Effect of sucrose polyester on fecal bile acid excretion and composition in normal men.

The effects of sucrose polyester (SPE) (a nonabsorbable mixture of hex-a, hepta,- and octa-fatty acid esters of sucrose with physical properties similar to those of common dietary fats) on fecal bile acid excretion and composition were assessed in 24 healthy, nonobese, normolipemic male volunteers, in a 40-day, inpatient, metabolic balance study. Isocaloric diets provided either 800, 300, or less than 50 mg of cholesterol/day (P/S ratios respectively 0.4, 1.0, and 1.5). After diet-only perids of 10 days (for the 800 and 300 mg cholesterol regimens), and 21 days (for the 50 mg diet), the diets were continued for 30 days, with addition of SPE to diets over three successive treatment periods of 10 days each, with 8, 16, and 35 g of liquid SPE/day, or 15, 30, and 50 g SPE/day in a SPE-hydrogenated palm oil mix. On both the liquid SPE and SPE-hydrogenated palm oil mix, there were no significant changes in fecal bile acid excretion as a function of dietary SPE, at any level of cholesterol intake, P > 0.1. In most subjects SPE changed fecal bile acid composition; lithocholic acid was decreased, and in most instances this was accompanied by the appearance and increase in chenodeoxycholic acid. In one subject, both deoxycholic and 3 beta, 12 alpha-dihydroxycholanic acid were reduced, with an accompanying increase in cholic acid. The hypocholesterolemic effect of SPE appears to be mediated through its reduction of intestinal absorption of cholesterol, not through effects on bile acid excretion.

Commingling and complex segregation analysis of fasting plasma glucose in the Lipid Research Clinics family study.

Commingling and segregation patterns of fasting plasma glucose (GL) were examined in family data from 5 clinics (Cincinnati, Stanford, Iowa, Minnesota, and Oklahoma) of the Lipid Research Clinics (LRC) family study. In addition to the primary question of whether there was a major gene for GL, a secondary purpose was to investigate the possibility of genetic heterogeneity among the 5 clinics. No statistical support was found for heterogeneity among clinics, either in the commingling of distributions or in the segregation patterns. For the combined clinics sample, both a major effect and a multifactorial component were significant. However, the major effect (accounting for 73% of the variance) was not found to be consistent with a major gene, as the hypothesis of Mendelian transmission was rejected. The most parsimonious model involved equal transmission probabilities, which suggests that the major effect is not transmitted from parents to offspring. Possible sources of this major non-Mendelian effect were explored. The multifactorial component accounted for 10% of the variance in GL levels, and no generational differences were noted. Although our study was unable to provide evidence in favor of a major gene effect, it should be noted that a major gene cannot be firmly refuted. For example, a variety of interactions, such as genotype-dependent age effects, could have masked the transmission probabilities.

Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Stanford Lipid Research Clinics Family Study.

We examined the familial aggregation of lipids [total cholesterol (CH) and triglyceride (TG)] and lipoproteins [high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL)] in families ascertained through random and nonrandom probands in the Stanford Lipid Research Clinics Family Study. Nonrandom probands were selected because their lipid levels at a prior screening visit exceeded a certain prespecified threshold. The statistical method is based on selection through indirect truncation on a correlated trait (in which the likelihood function is conditioned on the actual event that the proband's value is beyond the threshold). This method allows for estimation of the path model parameters in randomly and nonrandomly ascertained families jointly and separately, thus enabling tests of heterogeneity between the two types of samples. The results suggest that the multifactorial transmission is homogeneous in the random and hyperlipidemic samples for CH. However, the evidence for heterogeneity is moderate for LDL, marked HDL, and mixed for TG. The general pattern of observed results is for somewhat higher genetic heritabilities in the random than nonrandom samples, which is compatible with a higher prevalence in the random sample of certain dyslipoproteinemias associated with nonelevated lipids. Substantial genetic heritability is found for CH, HDL, and LDL, with somewhat lower estimates for TG. Cultural heritability is low but significant for all four traits. Little or no spouse resemblance or nontransmitted shared sibship effects are seen. In contrast to the findings from previous studies, little or no parental cultural transmission is seen.

Cincinnati myocardial infarction and hormone family study: family resemblance for testosterone in random and MI families.

Familial correlations for total testosterone and free testosterone were examined in both random and nonrandom families participating in the Cincinnati Myocardial Infarction and Hormone Family Study (CIMIH). The non-random families were ascertained through Caucasian males who had survived a myocardial infarction (MI) prior to age 56 years, while random families were recruited largely through an adolescent boy maturation study. Eight sex-specific familial correlations were estimated (father-mother, father-son, father-daughter, mother-son, mother-daughter, son-son, daughter-daughter, and son-daughter) for each of the MI and random samples using maximum likelihood methods with appropriate ascertainment correction. These familial correlations were examined for differences between the random and MI samples, as well as for sex-specific familial patterns. The results suggest that total testosterone levels may have a limited role in determining MI risk, as evidenced by the overall heterogeneity between samples, and lower serum levels in MI than random probands. The pattern of correlations for both androgens suggests that a simple genetic model appears unlikely; however, familiarity cannot be ruled out. Although possible covariate effects such as age and sex may have masked some potentially significant results, especially in males, familiarity in females is suggested (correlations ranging from .3-.9). The relative stability of these hormones in females as compared to that in males may have contributed to its identification, and suggests the familial transmissibility may be associated with adrenal production and/or metabolic clearance of testosterone.

Heterogeneity in the familial aggregation of fasting serum uric acid level in five North American populations: the Lipid Research Clinics Family Study.

This study represents the first formal examination for heterogeneity in the familial aggregation of fasting serum uric acid (UA) levels. Data from 5 clinics (Cincinnati, Stanford, Iowa, Minnesota, and Oklahoma) participating in the Lipid Research Clinics (LRC) family study, which included a total of 685 nuclear families (N = 2,146), were analyzed. Heterogeneity among the clinics in familial resemblance was detected. However, this heterogeneity could not be attributed to differences in distributional properties (such as means and variances) or to path model parameters representing latent genetic or cultural (environmental) components associated with UA levels. Intergenerational differences in genetic heritabilities were found, with higher offspring (h2 = 43%) than parent (h2z2 = 16%) estimates, but no generational differences were detected for cultural heritability (c2 = 0.09). Equal maternal and paternal cultural transmission was found, and effects due to extra sibling environments and to marital resemblance were both significant. These results show no clear indication as to the source of the heterogeneity observed for familial resemblance of UA levels in randomly selected data. This question should be further investigated, especially in clinical samples such as dyslipoproteinemic families.

Heterogeneity in the familial aggregation of fasting plasma glucose in five North American populations: the Lipid Research Clinics Family Study.

Heterogeneity in the familial aggregation of plasma glucose in five samples of the Lipid Research Clinics Family Study (LRC) was investigated using path analysis. This study was deemed appropriate since recent investigations reported a wide range of estimates for genetic and cultural factors. The path model incorporated a measured index of the familial environment in order to separate the effects of genes and environments in the nuclear family design, genetic and environmental heritabilities, spouse resemblance, sibling environmental effects, and parental cultural transmission. The methodology was completely general in allowing sample-specific, as well as pooled-sample, estimation of all or any subset of the model parameters. Genetic heritability estimates were heterogeneous, ranging from zero to 33% across the clinics. Environmental heritability (7%), spouse resemblance, non-transmitted sibling environmental effects, and parental cultural transmission were homogeneous across samples. No support was found for specific maternal effects, nor for intergenerational differences in cultural or genetic heritability. We conclude that the genetic and environmental heritabilities for plasma glucose in the LRC are consistent with the diverse reports by earlier investigators. In addition, we were able to exclude methodological differences as a cause of this heterogeneity. Furthermore, formal hypothesis tests suggest that the aetiology of this heterogeneity is genetic (and not cultural), taking the form of two distinct homogeneous patterns (one for no genetic effect, and one for a moderate genetic effect). Only formal heterogeneity tests of the type described here can detect these effects, and allow pooling of separate studies in order to obtain more precise estimates of the parameters of interest.

Tracking of high- and low-density-lipoprotein cholesterol from childhood to young adulthood in a single large kindred with familial hypercholesterolemia.

Tracking of high- and low-density-lipoprotein cholesterol (HDLC, LDLC) from childhood to young adulthood was assessed in 77 children and in 53 adults from a single large pedigree with familial hypercholesterolemia who were respectively less than or equal to 19 and greater than or equal to 20 years old when first studied in 1973, with reassessment in 1984. No children and only five of the adults had received LDLC lowering therapy from 1973 to 1984. The rank correlations between the 1973 and 1984 measurements for LDLC were 0.73, 0.74, and 0.87; and for HDLC were 0.55, 0.73, and 0.65 (P less than 0.0001 for all correlations), respectively for relatives who were less than or equal to 12, 13 to 19, and greater than or equal to 20 years old in 1973. The 1973:1984 LDLC and HDLC correlations, categorized by relationships to the proband, were as follows: (1) unrelated, LDLC = 0.16, HDLC = 0.56;* (2) first-degree relatives, LDLC = 0.90, HDLC = 0.30; (3) second-degree relatives, LDLC = 0.79, HDLC = 0.39; and (4) other relatives, LDLC = 0.62, HDLC = 0.64. All nine of the probands' first-degree relatives who were above the age-sex specific LDLC 95th percentile in 1973 were also greater than the 95th percentile for LDLC in 1984. Similarly, seven of eight second-degree relatives with LDLC greater than the 95th percentile in 1973 were greater than the 95th percentile in 1984, as were ten of 15 other relatives. LDLC levels in childhood in this extended kindred were highly predictive of adult values.(ABSTRACT TRUNCATED AT 250 WORDS)

Parent-offspring and sibling body mass index associations during and after sharing of common household environments: the Princeton School District Family Study.

Using the Princeton School Family Study cohort, our specific aim was to determine whether, and to what degree, parent-offspring and sibling associations for measures of body habitus outlast the period of shared common household environment in a single well characterized community. Familial associations of measures in body habitus were assessed in two and three generation kindreds, in parents and their pediatric offspring (less than 20-yr-old), parents and their adult offspring (less than or equal to 20-yr-old), and in pediatric and adult siblings. The cohort included 177 randomly recalled probands and 202 probands from a hyperlipidemic recall group (top decile plasma cholesterol and/or triglyceride). In randomly recalled whites, significant associations of body mass indices in parents and pediatric offspring and in pediatric siblings, and the absence of significant correlations in parents and adult offspring and in adult siblings, emphasize the potency of common household environmental effects relative to within-family similarities for shared body habitus. In whites from the hyperlipidemic recall group, only the mother-pediatric and adult offspring correlations for body mass indices were significant. We speculate that mothers and their offspring from kindreds selected by hyperlipidemic probands are more likely than fathers and their offspring to share eating habits and relative ponderosity, with these communal behaviors outlasting the period of common household environment. Alternatively, and speculatively, in the hyperlipidemic recall group, determinants for ponderosity may be shared more by mothers and their offspring than by fathers and their offspring. Particularly in the random recall group, within-family associations of body mass indices primarily reflect shared common household environments, and probably secondarily, the outcome of genes held in common.

Severe depression of high-density lipoprotein cholesterol levels in weight lifters and body builders by self-administered exogenous testosterone and anabolic-androgenic steroids.

The effects of nonphysician prescribed, self-obtained, self-administered exogenous anabolic-androgenic steroids and testosterone on plasma total, high- and low-density lipoprotein cholesterol (HDLC, LDLC), and triglycerides were evaluated in 14 adult white men, 11 body builders and 3 power weight lifters. Lipids and lipoprotein cholesterols were quantified during active physical conditioning, both on (for at least 1 month, mean +/- SD 1.8 months) and off (for at least 4 months, 7.3 +/- 2.7 months) self-administered exogenous androgenic steroids. The subjects took 50 to 100 mg methandrostenolone daily plus weekly injections of testosterone 100 to 200 mg and nandrolone decanoate 100 to 200 mg per week. Mean (SD) HDLC on exogenous androgenic steroids, 29 +/- 8 mg/dL, was severely depressed, and was less than 50% of the consistently elevated mean HDLC when exogenous steroids were not used (61 +/- 14 mg/dL, P less than .01 for paired differences). During anabolic steroid use, HDLC was less than or equal to the age- race- and sex-specific 10th percentile in 11 of the 14 men, whereas while off anabolic steroids, HDLC was greater than or equal to the 90th percentile in 7 of the 13 men, and in the top quartile for 3 of the remaining 6 men. Mean LDLC was higher on androgenic steroids (150 +/- 44) than off (125 +/- 38 mg/dL), P less than .05 for paired differences. The ratio of LDLC/HDLC during exogenous steroid use (6.0 +/- 3.7) was nearly triple the ratio obtained when steroids were not taken (2.2 +/- 1.0), P less than .01 for paired differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial hyper- and hypouricemias in random and hyperlipidemic recall cohorts: the Princeton School District Family Study.

Using the Princeton School Family Study, our specific aim was to estimate the prevalence of familial hyper- and hypouricemia, to estimate the proportion of probands' first-degree relatives who were similarly affected, and to evaluate the contribution of diseases, drugs, and alcohol intake (if any) to uric acid levels. We studied 379 probands and a total of 1928 subjects, 125 and 52 black probands from a randomly recalled group, 147 white and 55 black probands from a hyperlipidemic recall (top decile cholesterol and/or triglyceride) group. Familial hyper- and hypouricemias were arbitrarily identified in those kindreds having at least two first-degree relatives in the same decile as the proband, top or bottom respectively, for serum uric acid. No probands had symptomatic gout. Diseases, drugs, and alcohol intake were not consistently associated with aggregations of high and/or low uric acid levels in families, and had little relationship to uric acid levels in individuals. Of the 177 randomly recalled probands, and of the 55 black probands in hyperlipidemic recall familial hyperuricemia, with concurrent primary hyperlipoproteinemia and hypertension. Familial hypouricemia was present in 1 of 125 white and in 1 of 52 randomly recalled black kindreds, and in 3 of 147 white and 3 of 55 hyperlipidemic recall black kindreds. While familial clustering of hyperuricemia was limited, clustering of hypouricemia was much more marked. Seventy-four and 84% respectively of first-degree relatives of hypouricemic white and black probands had uric acid less than the 50th percentile. In randomly recalled probands and their first-degree relatives there were significant inverse partial correlations between uric acid and high density lipoprotein cholesterol. Inverse associations of uric acid with high density lipoprotein cholesterol and the concurrence of hyperlipoproteinemia and hypertension in hyperuricemic families points to the importance of lipoprotein and blood pressure screening in families with asymptomatic hyperuricemia. The potential ramifications of within-family clustering of hypouricemia need to be further assessed in populations, particularly in regards to uric acid nephrolithiasis.

The Cincinnati Myocardial Infarction and Hormone Family Study: family resemblance for dehydroepiandrosterone sulfate in control and myocardial infarction families.

Dehydroepiandrosterone sulfate (DHEAS) was examined in random (control) and nonrandom (case) families participating in the Cincinnati Myocardial Infarction and Hormone (CIMIH) family study. The case families were ascertained through white men who survived a myocardial infarction (MI) before the age of 56, whereas control families were recruited through advertisements and through an adolescent boy maturation study. Both familial correlations and genetic effects of DHEAS were investigated. First, maximum likelihood estimates of the sex-specific familial correlations (corrected for nonrandom ascertainment) suggested that there was significant heterogeneity between the two sampling types. This heterogeneity was isolated to the male sibling correlation, which was higher in the case than control families. Post hoc analyses suggested that the sibling group heterogeneity may be in part a function of age, since the control sample offspring were on average much younger than those in case families. No sex differences other than those for the siblings were noted in the familial correlations. Second, heritability was investigated in control families using a simple path model (TAU) that allowed for sex differences. The only significant model parameter was the sex-specific familiarity (combined polygenic and familial environmental effects), which was larger in females (74%) than in males (29%). In general, these analyses suggested that (1) DHEAS may play only a limited role in the increased risk for premature MI, and (2) the degree of heritable (familial) variation may be dependent on sex.

The low HDL cholesterol/high triglyceride trait.

In 748 probands and 3,283 first-degree relatives from the Collaborative Lipid Research Clinics (LRC) Family Study, our specific aim was to examine the degree to which low (bottom decile) high density lipoprotein cholesterol (HDL-C, hypoalpha) and high (top decile) triglyceride (TG, hyperTG) levels occur conjointly (CT) and the extent to which these characteristics were shared within families. To control for family size and permit a comparison with the proband percentages, mean familial percentages of HDL-C/TG abnormalities were calculated. Concurrent low HDL-C and high TG levels were present in 2.7% of the probands, a value that was enriched to 12.7% (p = 0.003) of their associated first-degree relatives. If the proband had a low HDL-C value, 7.7% (p = 0.013) of relatives had CT. Familial (proband and at least one first-degree family member share the same lipoprotein/lipid phenotype) hypoalpha was observed in 2.4% of families while familial hyperTG was observed in 4.1%. Familial CT was seen in approximately 0.7%. If the proband had CT, 80% of their families had at least one other first-degree member with an HDL-C/TG abnormality, whereas the corresponding percentage for families associated with probands with only hypoalpha was 64% and for those with hyperTG alone, 54%. A broadly shared environmental factor cannot easily explain the familial association of hypoalpha, hyperTG, and CT. In probands with low HDL-C values alone or the conjoint low-HDL-C/high-TG trait, family screening is extremely valuable because low HDL-C/high TG is enriched in the respective family members, a conjoined trait closely associated with increased coronary heart disease risk.

Conjoint high triglycerides and low HDL cholesterol across generations. Analysis of proband hypertriglyceridemia and lipid/lipoprotein disorders in first-degree family members.

BACKGROUND: To discern whether hypertriglyceridemia (hyper-TG, TG > 95th percentile) and hypoalphalipoporteinemia (hypoalpha, high-density lipoprotein [HDL-C] < or = 10th percentile) are jointly transmitted in families, we studied 385 probands with marked elevations in TG or cholesterol levels (TG or cholesterol > 99th percentile in a previous visit) and their 2072-first-degree relatives in the Lipid Research Clinics' Family Study. Repeat TG measurement, with exclusion criterion of TG < or = 95th percentile, resulted in 162 probands with hyper-TG. METHODS AND RESULTS: When the proband demonstrated the conjoint trait (CT; ie, TG > 95th percentile, HDL-C < or = 10th percentile, n = 82), an average of 10.6% of first-degree relatives conjointly expressed hyper-TG and hypoalpha in contrast to only 4.1% of first-degree relatives of a proband who expressed high TG levels with normal HDL-C levels (TG > 95th percentile, HDL-C > 10th percentile, n = 80). Hyper-TG was expressed in 24.2% of first-degree relatives of probands with CT. However, hyper-TG was expressed in only 14.4% of first-degree degree relatives of probands with hyper-TG alone. CT probands and their family members tended to have more reported cardiac events and symptoms (P = .02 and .09, respectively) than those subjects associated with hyper-TG alone. CONCLUSIONS: The differences in HDL-C-TG abnormalities between families related to hyper-TG probands with or without hypoalpha indicate that bottom decile HDL-C is not simply secondary to hyper-TG. A familial interaction is suggested between HDL-C and TG levels consistent with the transmission of hyper-TG and hypoalpha among first-degree relatives. Among subjects and their families with hyper-TG, those who in addition have low HDL-C demonstrate a tendency for more coronary artery disease than do those with normal HDL-C levels.

A simulation study of parameter estimation in the one and two compartment models.

Few attempts have been made to examine the statistical problems that the user of compartmental models must face. Some properties of the estimators of parameters for one and two compartmental models based on nonlinear estimation were studied through simulation. Of particular interest were the effect of the experimental design and the effect of different error structures on the empirical sampling distribution for the estimators. For the one compartment model it was found that nonlinear estimation yielded essentially unbiased estimators that were normally distributed unless the random error for the model was large. In the two compartment model simulations, bias appeared in the estimators to the extent that bimodal sampling distributions of the estimators were observed as the random error for the model was increased.

The Cincinnati Lipid Research Clinic Family Study: analysis of commingling and family resemblance for fasting blood glucose.

Our specific aim in this study was to investigate commingling and family resemblance for fasting blood glucose in 160 randomly selected white families from the Princeton School District Lipid Research Clinics Family Study. Adjustment of fasting blood glucose for the influence of age, sex, and the use of oral contraceptives and construction of indices were performed simultaneously using multiple regression methods. Path analysis was carried out, constructing an environmental index based on special diet usage, hematocrit, and obesity, which was also adjusted for the influences of age and sex. Commingling analysis and segregation analysis using the mixed model were also performed. Nearly 16% of the variance of fasting blood glucose was accounted for by age and sex. Obesity itself, which constituted the index, explained an additional 4% of the variance of fasting blood glucose. Significant genetic heritability for fasting blood glucose was documented by both path analysis and segregation analysis. In aggregate, we conclude that though there was a major familial vector accounting for within-family aggregation of blood glucose, it was probably generated by a multifactorial component as compared to a major locus. Under the most parsimonious model, path analysis estimated the genetic and cultural heritabilities as h2 = .39 +/- .08 and c2 = .06 +/- .03., respectively.