Long-term safety and efficacy of low-fat diets in children and adolescents.

The safety and efficacy of low-fat diets in children and adolescents were evaluated through a systematic review of the current literature. Eight major studies were reviewed. The safety of the diets was judged by measures of growth and development and by meeting nutritional requirements. The efficacy of the diets was evaluated by their effect on the plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. All studies except 1 showed that children and adolescents exhibited normal growth and development while on a low-fat diet. In 3 of the studies, nutritional requirements for calcium, zinc, phosphorous and vitamin E were below the recommended daily intake. In each of the 5 studies in which efficacy was determined, a significant decrease in the levels of total or LDL cholesterol was observed. Low-fat diets are generally safe and efficacious when performed under medical supervision.

Racial differences in low-density lipoprotein particle size in families at high risk for premature coronary heart disease.

OBJECTIVE: Although small, dense low-density lipoprotein (LDL) has been implicated in atherogenesis and coronary heart disease (CHD) events, little is known about possible racial differences in LDL particle size. This study was designed to examine racial differences in the prevalence of small, dense LDL among 159 African-American and 477 White siblings of persons with premature (<60 years of age) CHD. METHODS AND RESULTS: This study examined fasting levels of total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, apolipoprotein B (ApoB), apolipoprotein A-1, and triglycerides, as well as factors known to be associated with small, dense LDL, including age, sex, obesity, hypertension, and diabetes. Relative LDL particle size was defined by the LDL cholesterol to ApoB ratio. Direct measurement of LDL particle size was obtained by proton NMR spectroscopy in a subset of 64 siblings. Despite similar levels of total and LDL cholesterol, White siblings were more likely to have low LDL cholesterol to ApoB ratios, indicative of atherogenic small, dense LDL, compared with African-American siblings. Multiple logistic regression analysis predicting the presence of LDL cholesterol/ApoB < or = 1.0 demonstrated that race (P = .009), triglyceride level (P = .0001), and diabetes (P = .02) were independent predictors, controlling for age and all other variables. Direct measurement of LDL particle size by NMR spectroscopy supported these findings. CONCLUSION: These findings provide the first known evidence that White individuals from a population at high risk for premature CHD have a greater probability of having a preponderance of small, dense LDL particles than do African Americans, independent of triglyceride levels, and despite comparable levels of total and LDL cholesterol.

An HphI polymorphism in the E-selectin gene is associated with premature coronary artery disease.

An increased expression of E-selectin has been observed in the arterial endothelium interacting with lymphocytes and macrophages in human atherosclerotic lesions. We examined whether a polymorphism in the E-selectin gene, due to a G to T mutation (G98T) in the untranslated region of exon 2, was associated with premature coronary artery disease (CAD). Other lipid and nonlipid risk factors including a Ser to Arg (S128R) substitution in the E-selectin gene were also assessed. In patients with premature CAD (men < or = 45 years old and women < or =55 years old, N = 51) who underwent an elective diagnostic coronary arteriography, the frequency of the mutation was significantly higher than in controls (N = 50, 0.22 vs. 0.10, p = 0.024). After controlling for other CAD risk factors (plasma total cholesterol, triglyceride, LDL-apolipoprotein B. cigarette smoking and the S128R mutation) by multiple logistic analysis, the G98T mutation in the E-selectin gene was still a significant predictor of premature CAD [p = 0.022, odds ratio (95%, CI)= 3.58 (1.20-10.67)].

Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC).

OBJECTIVE: Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. METHODS: Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' follow-up. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. RESULTS: Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (.13 mmol/L), 3.3 mg/dL (.09 mmol/L), and 2.0 mg/dL (.05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. CONCLUSION: Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence.

Safety and efficacy of treatment of children and adolescents with elevated low density lipoprotein levels with a step two diet or with lovastatin.

BACKGROUND AND AIM: The risk factor precursors of arteriosclerotic cardiovascular disease (ASCVD) are expressed in children and adolescents and development of coronary atherosclerosis in adulthood. Certain pediatric subjects have inherited disorders such as familial hypercholesterolemia (FH), familial combined hyperlipidemia, hyperapobetalipoproteinemia, and the metabolic syndrome, which often lead to more marked elevations in plasma low-density lipoprotein (LDL) levels, placing them at increased risk of premature ASCVD. The aim of this report was to examine available data on the safety and efficacy of treatment of children and adolescents with elevated LDL-cholesterol (LDL-C). DATA SYNTHESIS: Treatment of adolescents with elevated LDL-C levels of 130 mg/dL, randomized to an intervention group receiving a stricter Step Two diet, produced a significantly greater fall in LDL-C than those randomized to the usual care group after three years of follow-up in the Dietary Intervention Study in Children (DISC). CONCLUSIONS: There were no differences between the intervention and usual care groups in growth and development after either 3 or 7 years of follow-up. In the Lovastatin in Adolescent Males Study (LAMS), 132 boys aged 10 to 17 years with heterozygous FH were randomized into a placebo group or a group receiving up to 40 mg/day of lovastatin. The treatment group had up to a 27% reduction in LDL-C, compared with the placebo group and there were no differences in growth, sexual maturation, hormone or biochemical levels. Longer-term studies are required to assess further the safety of such treatments, and whether treatment will delay the early expression of atherosclerosis such as intima media thickness and endothelial dysfunction.

Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol.

Genes influence quantitative variations in plasma lipoprotein concentrations. For example, intake of dietary saturated fat and cholesterol raises the average serum cholesterol concentration, leading to a higher risk of coronary artery disease in populations. However, not all individuals within the population are susceptible: genetic factors appear to render individuals either "dietary responsive" or "dietary nonresponsive." In this review, we focus on current knowledge about the influence of genetic polymorphisms in certain genes on the lipoprotein response to dietary fat and cholesterol. Our preliminary studies in the Dietary Intervention Study in Children suggest a significant dose-response relation between the decrease in LDL cholesterol from baseline to 36 mo of follow-up in both the intervention group (who consumed a low-fat, low-cholesterol diet) and the usual care group (who consumed a regular diet) and the presence of the APOA1*A allele at the M1 site and the + site at the M2 site of the gene encoding apolipoprotein (apo) A-I. The DNA polymorphisms on the genes encoding apo A-IV, apo B, apo C-III, apo E, lipoprotein lipase, cholesteryl ester transfer protein, lecithin:cholesterol acyltransferase (phosphatidylcholine-sterol O:-acyltransferase), and LDL receptor were found by others to be associated with the plasma lipoprotein response to dietary intervention. Possible mechanisms involved in these effects are discussed and certain discrepancies in the literature about some genetic effects on responsiveness are analyzed. An improved understanding of the influence of specific genes on lipoprotein responsiveness to dietary fat and cholesterol may allow us to identify and counsel certain individuals to avoid high-fat diets so that they may reduce their risk of developing hyperlipidemia and coronary artery disease.

Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children.

BACKGROUND: Few studies have shown the efficacy and safety of lower-fat diets in children. OBJECTIVE: Our objective was to assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease LDL-cholesterol concentrations in children. DESIGN: A 6-center, randomized controlled clinical trial was carried out in 663 children aged 8-10 y with LDL-cholesterol concentrations greater than the 80th and less than the 98th percentiles for age and sex. The children were randomly assigned to either an intervention group or a usual care group. Behavioral intervention promoted adherence to a diet providing 28% of energy from total fat, <8% from saturated fat,

miniSAGE: gene expression profiling using serial analysis of gene expression from 1 microg total RNA.

The use of serial analysis of gene expression (SAGE) to determine gene expression profiles is increasing because the technique can provide absolute transcript numbers in a digital format and identify new genes. We developed a miniSAGE technique, which uses only 1 microg total RNA and reduces the amount of the starting material by 250- to 500-fold. Unlike the other modified SAGE methods, the miniSAGE technique does not require the additional PCR amplifications. The additional PCR amplifications potentially introduce bias and compromise the quantitative aspects of the SAGE method. Three key modifications in the miniSAGE technique are: (i) using the phase lock gel (PLG, Eppendorf) to increase the recovery and the purity of DNA material after each phenol extraction step; (ii) reducing the amount of linkers in the ligation, thereby minimizing their interference with SAGE ditag amplification and increasing the SAGE ditag yield; and (iii) employing the mRNA capture kit (Boehringer Mannheim) to allow the first five steps: mRNA isolation, cDNA synthesis, enzyme cleavage of cDNA, binding of the cleaved biotin-cDNA to the streptavidin-magnetic beads, ligating linkers to the bound cDNA, and the release of cDNA tags to occur within one tube to significantly reduce the loss of material between successive steps. Two fibroblast SAGE libraries have been successfully prepared. The preliminary analysis of 3838 tags from one library demonstrated a typical fibroblast gene expression pattern. This miniSAGE technique will permit a broader application of SAGE.

Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors.

Many human immunodeficiency virus (HIV)-infected patients taking combination antiretroviral therapy that includes HIV protease inhibitors experience atrophy of peripheral subcutaneous adipose tissue. We investigated the effects of HIV protease inhibitors on adipogenesis and adipocyte survival using the 3T3-L1 preadipocyte cell line. Several HIV protease inhibitors were found either to inhibit preadipocyte differentiation or to promote adipocyte cell death. One protease inhibitor, nelfinavir, elicited both of these effects strongly. When induced to differentiate in the presence of nelfinavir, 3T3-L1 preadipocytes failed to accumulate cytoplasmic triacylglycerol and failed to express normal levels of the adipogenic transcription factors CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. The level of the proteolytically processed, active 68-kDa form of sterol regulatory element-binding protein-1, a transcription factor known to promote lipogenic gene expression, also was reduced markedly in nelfinavir-treated cells, whereas the level of the 125-kDa precursor form of this protein was unaffected. The inhibitory effect of nelfinavir occurred subsequent to critical early events in preadipocyte differentiation, expression of CCAAT/enhancer-binding protein beta and completion of the mitotic clonal expansion phase, because these events were unaffected by nelfinavir treatment. In addition, nelfinavir treatment of fully differentiated 3T3-L1 adipocytes resulted in DNA strand cleavage and severe loss of cell viability. In contrast, cell proliferation and viability of preadipocytes were unaffected by nelfinavir treatment. Thus, molecular or cellular changes that occur during acquisition of the adipocyte phenotype promote susceptibility to nelfinavir-induced cell death. When considered together, these results suggest that nelfinavir may promote adipose tissue atrophy by compromising adipocyte viability and preventing replacement of lost adipocytes by inhibiting preadipocyte differentiation.

Incorporation of lean red meat into a National Cholesterol Education Program Step I diet: a long-term, randomized clinical trial in free-living persons with hypercholesterolemia.

OBJECTIVE: Clinicians often recommend that intake of all meat, particularly red meat, be reduced in conjunction with a low-fat, low-cholesterol diet to reduce low-density lipoprotein (LDL) cholesterol. This study was designed to determine the long-term effects of lean red meat (beef, veal and pork) compared to lean white meat (poultry and fish) consumption on lipoprotein concentrations in free-living hypercholesterolemic subjects consuming a National Cholesterol Education Program (NCEP) Step I diet. METHODS: A randomized, crossover design was utilized. Hypercholesterolemic men and women (LDL cholesterol between 3.37 and 4.92 mmol/L) (triglycerides <3.96 mmol/L) (n = 145) were counseled to consume > or =80% of their 170 g/d meat intake as either lean red meat or lean white meat for two 36-week phases, separated by a four-week washout period of free meat selection. Subjects were instructed to follow an NCEP Step I diet throughout the study. RESULTS: There were no significant differences in lipid concentrations between the lean red meat and lean white meat phases. LDL cholesterol was 4.02+/-0.04 (SEM) and 4.01+/-0.04 mmol/L in the white and red phases, respectively; this represented a decrease of approximately 2% from baseline concentrations (p < 0.01). Total cholesterol also declined by 1% from baseline (p < 0.05), and high-density lipoprotein (HDL) cholesterol rose over the study period by approximately 2% to approximately 3% from baseline to reach concentrations of 1.37+/-0.03 mmol/L and 1.38+/-0.03 mmol/L in the white and red phases, respectively (p < 0.001). Triglycerides were not altered by treatment. CONCLUSIONS: Consumption of lean red meat or lean white meat, as part of an NCEP Step I diet, is similarly effective for reducing LDL cholesterol and elevating HDL cholesterol concentrations in free-living persons with hypercholesterolemia.

The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: a current review.

Three major interconnected pathways are involved in lipoprotein metabolism: (1) the transport of dietary or exogenous fat; (2) the transport of hepatic or endogenous fat; and (3) reverse cholesterol transport. These pathways are interdependent and disruptions in one will affect the function and products of the others. For example, a mutation such as one in the ABC1 protein can disrupt normal transport and processing of cholesterol. High-density lipoprotein cholesterol (HDL-C) appears to have cardioprotective properties because of its involvement in certain processes such as reverse cholesterol transport and inhibition of low-density lipoprotein cholesterol (LDL-C) oxidation. Certain agents, such as niacin, which increases HDL-C, lowers lipoprotein (a), and targets specific enzymes or receptors, may be highly beneficial for patients at risk of cardiovascular disease.

Long-term blood cholesterol-lowering effects of a dietary fiber supplement.

BACKGROUND: The study evaluated the blood cholesterol-lowering effects of a dietary supplement of water-soluble fibers (guar gum, pectin) and mostly non-water-soluble fibers (soy fiber, pea fiber, corn bran) in subjects with mild to moderate hypercholesterolemia (LDL cholesterol, 3.37-4.92 mmol/L). METHODS: After stabilization for 9 weeks on a National Cholesterol Education Program Step 1 Diet, subjects were randomly assigned to receive 20 g/d of the fiber supplement (n = 87) or matching placebo (n = 82) for 15 weeks and then receive the fiber supplement for 36 weeks. The efficacy analyses included the 125 subjects (58 fiber; 67 placebo) who were treatment and diet compliant. One hundred two (52 fiber; 50 placebo) completed the 15-week comparative phase. Of these subjects 85 (45 fiber; 40 placebo) elected to continue in the 36-week noncomparative extension phase. RESULTS: The mean decreases during the 15-week period for LDL cholesterol (LDL-C), total cholesterol (TC), and LDL-C/HDL-C ratio were greater (P < 0.001) in the fiber group. The mean changes from pre-treatment values in LDL-C, TC, and LDL-C/HDL-C ratio for subjects in the fiber group were -0.51 mmol/L (-12.1%), -0.53 mmol/L (-8.5%), and -0.30 (-9.4%), respectively. The corresponding changes in the placebo group were -0.05 mmol/L (-1.3%), -0.05 mmol/L (-0.8%), and 0.05 (1.5%), respectively. The fiber supplement had no significant effects (P > 0.05) on HDL cholesterol (HDL-C), triglyceride, iron, ferritin, or vitamin A or E levels. Similar effects were seen over the subsequent 36-week noncomparative part of the study. CONCLUSIONS: The fiber supplement provided significant and sustained reductions in LDL-C without reducing HDL-C or increasing triglycerides over the 51-week treatment period.

Comparison of the effects of lean red meat vs lean white meat on serum lipid levels among free-living persons with hypercholesterolemia: a long-term, randomized clinical trial.

BACKGROUND: Patients with hypercholesterolemia are often counseled to limit or eliminate intake of red meats, despite evidence that lean red meats (LRMs) are not hypercholesterolemic in comparison with lean white meats (LWMs). The objective of this study was to evaluate the long-term effects on serum lipids of incorporating LRM (beef, veal, and pork) vs LWM (poultry and fish) into a National Cholesterol Education Program (NCEP) Step I diet in free-living individuals with hypercholesterolemia. METHODS: Subjects included 191 men and women with a serum low-density lipoprotein cholesterol level of 3.37 to 4.92 mmol/L (130-190 mg/dL) and triglyceride level less than 3.96 mmol/L (350 mg/dL). After a 4-week baseline phase, subjects were counseled to follow an NCEP Step I diet including 170 g (6 oz) of lean meat per day, 5 to 7 days per week. Based on random assignment, subjects were instructed to consume at least 80% of their meat in the form of LRM or LWM. Fasting serum lipid levels were assessed 4, 12, 20, 28, and 36 weeks after randomization. RESULTS: After randomization, mean concentrations of total cholesterol (6.09 mmol/L [235.7 mg/dL] vs 6.08 mmol/L [235.2 mg/dL]) and low-density lipoprotein cholesterol (3.99 mmol/L [154.1 mg/dL] vs4.01 mmol/L [154.7 mg/dL]) were nearly identical in the LRM and LWM groups (1%-3% below baseline) during treatment. Mean triglyceride levels remained similar to baseline values and high-density lipoprotein cholesterol concentrations increased by approximately 2% in both groups. CONCLUSIONS: The NCEP Step I diets containing primarily LRM or LWM produced similar reductions in low-density lipoprotein cholesterol and elevations in high-density lipoprotein cholesterol levels, which were maintained throughout 36 weeks of treatment.

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.

No common major gene for apolipoprotein A-I and HDL3-C levels: evidence from bivariate segregation analysis.

Apolipoprotein A-I (apo A-I) is the most abundant protein in high-density lipoprotein (HDL) particles, and it plays an important role in HDL metabolism. Both apo A-I and HDL cholesterol (HDL-C) levels are inversely associated with risk of cardiovascular disease. Segregation analyses suggest apo A-I levels are under the control of one or more major loci. Since HDL particles are heterogeneous in their composition and size, genetic influence on its subfractions (i.e., HDL2 and HDL3) could vary. A previous report showed evidence of a major locus controlling HDL3-C levels in a subset of the current study population. Because quantitative trait loci involved in complex diseases are likely to have pleiotropic effects on several related traits, it is possible to have a common major gene involved in regulating apo A-I and HDL3-C levels. We performed a bivariate segregation analysis of apo A-I and HDL3-C levels in 1,006 individuals from 137 families ascertained through probands undergoing elective, diagnostic coronary angiography at the Johns Hopkins Hospital. The results showed significant genetic correlation between these two traits, but the hypothesis of a common major gene was rejected. Bivariate segregation analysis favored a model with two genes controlling apo A-I and a third gene independently controlling HDL3-C, and the genetic correlation between these two traits is due to residual additive polygenes. Overall, results from this study suggest that there are distinct genetic mechanisms for apo A-I and HDL3-C levels. Future studies, especially linkage analysis, should consider distinct genetic mechanisms and multiple major gene loci.

The antiatherogenic role of high-density lipoprotein cholesterol.

Landmark clinical studies in the past 5 years that demonstrated diminished mortality and first coronary events following lowering of low-density lipoprotein (LDL) cholesterol stimulated considerable interest in the medical community. Yet, high-density lipoprotein (HDL) cholesterol, which transports circulating cholesterol to the liver for clearance, clearly also exerts antiatherogenic effects. The Framingham Heart Study produced compelling epidemiologic evidence indicating that a low level of HDL cholesterol was an independent predictor of coronary artery disease (CAD). Emerging experimental and clinical findings are, collectively, now furnishing a solid scientific foundation for this relation. First, the reverse cholesterol transport pathway--including the roles of nascent (pre-beta) HDL, apolipoprotein A-I, lecithin-cholesterol acyltransferase (LCAT), cholesteryl ester transport protein, and hepatic uptake of cholesteryl ester from HDL by liver--is better understood. For example, the identification of a hepatic HDL receptor, SR-BI, suggests a mechanism of delivery of cholesteryl ester to liver that differs from the receptor-mediated uptake of LDL. Second, apolipoprotein A-I, the major protein component of HDL, and 2 enzymes on HDL, paraoxonase and platelet-activating factor acetylhydrolase appear to diminish the formation of the highly atherogenic oxidized LDL. Third, lower levels of HDL cholesterol are associated in a dose-response fashion with the severity and number of angiographically documented atherosclerotic coronary arteries. Fourth, low HDL cholesterol predicts total mortality in patients with CAD and desirable total cholesterol levels (<200 mg/dL). Fifth, low HDL cholesterol concentrations appear to be associated with increased rates of restenosis after percutaneous transluminal coronary angioplasty. In terms of elevating HDL cholesterol, cessation of cigarette smoking, reduction to ideal body weight, and regular aerobic exercise all appear important. Most medications used to treat dyslipidemias will raise HDL cholesterol levels modestly; however, niacin appears to have the greatest potential to do so, and can increase HDL cholesterol up to 30%. Recognizing these data, the most recent report of the National Cholesterol Education Program identified low HDL cholesterol as a CAD risk factor and recommended that all healthy adults be screened for both total cholesterol and HDL cholesterol levels.

Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body's ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver's ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore throw light on regulation of net dietary cholesterol absorption and lead to an advancement in the management of this important cardiovascular risk factor. By studying 10 well-characterized families with this disorder, we have localized the genetic defect to chromosome 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lodscore 4.49, theta = 0.0).

Applicability of LDLR flanking microsatellite polymorphisms for prenatal diagnosis of homozygous state for familial hypercholesterolemia.

Analysis of newly identified microsatellite polymorphisms flanking the low density lipoprotein receptor (LDLR) gene was undertaken in the kindred of a child with apparent homozygous LDLR deficiency. The applicability of these approaches to prenatal diagnosis is considered and compared with previous approaches applying functional studies of the LDLR in amniotic fibroblasts.

Segregation analysis of two-locus models regulating apolipoprotein-A1 levels.

For quantitative traits associated with risk to complex diseases, such as heart disease, single major locus models are likely to be too simplistic. Currently, researchers have begun to use oligogenic models of inheritance, but the resolving power of these models remains to be determined. As the major apoprotein of high density lipoprotein (HDL), apolipoprotein A1 (apo-A1) is generally accepted as a protective factor for coronary artery disease. Although familial aggregation of apo-A1 levels has been reported, the mode of inheritance of apo-A1 remains ill defined. In the present study, we conducted a segregation analysis comparing a series of one-locus and two-locus univariate models for apo-A1 levels in a sample of 137 families ascertained through probands undergoing elective, diagnostic coronary angiography. A two-locus Mendelian model fit these data significantly better than any one-locus model. The incorporation of the second major locus into the model of inheritance leads to a significant improvement in the fit, and a significant decrease of the residual heritability. The best-fitting model included two loci with a reciprocal pattern of epistasis generating 4 distinct genotypic distributions. Taken together, these two major loci account for 58% of the variance of adjusted apo-A1 levels. This demonstration of a second major locus controlling apo-A1 levels may explain the equivocal results obtained from previous studies. This two-locus model may be more powerful for linkage analysis to map one or both of these quantitative trait loci.