects. Compared with spouse control subjects, 20-year CVD mortality risk was increased among siblings and offspring in FCHL (relative risk 1.7, P=0.02) after adjustment for baseline covariates. In FHTG families, the relative risk was also 1.7 but was not statistically significant (P=0.39). Baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in FHTG families (relative risk 2.7, P=0.02) but not in FCHL families (relative risk 1.5, P=0.16) after adjustment for baseline covariates. CONCLUSIONS: This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and illustrates the need for effective prevention strategies in this group. Baseline triglyceride level predicted subsequent CVD mortality among relatives in FHTG families, adding to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.

Adult↗

PubMed2000

Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter.

BACKGROUND: A preponderance of small, dense LDL particles, elevated levels of plasma triglycerides (TG), and low levels of HDL characterize the atherogenic lipoprotein phenotype, which is associated with increased coronary artery disease (CAD) risk. Genetic and environmental factors influence LDL size, cholesteryl ester transfer protein (CETP) being one of the candidate genes. CETP mediates the transfer of cholesteryl ester from HDL to apolipoprotein (apo) B-containing lipoproteins in exchange for TG, promoting reverse cholesterol transfer and remodeling of lipoprotein particles. METHODS AND RESULTS: We have identified a tetranucleotide repeat (fragment sizes from 324 to 464 bp; heterozygosity index = 0.74) within the CETP promoter and used it in quantitative sib-pair linkage analysis in 119 female dizygotic (DZ) twins. Linkage was found to LDL size (P<0.001), TG (P<0.005), and plasma apoB (P = 0.02). The distribution of the tetranucleotide repeats was bimodal, and there was strong allelic association of the "short" alleles with the B2 allele of CETP TaqIB polymorphic site (P<0.001). CONCLUSIONS: This report of linkage of the CETP gene to LDL particle size adds to the list of candidate genes linked to LDL size, supporting the hypothesis of multigenic determination of LDL size heterogeneity. Whether this promoter variation is itself functional or is a marker for a functional site in the CETP gene remains to be determined.

Apolipoproteins↗

PubMed2000

Sib-pair linkage analysis of longitudinal changes in lipoprotein risk factors and lipase genes in women twins.

Based on longitudinal twin data in women, we have previously demonstrated a genetic influence on changes in lipoprotein risk factors, blood pressure measurements, and body mass index over a decade. The present study examined the linkage between changes in lipoprotein variables and candidate genes encoding the hormone-sensitive lipase (HSL), hepatic lipase (HL), and lipoprotein lipase (LPL). The sample consisted of 126 dizygotic (DZ) pairs of women twins who participated in the two examinations of the Kaiser Permanente Women Twins Study, performed a decade apart. Using quantitative sib-pair linkage analysis, a linkage was demonstrated between the locus for hormone-sensitive lipase and age-adjusted changes in plasma triglyceride (P = 0.015), which became more significant after adjustment for environmental factors and the exam-1 level (P = 0.005). There was also evidence suggesting linkage between the locus for hepatic lipase and changes in triglyceride (P = 0.023), but no linkage was detected for lipoprotein lipase and changes of lipid levels with time. These findings suggest that variation at these candidate gene loci may underlie a portion of the intraindividual variations in these coronary heart disease (CHD) risk factors, and that studies to identify the functional variants could provide new insights into genetic susceptibility to cardiovascular disease.

Adult↗

PubMed1999

Inheritance of LDL peak particle diameter: results from a segregation analysis in Israeli families.

Genetic and environmental determinants of LDL peak particle diameter (LDL-PPD) were investigated in a sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 182 males and 191 females ages 15-93 years. LDL-PPD levels were first adjusted for variability in sex and age. Commingling analysis demonstrated that a mixture of two normal distributions fit the adjusted LDL-PPD levels better than did a single normal distribution. Complex segregation analysis was first applied to these sex and age adjusted data but was not conclusive. However, when the regression model for sex and age allowed coefficients to be ousiotype (class) specific, the mixed environmental model was rejected while a major Mendelian model was not. These results suggest that the particular genotypes determined by the major gene, which are associated with different phenotypic variances, are likely to be more realistic, and that this analytic approach can contribute to improving our understanding of the genetics of LDL particle size.

Adolescent↗

PubMed1999

Pleiotropic genetic effects on LDL size, plasma triglyceride, and HDL cholesterol in families.

The interrelationships among low density lipoprotein (LDL) particle size, plasma triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) are well established and may involve underlying genetic influences. This study evaluated common genetic effects on LDL size, TG, and HDL-C by using data from 85 kindreds participating in the Genetic Epidemiology of Hypertriglyceridemia (GET) Study. A multivariate, maximum likelihood-based approach to quantitative genetic analysis was used to estimate the additive effects of shared genes and shared, unmeasured nongenetic factors on variation in LDL size and in plasma levels of TG and HDL-C. A significant (P<0.001) proportion of the variance in each trait was attributable to the additive effects of genes. Maximum-likelihood estimates of heritability were 0.34 for LDL size, 0.41 for TG, and 0.54 for HDL-C. Significant (P<0.001) additive genetic correlations (rho(G)), indicative of the shared additive effects of genes on pairs of traits, were estimated between all 3 trait pairs: for LDL size and TG rho(G)=-0.87, for LDL size and HDL-C rho(G)=0.65, and for HDL-C and TG rho(G)=-0.54. A similar pattern of significant environmental correlations between the 3 trait pairs was also observed. These results suggest that a large proportion of the well-documented correlations in LDL size, TG, and HDL-C are likely attributable to the influence of the same gene(s) in these families. That is, the gene(s) that may contribute to decreases in LDL size also contribute significantly to higher plasma levels of TG and lower plasma levels of HDL-C. These relationships may be useful in identifying genes responsible for the associations between these phenotypes and susceptibility to cardiovascular disease in these families.

Adult↗

PubMed1998

Factors of the insulin resistance syndrome in nondiabetic and diabetic elderly Japanese-American men.

Factor analysis has previously identified four independent factors that characterize the insulin resistance syndrome in women, interpreted as 1) weight/waist, 2) lipids, 3) insulin/glucose, and 4) systolic and diastolic blood pressure. Because it is not known whether similar factors emerge for men, or for diabetics, factor analysis was used to investigate the clustering of features characterizing the insulin resistance syndrome using data from 3,159 elderly (71-93 years) Japanese-American men participating in the fourth examination of the Honolulu Heart Program during 1991-1993. Consistent with previous results, factor analysis reduced eight risk factors (insulin, glucose, systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, weight, and waist circumference) to four uncorrelated factors that explained 78.2% and 74.7% of the variance in nondiabetics (n = 2,760) and diabetics (n = 399), respectively. These factors were interpreted as 1) weight/waist, 2) blood pressure, 3) lipids, and 4) insulin/glucose. Modest differences in the associations between fasting insulin and factors 1, 3, and 4 were noted for diabetics. These consistently identified composite factors may represent markers for underlying pathophysiologic mechanisms of the insulin resistance syndrome and risk of non-insulin-dependent diabetes mellitus.

Aged↗

PubMed1998

Hypertriglyceridemia as a cardiovascular risk factor.

To determine the relation between plasma triglyceride levels and the risk of incident cardiovascular disease, the semiquantitative techniques of meta-analysis were applied to 17 population-based prospective studies of triglyceride and cardiovascular disease. Sixteen of these studies represented 2,445 events among 46,413 Caucasian men followed for an average period of 8.4 years, and 5 studies represented 439 events among 10,864 Caucasian women followed for an average period of 11.4 years. Univariate relative risk (RR) estimates for incident cardiovascular disease associated with a 1-mmol/L increase in triglyceride was 1.07-1.98 in men, with a summary RR of 1.32 (95% confidence interval [CI]: 1.26-1.39), indicating a 32% increase in disease risk associated with increased triglyceride. In the studies involving women, individual RR estimates for triglyceride were 1.69-2.05, with a summary RR of 1.76 (95% CI: 1.50-2.07), indicating a 76% increase in disease risk associated with increased triglyceride. After adjustment for high-density lipoprotein cholesterol and other risk factors, these risks were decreased to 14% in men and 37% in women but remained statistically significant. Three recent prospective epidemiologic studies have also shown that plasma triglyceride and low-density lipoprotein particle size predict subsequent coronary artery disease in Caucasian populations. Taken together, these studies demonstrate the importance of triglyceride levels as a risk factor for cardiovascular disease.

Cardiovascular Diseases↗

PubMed1998

Candidate-gene studies of the atherogenic lipoprotein phenotype: a sib-pair linkage analysis of DZ women twins.

There is a growing body of evidence supporting the roles of small, dense LDL and plasma triglyceride (TG), both features of the atherogenic lipoprotein phenotype, as risk factors for coronary heart disease. Although family studies and twin studies have demonstrated genetic influences on these risk factors, the specific genes involved remain to be determined definitively. The purpose of this study was to investigate genetic linkage between LDL size, TG, and related atherogenic lipoproteins and candidate genes known to be involved in lipid metabolism. The linkage analysis was based on a sample of 126 DZ women twin pairs, which avoids the potentially confounding effects of both age and gender, by use of a quantitative sib-pair linkage-analysis approach. Eight candidate genes were examined, including those for microsomal TG-transfer protein (MTP), hepatic lipase, hormone-sensitive lipase, apolipoprotein (apo) B, apo CIII, apo E, insulin receptor, and LDL receptor. The analysis suggested genetic linkage between markers for the apo B gene and LDL size, plasma levels of TG, of HDL cholesterol, and of apo B, all features of the atherogenic lipoprotein phenotype. Furthermore, evidence for linkage was maintained when the analysis was limited to women with a major LDL-subclass diameter >255 A, indicating that the apo B gene may influence LDL heterogeneity in the intermediate-to-large size range. In addition, linkage was found between the MTP gene and TG, among all the women. These findings add to the growing evidence for genetic influences on the atherogenic lipoprotein phenotype and its role in genetic susceptibility to atherosclerosis.

Apolipoproteins B↗

PubMed1998

Recent advances in our understanding of protein conformational stability from a pharmaceutical perspective.

The marginal conformational stability of proteins has made them in some cases less than ideal candidates for pharmaceutical agents. Recent progress in our understanding of protein structure and stability has provided the opportunity to design the desired degree of stability into protein drug candidates. Modifications such as the optimisation of interior side-chain packing, the introduction of new ion-pairs, as well as the design of stabilising disulfide bridges and ligand binding sites, all offer the opportunity to produce proteins with enhanced stability properties.

Journal Article↗