Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.

CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). OBJECTIVE: To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. DESIGN: One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994. SETTING: Fourteen pediatric outpatient clinics in the United States and Finland. PATIENTS: Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively. INTERVENTION: Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo. MAIN OUTCOME MEASURES: The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. RESULTS: Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25 % lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P = .85) and 48 weeks (P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. CONCLUSIONS: This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.

Month-to-month variability of lipids, lipoproteins, and apolipoproteins and the impact of acute infection in adolescents.

OBJECTIVE: To assess month-to-month variability of total cholesterol, triglycerides, high-density lipoprotein-cholesterol (HDL-C), calculated low-density lipoprotein-cholesterol (LDL-C), apolipoprotein A1, apolipoprotein B, and lipoprotein (a), as well as factors that could influence variability, including recent acute infection in an adolescent population. METHODS: Sixty-three high school students had fasting lipids and lipoproteins measured at 4 separate times during the school year and another venipuncture 3 to 7 days after recovery from an acute infection. Erythrocyte sedimentation rate was also measured. Coefficients of variation were calculated for each study variable. The influence of recent infection on variability was assessed. RESULTS: The 50th and 95th percentiles, respectively, for the coefficient of variation for each variable were as follows: total cholesterol, 7.3% and 13.6%; triglycerides, 22% and 47.3%; HDL-C, 7.9% and 16.8%; LDL-C, 12.1% and 25%; apolipoprotein A1, 6.3% and 15.2%; apolipoprotein B, 9.5% and 17.2%; and lipoprotein (a), 19.3% and 40%. Recent infection significantly lowered HDL-C (4 mg/dL; P < .0001) and apolipoprotein A1 (7 mg/dL; P < .005). CONCLUSIONS: Clinicians evaluating lipids and lipoproteins serially should expect significant visit-to-visit variation in triglycerides and calculated LDL-C values. Assessment of HDL-C and apolipoprotein A1 should not be done within 2 weeks of an acute infection. Apolipoproteins B and A1 have slightly less variability than their respective lipoprotein cholesterol values (LDL-C and HDL-C).

Definition and application of the discretionary screening indicators according to the National Cholesterol Education Program for Children and Adolescents.

OBJECTIVES: (1) To propose definitions for the discretionary screening indicators described by the National Cholesterol Education Program for Children and Adolescents (NCEP-Peds); (2) to examine the relative prevalence of major screening indicators (family history of premature heart disease and parental plasma cholesterol concentration > or = 6.21 mmol/L (240 mg/dl)) and discretionary screening indicators (excessive consumption of fat or cholesterol or both, smoking, diabetes, hypertension, and steroid use) in a family population; and (3) to evaluate the relative value of the major and the discretionary indicators in detecting high serum levels of low-density lipoprotein-cholesterol (LDL-C) (> or = 3.36 mmol/L (> or = 130 mg/dl)). DESIGN: Control cohort from a case-control study. SETTING: Lipid research clinic. PARTICIPANTS: White children and adolescents < 20 years of age from 232 nuclear families who participated in the Cincinnati Myocardial Infarction Hormone Study. MAIN OUTCOME MEASURES: (1) Number of children who have major and discretionary screening indicators; (2) sensitivity and specificity of the major and the discretionary screening indicators in identifying children with LDL-C concentrations > 3.36 mmol/L (130 mg/dl) (high LDL-C). RESULTS: With cutoff points of the 90th percentile for blood pressure, the 85th percentile for obesity, and the 80th percentile for dietary fat and cholesterol, and self-report for diabetes, smoking, and corticosteroid use, 54% of the 232 children in the cohort had one or more discretionary indicators. Additionally, applying the major screening indicators raised the percentage of children identified to 74%. Twenty-eight percent had both major and discretionary indicators. Having a discretionary screening indicator did not increase the probability of having a major indicator. Applying both discretionary and major screening indicators to the cohort identified 96% of the children who had a high concentration of LDL-C; 30% of the children with high LDL-C levels were discovered solely by the discretionary indicators. Similar sensitivity and specificity were noted between the major and the discretionary indicators. Children with high LDL-C concentrations were more likely to have multiple screening indicators. CONCLUSION: Discretionary and major screening indicators suggested by the National Cholesterol Education Program for Children and Adolescents identify different subsets of children at risk of having premature cardiovascular disease. Both major and discretionary indicators contribute to the identification of children with high LDL-C concentrations.

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.

Evidence for an association between dehydroepiandrosterone sulfate and nonfatal, premature myocardial infarction in males.

BACKGROUND: Several studies indicate that endogenous hormones play a role in the etiology of coronary artery disease, either as independent risk factors or indirectly, via an effect on lipids, lipoproteins, or other heart disease risk factors. METHODS AND RESULTS: The relation between endogenous hormone levels and premature (< 56-year-old patients) myocardial infarction was assessed in a retrospective study involving 49 male survivors of premature myocardial infarction and 49 age-matched, volunteer male controls. Serum samples were obtained for each subject the morning after a > or = 12-hour fast and frozen at -70 degrees C for subsequent hormonal analysis. Among the male patients, the average duration between the most recent myocardial infarction and blood sampling was 3.4 years (range, 0.7 to 19.2 years). Individuals reporting the use of any medications with the potential to alter lipid, lipoprotein, or hormone levels were excluded from these analyses. Dehydroepiandrosterone sulfate levels were significantly lower in the patients than in the control subjects. This association remained statistically significant even after accounting for the effects of total cholesterol, triglycerides, the ratio of total to high-density lipoprotein (HDL) cholesterol, HDL, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, and body mass index. There were no significant differences in the levels of estradiol, testosterone, or free testosterone or the ratio of estradiol to testosterone between patients and control subjects. CONCLUSIONS: Our conclusions are limited by the retrospective nature of this study. However, these data indicate that serum dehydroepiandrosterone sulfate levels are inversely related to premature myocardial infarction in males and that this association is independent of the effects of several known risk factors for premature myocardial infarction.

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.

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.

The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolemia.

BACKGROUND: A diet low in saturated fat and cholesterol is the standard initial treatment for hypercholesterolemia. However, little quantitative information is available about the efficacy of dietary therapy in clinical practice or about the combined effects of diet and drug therapy. METHODS: One hundred eleven outpatients with moderate hypercholesterolemia were treated at five lipid clinics with the National Cholesterol Education Program Step 2 diet (which is low in fat and cholesterol) and lovastatin (20 mg once daily), both alone and together. A diet high in fat and cholesterol and a placebo identical in appearance to the lovastatin were used as the respective controls. Each of the 97 patients completing the study (58 men and 39 women) underwent four consecutive nine-week periods of treatment according to a randomized, balanced design: a high-fat diet-placebo period, a low-fat diet-placebo period, a high-fat diet-lovastatin period, and a low-fat diet-lovastatin period. RESULTS: The level of low-density lipoprotein (LDL) cholesterol was a mean of 5 percent (95 percent confidence interval, 3 to 7 percent) lower during the low-fat diet than during the high-fat diet (P < 0.001). With lovastatin therapy as compared with placebo, the reduction was 27 percent. Together, the low-fat diet and lovastatin led to a mean reduction of 32 percent in the level of LDL cholesterol. The level of high-density lipoprotein (HDL) cholesterol fell by 6 percent (95 percent confidence interval, 4 to 8 percent) during the low-fat diet (P < 0.001) and rose by 4 percent during treatment with lovastatin (P < 0.001). The ratio of LDL to HDL cholesterol and the level of total triglycerides were reduced by lovastatin (P < 0.001), but not by the low-fat diet. CONCLUSIONS: The effects of the low-fat-low-cholesterol diet and lovastatin on lipoprotein levels were independent and additive. However, the reduction in LDL cholesterol produced by the diet was small, and its benefit was possibly offset by the accompanying reduction in the level of HDL cholesterol.

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.

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.

Commingling and segregation analysis of serum uric acid in five North American populations: the Lipid Research Clinics family study.

The role of major genes in the expression of serum uric acid (UA) levels was investigated in data collected from five clinics of the Lipid Research Clinics (LRC) family study. Over 2,000 randomly ascertained individuals were analyzed. The UA distributions were homogeneous among the five LRC clinics and between the parental and offspring generations. This result suggested that the data could be pooled across clinics, thereby increasing the statistical power associated with larger sample sizes for testing various null hypotheses. Additionally, a mixture of three normal distributions best characterized the combined-clinics data. Segregation patterns were examined in the untransformed data, as well as in a more conservative (and biologically meaningful) log transformation. Prior to log transformation, both major and multifactorial effects were detected. The major effect was not transmissible, i.e., was not compatible with Mendelian transmission, and accounted for 39% of the variance in UA levels. However, after the log transform was applied to the data and the segregation analysis was repeated, support for the major effect disappeared altogether and only the multifactorial component remained, accounting for 50% of the variation in offspring and 19% in patients.

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

The familial aggregation of lipids [total cholesterol (CH) and triglyceride (TG)] and lipoproteins [high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL)] was investigated in families ascertained through both random and nonrandom probands in the Minnesota Lipid Research Clinic Family Study. Nonrandom proband ascertainment was based on single selection through truncation for hyperlipidemia at an earlier screening. A path model was used to investigate the nature of familial resemblance using appropriate adjustments for ascertainment and to determine whether random and hyperlipidemic samples are heterogeneous with regard to the multifactorial model. The results suggest that parameter estimates are consistent with those from previous studies in which only random families were used and that random and nonrandom samples are homogeneous with regard to the path model for CH and LDL. However, for TG and HDL the random and hyperlipidemic samples are significantly heterogeneous. This heterogeneity would be observed if familial hypertriglyceridemia and/or familial hypoalphalipoproteinemia segregates predominantly in the hyperlipidemic rather than in the random sample, as on might expect.

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.

Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study.

The 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 Iowa Lipid Research Clinics family study was examined. Nonrandom probands were selected because their lipid levels (at a prior screening visit) exceeded a certain pre-specified threshold. The statistical method conditions the likelihood function 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. Marked heterogeneity between the random and the hyperlipidemic samples is detected in the multifactorial transmission for TG and HDL, and moderate heterogeneity is detected for CH and LDL, with a pattern of higher genetic heritability estimates in the random than nonrandom samples. The observed pattern of heterogeneity is compatible with a higher prevalence in the random sample of certain dyslipoproteinemias that are associated with nonelevated lipids. For the random samples, genetic heritabilities are higher for CH and HDL (about 60%) than for TG and LDL (about 50%). For the nonrandom samples those estimates are about 45, 40, 35 and 30% for HDL, CH, LDL and TG, respectively. Little to no cultural (familial environmental) heritability is evident for CH and LDL, although 10-20% of the phenotypic variance is due to cultural factors for TG and HDL. These results suggest that the etiologies for lipids and lipoproteins may be quite different in random versus hyperlipidemic samples.

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.

Heterogeneity in the biological and cultural determinants of high-density lipoprotein cholesterol in five North American populations: the Lipid Research Clinics Family Study.

Heterogeneity in the source of familial resemblance for high-density lipoprotein (HDL) cholesterol in 5 different Lipid Research Clinics (Cincinnati, Iowa, Minnesota, Oklahoma and Stanford) was assessed using a general linear model for cultural and biological inheritance. No evidence of heterogeneity was found in any of the parameters of the model. Under the most parsimonious hypothesis, using data pooled over all clinics, genetic and cultural heritability were both significant and were estimated to be 0.52 +/- 0.04 and 0.09 +/- 0.02, respectively; there was cultural transmission but no maternal effects; marital and nontransmitted sibship environmental resemblance were significant.

Multivariate analysis of lipoprotein cholesterol fractions.

Intervention and prevention of multifactorial diseases such as coronary heart disease can be effective only when the joint effects of multiple risk factors are known. This process is facilitated by multivariate analysis of correlated risk factors, such as the serum cholesterol fractions, high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoprotein (VLDL). Whereas evidence for genetic covariation provides focus for further refined biochemical analysis, covariation among environmental factors can point to efficacious intervention strategies. To assess sources of variation and covariation among HDL, LDL, and VLDL, a multivariate path model was developed and applied to family data. Phenotypic variance is due primarily to specific environmental influences with substantial genetic influences, with the common family environment contributing less than 10% of the variance. There are genetic correlations of -0.22 for HDL-VLDL and 0.35 for VLDL-LDL, consistent with the known inverse associations of HDL and VLDL and the precursor-product relationship between VLDL and LDL, whereas there is no evidence for a direct HDL-LDL genetic relationship. Strong specific environmental correlations are found between HDL and VLDL (-0.35 in children and -0.50 in adults). Thus, intervention focused primarily on one fraction (e.g., triglycerides and VLDL) might beneficially affect levels of both lipoproteins (e.g., lowering VLDL cholesterol and elevating HDL cholesterol). Multivariate analysis can facilitate understanding of the linked effects of intervention on lipoprotein cholesterols, and, hence, should benefit approaches to maximize the effects of lipoprotein cholesterol intervention on coronary heart disease morbidity and mortality.

A major gene for primary hypoalphalipoproteinemia.

Sixteen kindreds were ascertained through probands clinically determined to have primary hypoalphalipoproteinemia, characterized by bottom decile high-density lipoprotein cholesterol (HDL-c), but otherwise normolipidemic. Age- and sex-adjusted, standardized HDL-c levels on 64 individuals in 14 nuclear families in which the proband was a parent were analyzed using the unified mixed model of segregation analysis as implemented in the computer program POINTER. The analysis proceeded by using the likelihood of offspring conditional on the parental phenotypes (conditional likelihood), which appears to overcome the limitation of possible heterogeneity in the selection criteria and provides an appropriate correction for the ascertainment. In these families, the multifactorial contribution to the phenotype appears to be small and significant only in the offspring generation. Although it was not possible to resolve the dominance pattern at the major locus since none of a recessive, additive, or dominant hypothesis could be firmly rejected, these families provided clear evidence for a major gene. Genetic heterogeneity is still a possibility, even within "primary" hypoalphalipoproteinemia.