Familial Lipoprotein Disorder Research Articles

Genetics of Familial Combined Hyperlipidemia (FCHL) Disorder: An Update.

Familial combined hyperlipidemia (FCHL) is one of the most common familial lipoprotein disorders of the lipoproteins, with a prevalence of 0.5% to 2% in different populations. About 10% of these patients suffer from cardiovascular disease and this number is increased by up to 11.3% in the young survivors of myocardial infarction and by 40% among all the survivors of myocardial infarction. Although initially thought to be that FCHL has an inheritance pattern of monogenic, the disease's etiology is still not fully understood and it appears that FCHL has a complex pattern related to genetic variants, environmental factors, and lifestyles. Two strategies have been used to identify its complex genetic background: candidate gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL with a variable degree of scientific evidence. Until now, more than 30 different genetic variants have been identified related to FCHL. In this study, we aimed to review the individual genes that have been described in FCHL and how these genes and variants can be related to the current concept of metabolic pathways resulting in familial combined hyperlipidemia.

ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?

Among the three human apolipoprotein E (apoE) isoforms, apoE4 increases the risk of Alzheimer's disease (AD). While transporting cholesterol is a primary function, apoE also regulates amyloid-β (Aβ) metabolism, aggregation, and deposition. Although earlier work suggests that different affinities of apoE isoforms to Aβ might account for their effects on Aβ clearance, recent studies indicate that apoE also competes with Aβ for cellular uptake through apoE receptors. Thus, several factors probably determine the variable effects apoE has on Aβ. In this Review, we examine biochemical, structural, and functional studies and propose testable models that address the complex mechanisms underlying apoE-Aβ interaction and how apoE4 may increase AD risk and also serve as a target pathway for therapy.

Pattern of plasma lipoprotein (a) in Sudanese patients with coronary artery disease

Coronary artery disease is one of the l wide. lipoprotein(a) [Lp (a)] is a cholesterol rich plasma lipoprotein Its structure and composition closely resembles low density lipoproteins (LDL). Elevated Lp (a) is the most common familial lipoprotein disorder in patients with premature Coronary Artery Disease (CAD). Objective: To study the pattern of plasma LP(a) levels in Sudanese patients who presented with coronary artery disease [CAD]. Material and Methods: This is a case control study. 30 patients randomly se admitted to the coronary care unit [C.C.U] in Elshaab Teaching Hospital with acute coronary syndrome in the period from April 2004 to July 2005 while 30 patients with non ischaemic cardiac problems admitted to the same ho randomly selected as a matched control group. Serum LP(a), cholesterol and low C) concentrations were determined using the conventional enzymatic colorimetric methods. Results: LP(a), cholesterol and LDL lev respectively]. Lp(a) is also high in patients blew 60years of age. High LP(a) correlates with high cholesterol, LDL and other risk factors. The role of Lp(a) as an independent 15 patients with no other risk factors had high LP(a) level. Conclusion: This study demonstrated significant Lp(a) level in patients with other risk factors of CAD [including cholesterol and LDL].

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.

Genetic lipoprotein disorders and coronary atherosclerosis

Familial lipoprotein disorders are seen frequently in subjects with premature coronary artery disease. The genetic basis for several dyslipoproteinemias has been elucidated in the past two decades. The majority of lipoprotein disorders result from a combination of polygenic predisposition and poor lifestyle habits, including physical inactivity, increased visceral adipose tissue, increased caloric intake, and cigarette smoking. Monogenic disorders are seen in approximately 5% of premature coronary artery disease cases, and this prevalence is higher in populations with the Founder effect. Unraveling the genetic basis of many lipoprotein disorders has allowed fundamental discoveries in molecular cellular physiology and has paved the way for novel therapeutic approaches.

A critical evaluation of the putative role of C3adesArg (ASP) in lipid metabolism and hyperapobetalipoproteinemia

The acylation stimulating protein, ASP is a small, basic serum protein capable of stimulating triglyceride synthesis in cultured fibroblasts and adipocytes. Sequence analysis of ASP has shown that ASP is identical to C3adesArg — the inactive fragment of the complement anaphylatoxin peptide, C3a. It has been proposed that C3adesArg (ASP) can be generated by mature adipocytes secreting the three complement proteins: complement protein C3, factor B and factor D (adipsin). There have also been indications that adipocytes may express a specific C3adesArg (ASP)-receptor that is distinct from the recently cloned C3a-receptor. This suggests that C3adesArg (ASP) acts as an adipocyte autocrine and that it plays a central role in the metabolism of adipose tissue. Based on these observations a hypothesis for the etiology of hyperapobetalipoproteinemia (hyperapoB) has been proposed. Hyperapobetalipoproteinemia (hyperapoB), is a familial lipoprotein disorder characterized by increased hepatic secretion of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) particles. If C3adesArg (ASP) function in the adipose tissue is impaired, a reduced rate of triglyceride synthesis will follow, generating an increased flux of fatty acids to the liver. In response to an increased flow of fatty acids, the liver will increase its production of VLDL particles yielding the phenotype of hyperapoB. This review critically assesses this hypothesis and the potential role of C3adesArg (ASP) as a major determinant for triglyceride synthesis in the light of data collected in vitro and in vivo.

Haplotypes of the ApoA-I/C-III/A-IV gene cluster and familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is the most frequent familial lipoprotein disorder associated with premature coronary heart disease. However, no genetic defect(s) underlying FCHL has been identified. A linkage between FCHL and the apoA-I/C-III/A-IV gene cluster has been reported but not verified in other populations. A recent study identified FCHL susceptibility haplotypes at this gene cluster. To study whether such haplotypes are also associated with FCHL susceptibility in Finns, we studied 600 well-defined Finnish FCHL patients and their relatives belonging to 28 extended FCHL families by using haplotype, linkage, sib-pair, and linkage disequilibrium analyses. The genotypes of the MspI polymorphisms were associated with total serum cholesterol (P<0.01) and apoB (P<0.05) levels in spouses, which represent the general Finnish population. However, no evidence of direct involvement of any of these loci or their specific haplotypes in the expression of FCHL in the Finnish FCHL families was found.

Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.

More than half of the patients with angiographically confirmed premature coronary heart disease (CHD) have a familial lipoprotein disorder. Familial combined hyperlipidaemia (FCHL) represents the most common genetic dyslipidemia with a prevalence of 1.0-2.0%. FCHL is estimated to cause 10-20% of premature CHD and is characterized by elevated levels of cholesterol, triglycerides, or both. Attempts to characterize genes predisposing to FCHL have been hampered by its equivocal phenotype definition, unknown mode of inheritance and genetic heterogeneity. In order to minimize genetic heterogeneity, we chose 31 extended FCHL families from the isolated Finnish population that fulfilled strictly defined criteria for the phenotype status. We performed linkage analyses with markers from ten chromosomal regions that contain lipid-metabolism candidate genes. One marker, D1S104, adjacent to the apolipoprotein A-II (APOA2) gene on chromosome 1, revealed a lod score of Z = 3.50 assuming a dominant mode of inheritance. Multipoint analysis combining information from D1S104 and the neighbouring marker D1S1677 resulted in a lod score of 5.93. Physical positioning of known genes in the area (APOA2 and three selectin genes) outside the linked region suggests a novel locus for FCHL on 1q21-q23. A second paper in this issue (Castellani et al.) reports the identification of a mouse combined hyperlipidaemia locus in the syntenic region of the mouse genome, thus further implicating a gene in this region in the aetiology of FCHL.

A competitive reverse transcription–PCR to study apolipoprotein ε gene expression

We developed a rapid and simple competitive reverse transcription-polymerase chain reaction for the quantification of apo epsilon mRNA in human monocyte-derived macrophages. The method was applied, and its reliability was shown in patients with the familial lipoprotein disorder, type III hyperlipoproteinemia. Type III hyperlipoproteinemic patients express markedly higher concentrations of apo epsilon mRNA when compared with healthy controls. Patients with this disease are usually (>90%) homozygous for a receptor binding-defective isoform of apolipoprotein apo E (apo E2). The higher expression of apo epsilon mRNA in the patients could, therefore, be a physiological mechanism to compensate for functionally defective apo E. The developed procedure might be valuable in assessment of apo epsilon gene expression in human disease.

Etiologic Heterogeneity of Hyperapobetalipoproteinemia (HyperapoB)

Hyperapobetalipoproteinemia (hyperapoB) is a common familial lipoprotein disorder associated with premature coronary artery disease (CAD). HyperapoB is characterized by an increased number of small, dense LDL particles. Patients with hyperapoB may be normotriglyceridemic (normoTG) or hypertriglyceridemic (hyperTG). We tested the hypothesis that a major locus controls the hyperapoB phenotype by using data from 1035 participants in 145 families enriched for premature CAD. Segregation analysis was conducted, and results suggest etiologic heterogeneity in these families. Families (n = 55) with one or more hyperTG hyperapoB individuals strongly supported mendelian recessive inheritance of hyperapoB. Under this mendelian model, individuals with the high-risk genotype had a baseline risk of 0.78, but parental and spouse's hyperapoB phenotypes did influence the probability of displaying hyperapoB. Low-risk genotypes had virtually no risk of displaying hyperapoB. The other subgroup of families (n = 72), in which all hyperapoB individuals were normoTG, did not show any clear pattern of inheritance. Eighteen families did not have any hyperapoB individual. In the 55 families with hyperTG hyperapoB, diabetes was more prevalent in hyperapoB individuals (18.3% of hyperTG hyperapoB individuals, 9.6% of normoTG hyperapoB individuals) than in normal individuals (4.9%). Both hyperTG hyperapoB and normoTG hyperapoB phenotypes were significant predictors for blood pressure in the 55 families, but not in the total population. These associations further suggest a link between hyperapoB and the small, dense LDL syndromes. This study successfully demonstrated mendelian inheritance of the hyperapoB phenotype and also suggested etiologic heterogeneity of hyperapoB.

Elevated Lp(a) is the most frequent familial lipoprotein disorder leading to premature myocardial infarction in a country with low cholesterol levels

Disorders of the lipoprotein metabolism are an important cause of premature coronary artery disease and myocardial infarction. Of the genetic lipoprotein disorders, elevation of apoprotein (apo) B containing lipoproteins is the most frequent one in the western population. We aimed to define the prevalence of genetic lipoprotein disorders and other risk factors in a population from a country with a low average cholesterol levels. We examined 48 consecutive patients with premature myocardial infarction below age 55, their 78 siblings and age and body mass index matched controls for familial lipoprotein disorders. The patients with premature myocardial infarction had higher triglyceride, low-density lipoprotein, apo B, lipoprotein (Lp) (a) and lower apo A1 levels then controls ( p<0.05). Of the nonlipid risk factors, 67% smoked, 8% had diabetes mellitus, 17% had hypertension and 58% a family history of premature coronary artery disease. Fifty percent of these patients with premature myocardial infarction had a familial lipoprotein disorder. Familial excess of Lp(a) was the most frequent lipoprotein abnormality present in 16% of the patients followed by familial combined hyperlipidemia. We conclude that, Lp(a) increase was the most frequent familial lipoprotein abnormality in this population. The frequency of familial lipoprotein disorders in this population emphasises the need to screen siblings of patients with premature myocardial infarction.

Genetics of type III hyperlipoproteinemia

One hundred forty-seven relatives of 43 patients with “classical” type III hyperlipoproteinemia (HLP) having the apolipoprotein (apo) E2/2 phenotype were studied to determine the occurrence of hyperlipidemia and the presence of further possible genes for lipoprotein disorders in these families. In 12 pedigrees primary dyslipidemia was prevalent among patients and respective blood-relatives. In these kindreds the coexistent presence of genes for familial combined hyperlipidemia (n = 6), familial hypertriglyceridemia (n = 5), and familial hypercholesterolemia (n = 1), respectively, was supposed. Our results, therefore, confirm and extend previous data on the multifactorial genesis of the diseases. Besides homozygosity for a receptor binding-defective isoform of apo E (apo E2), additional genes for familial lipoprotein disorders might operate in the pathogenesis of type III HLP. This is the largest family study performed so far in this primary lipoprotein disorder. Genet. Epidemiol. 14:283–297,1997. © 1997 Wiley-Liss, Inc.

Genetics of type III hyperlipoproteinemia

One hundred forty-seven relatives of 43 patients with "classical" type III hyperlipoproteinemia (HLP) having the apolipoprotein (apo) E2/2 phenotype were studied to determine the occurrence of hyperlipidemia and the presence of further possible genes for lipoprotein disorders in these families. In 12 pedigrees primary dyslipidemia was prevalent among patients and respective blood-relatives. In these kindreds the coexistent presence of genes for familial combined hyperlipidemia (n = 6), familial hypertriglyceridemia (n = 5), and familial hypercholesterolemia (n = 1), respectively, was supposed. Our results, therefore, confirm and extend previous data on the multifactorial genesis of the diseases. Besides homozygosity for a receptor binding-defective isoform of apo E (apo E2), additional genes for familial lipoprotein disorders might operate in the pathogenesis of type III HLP. This is the largest family study performed so far in this primary lipoprotein disorder.

Unusual xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia

We report on a 20-year-old man with the combination of two independent familial lipoprotein disorders: heterozygous familial hypercholesterolemia (FH) and type III hyperlipoproteinemia (HLP). Familial hypercholesterolemia was diagnosed by elevated total and low density lipoprotein cholesterol levels and family history. By denaturing gradient gel electrophoresis, DNA sequencing and restriction fragment length polymorphism analysis, a G→A splice donor mutation in intron 3 of the proband's low density lipoprotein receptor gene was identified as the underlying molecular defect. This mutation was described previously as a receptor-negative founder mutation in Norway (FH-Elverum) and subsequently in 6 unrelated heterozygous English patients, creating a severe phenotype of familial hypercholesterolemia. Type III HLP was confirmed by homozygosity for apolipoprotein (apo) E2 and an elevated ratio of very low density lipoprotein cholesterol to serum triglycerides (0.40; normal ratio about 0.20). The patient has unusual flat xanthomas in the interdigital webs of the hands which are normally not found in either disease. These dermatological findings might therefore be indicative of the rare combination of both disorders of lipoprotein metabolism in one individual. © 1996 Wiley-Liss, Inc.

Three-dimensional structure of the LDL receptor-binding domain of the human apolipoprotein E2 (Arg 136 → Cys) variant

The familial lipoprotein disorder type III hyperlipoproteinemia (HLP) is usually inherited as a recessive trait. Indeed, more than 90% of affected individuals are homozygous for a receptor binding-defective isoform of apolipoprotein (apo) E, apo E2. However, some rare apo E variants have been described that dominantly (thus in a single dose) predispose to the disease. Amino acid substitutions, which are accompanied with the loss of positive charges within the proposed apo E binding-region to lipoprotein receptors, seem to be responsible in most of these cases for the dominance with respect to the expression of type III HLP. So far available data in the literature on the naturally occurring human apo E2 (Arg 136 → Cys) variant are not conclusive about its recessive or dominant character. We recently identified a subject heterozygous for this mutation, presenting the typical clinical and biochemical characteristics of type III HLP. In the present study we performed further analysis of the mutation on apo E structure and function based on computer modeling. Our combined data point to a dominant influence of the apo E2 (Arg 136 → Cys) variant with respect to the transmission of the disease.

Lack of association of the apolipoprotein A-I-C-III-A-IV gene XmnI and SstI polymorphisms and of the lipoprotein lipase gene mutations in familial combined hyperlipoproteinemia in French Canadian subjects

Familial combined hyperlipoproteinemia (FCH) is a common familial lipoprotein disorder characterized by elevated plasma cholesterol and triglyceride levels with segregation in first-degree relatives. Most affected subjects with FCH have elevated plasma levels of apolipoprotein (apo) B. The disorder results from oversecretion of hepatic apoB-containing lipoprotein particles. The genetic defect(s) are unknown. Previous work has suggested that genetic polymorphisms of the apoA-I gene and functional abnormalities of the lipoprotein lipase (LPL) gene are associated with FCH. We investigated the XmnI and SstI restriction fragment length polymorphisms (RFLP) of the apoA-I gene in FCH subjects of French Canadian descent. We also investigated three common functional mutations of the lipoprotein lipase (LPL) gene (LPLGly188Glu, LPLPro207Leu, and LPLAsp250Asn) in French Canadians that account for approximately 97% of cases of complete LPL deficiency in the province of Québec, Canada. We identified and characterized 54 FCH probands in lipid clinics and examined at least one first-degree relative. There were 37 men and 17 women (mean age 48 +/- 9 and 58 +/- 8 years, respectively). None of the probands had diabetes mellitus; mean plasma glucose was 5.5 mmol/L. High blood pressure was diagnosed in 32% of men and 29% of women. The body mass index (weight (kg)/height(m2)) was elevated in probands (27 +/- 4 for men and 26 +/- 4 for women). Mean plasma levels of cholesterol (C) was 7.6 +/- 1.5 mmol/L, triglycerides 3.5 +/- 1.6 mmol/L, LDL-C 4.9 +/- 1.2 mmol/L, HDL-C 1.0 +/- 0.3 mmol/L, and apoB 1.83 +/- 0.67 g/L in the probands. Allele frequency of the rare alleles of the XmnI and SstI RFLP was not significantly different from a healthy reference group. In several families studied, the XmnI and SstI RFLP did not unequivocally segregate with the FCH phenotype. There was no significant effect of the presence or absence of the XmnI or SstI RFLP's on plasma lipids, lipoprotein cholesterol or apoB levels. Only one FCH proband was found to have a mutation of the LPL gene (Gly188Glu), and this did not segregate with the FCH phenotype in the family. We conclude that in our highly selected group of FCH subjects of French Canadian descent, the XmnI and SstI RFLPs of the apoA-I gene and common functional mutations of the LPL gene resulting in complete LPL deficiency are not associated with FCH.

Prevalence and association of atherosclerosis at three different arterial sites in patients with type III hyperlipoproteinemia

We have examined the prevalence of clinically significant atherosclerosis in 78 patients with type III hyperlipoproteinemia (HLP) and homozygosity for apolipoprotein (apo) E2. Forty-six of these individuals (59%) had no atherosclerosis, 32 patients (41%) had atherosclerosis, i.e., atherosclerosis of the extracranial carotid arteries (CAA), coronary arteries (CAD) or/and peripheral arteries of the legs (PVD), either singly or in combination. No association could be shown with respect to the co-prevalence of atherosclerotic lesions at these different arterial sites, except for the high predictive value ( pv = 0.88, P = 0.006) of CAA for the presence of PVD. Hence, documentation of atherosclerosis under clinical aspects at one of these exposed arterial territories does not allow a reliable prediction of generalised atherosclerosis or local atherosclerosis at other sites of the arterial tree in individuals with this familial lipoprotein disorder. Therefore, assessment of the extent of clinically significant atherosclerosis in type III HLP patients should include careful and thorough examination of the extracranial carotid arteries, the coronary arteries, and the peripheral arteries of the legs.

Genetic basis of lipoprotein disorders.

Lipoprotein disorders result from abnormal synthesis, processing, or catabolism of plasma lipoprotein particles. These particles consist of a core of cholesterol ester and triglyceride enclosed in a coat of phospholipids and apolipoproteins. More than half of patients with angiographically confirmed coronary artery disease (CAD) before age 60 years have a familial lipoprotein disorder.1 The association is most striking among younger patients and declines with increasing age at first myocardial infarction (MI). This suggests the presence of genetic factors that accelerate age-associated cardiovascular changes seen in the general population.2 Severe hyperlipidemia (total cholesterol >300 mg/dL or triglycerides >500 mg/dL) usually indicates a genetic disorder, and xanthomas almost always signal an underlying genetic defect. These findings warrant examination of the patient’s first-degree relatives.2 Four types of lipoprotein abnormalities are observed: elevated LDL cholesterol; reduced HDL cholesterol, usually with increased triglycerides and very-low-density lipoprotein (VLDL) cholesterol; elevated levels of chylomicron remnants and intermediate-density lipoproteins (IDL); and elevated levels of lipoprotein (a) [Lp(a)] particles.3 Lipoprotein transport genes have been implicated in each of these abnormal lipoprotein phenotypes (Table 1⇓). View this table: Table 1. Genetic Factors in Lipoprotein Abnormalities Cholesterol levels >240 mg/dL are associated with a threefold increased risk of death from ischemic heart disease in men relative to cholesterol levels <200 mg/dL, and there is a continuous risk gradient as cholesterol rises.2 Elevated total cholesterol primarily reflects elevated LDL cholesterol, which constitutes 70% of plasma cholesterol. Disorders characterized by elevation of cholesterol alone are classified as Fredrickson type IIa hyperlipoproteinemia. LDL particles are a constituent of the endogenous (nondietary) fat transport pathway and are formed via action of lipases on precursor particles. Excess carbohydrate or fat reaching the liver that is not required for energy or synthetic purposes is converted into triglycerides, packaged with apolipoproteins, and secreted as VLDL particles. Lipoprotein …

Tracking and predictiveness of serum lipid and lipoprotein measurements in childhood: a 12-year follow-up. The Cardiovascular Risk in Young Finns study.

The authors analyzed tracking and predictiveness of serum lipid and lipoprotein measurements in Finnish children and young adults over a 12-year follow-up period. A representative sample of 3,596 healthy subjects aged 3-18 years was examined in 1980. The follow-up studies were done in 1983, 1986, 1989, and 1992. Data were available on serum lipids and lipoproteins, anthropometric measurements, dietary and smoking habits, and use of oral contraceptives. Complete data on serum lipids in 1980 and 1992 were available for 883 subjects (47% males), and they comprised the study cohort for this analysis. Significant tracking was found in each of the serum lipid variables studied. The range of 12-year correlations was 0.48-0.58, 0.53-0.58, 0.53-0.58, 0.57-0.59, and 0.33-0.37 for serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, the LDL:HDL cholesterol ratio, and triglycerides, respectively. Males showed more tracking than females; there was no clear age trend. Tracking of HDL2 cholesterol was better than that of HDL3 cholesterol (0.64 vs. 0.43, respectively; 3-year tracking). Apolipoproteins A-I and B showed similar amounts of tracking compared with HDL and LDL cholesterol, respectively. Approximately 50% of subjects who initially fell into the extreme quintiles of total cholesterol, LDL cholesterol, and HDL cholesterol were in the same quintiles after 12 years. In multiple regression analyses, childhood obesity, exercise, diet, and smoking habits did not markedly aid the prediction of adult serum lipid values. However, the use of two childhood measurements increased the amount of adult serum lipid variability explained. Although universal screening cannot be endorsed, these findings emphasize the importance of serum lipid measurements in the early detection of familial lipoprotein disorders and in the initial evaluation of coronary heart disease risk in childhood.

Familial lipoprotein disorders and premature coronary artery disease

Significant risk factors for premature coronary heart disease include: (1) family history, (2) elevated low density lipoprotein (LDL) cholesterol level ≥ 160 mg/dl, 1, (3) decreased high density lipoprotein (HDL) cholesterol level < 35 mg/dl, 1, (4) cigarette smoking, (5) high blood pressure and (6) diabetes mellitus. All of these risk factors are common in patients with premature heart disease. Common familial lipid disorders associated with premature heart disease include familial lipoprotein(a) excess, familial dyslipidemia (elevated triglycerides and decreased HDL cholesterol), familial combined hyperlipidemia (elevations of LDL cholesterol and triglycerides, and often decreased HDL cholesterol), familial hypoapobetalipoproteinemia (elevated apolipoprotein B levels), familial hypoalphalipo-proteinemia (low HDL cholesterol levels), and familial hypercholesterolemia (elevated LDL cholesterol levels). All these disorders have been characterized using age and gender specific 90th and 10th percentile values from the normal population. The diagnosis and potential management of these disorders is reviewed.