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(Circulation. 1995;91:505-512.)
© 1995 American Heart Association, Inc.

Articles

Genetic Basis of Lipoprotein Disorders

Marilyn Dammerman, PhD; Jan L. Breslow, MD

From the Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY.

Correspondence to Jan L. Breslow, MD, Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, 1230 York Ave, New York, NY 10021.

Key Words: atherosclerosis • lipoproteins • apolipoproteins • genes

	Introduction

Top Introduction Elevated LDL Cholesterol Reduced HDL Cholesterol and... Elevated Chylomicron Remnants... Elevated Lp(a) Future Prospects References

 
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: [in this window] [in a new window]   Table 1. Genetic Factors in Lipoprotein Abnormalities

	Elevated LDL Cholesterol

Top Introduction Elevated LDL Cholesterol Reduced HDL Cholesterol and... Elevated Chylomicron Remnants... Elevated Lp(a) Future Prospects References

 
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 lipase (LPL), present on the capillary endothelium mainly in adipose tissue and skeletal muscle, hydrolyzes VLDL core triglycerides, with apolipoprotein CII (apo CII) as a cofactor. This results in conversion of VLDL to IDL particles. The fatty acids thus liberated are reesterified to form triglycerides in adipose tissue or are oxidized to generate energy in muscle. IDL is cleared from plasma by the LDL receptor, which binds apolipoprotein E (apo E) on the IDL surface. IDL particles that escape clearance via this route are subject to further triglyceride hydrolysis by hepatic lipase to form cholesterol ester–enriched LDL particles. The LDL surface contains a single molecule of apolipoprotein B100 (apo B), which is also recognized by LDL receptors. At least 70% of LDL is cleared by the LDL receptor, primarily in the liver.

A number of genetic conditions have been identified that affect LDL cholesterol levels (Table 2). Familial hypercholesterolemia (FH) is a relatively common cause of elevated LDL cholesterol and is present in 5% of patients with MI⁴ (Table 3). An autosomal-dominant disorder, FH is due to a defective LDL receptor gene on chromosome 19. As in other dominant disorders, 50% of first-degree relatives are affected. Since there is a gene dosage effect, patients inheriting a defective gene from both parents are severely affected. Reduction in or absence of functional cell-surface LDL receptor molecules impairs LDL catabolism, and failure to carry out receptor-mediated IDL uptake results in enhanced IDL conversion to LDL.

View this table: [in this window] [in a new window]   Table 2. Genes Affecting LDL Cholesterol Levels

View this table: [in this window] [in a new window]   Table 3. Familial Hypercholesterolemia: LDL Receptor Mutations

FH homozygotes typically have sixfold elevations in LDL cholesterol, with total cholesterol levels of 650 to 1000 mg/dL, and they can be identified at birth by markedly elevated cholesterol in umbilical cord blood.⁵ CAD is often clinically apparent before age 10 years, with MI as early as age 18 months,⁴ and most homozygotes suffer fatal MI by age 30 years. A unique type of planar cutaneous xanthoma is present at birth or develops in childhood, often between the thumb and index finger, and many patients are first identified by dermatologists. However, diagnosis may be delayed until the appearance of angina pectoris or until an episode of syncope due to xanthomatous aortic stenosis.⁴ A diagnosis of pediatric FH often serves as the impetus for further case-finding in the family.

FH heterozygotes have LDL cholesterol levels twice normal, or approximately 140 mg/dL higher than family members with two normal genes. Five percent of males have had an MI by age 30 years, 25% have died of MI by age 50 years, and 50% have died by age 60 years.⁵ Onset of MI is typically delayed by 10 years in women. Heterozygous FH may be distinguishable from most other hypercholesterolemias by the presence of nodular xanthomas of the Achilles and other tendons, seen in up to 75% of heterozygotes.⁴ Diabetes and obesity are not associated with FH, and a slender physique is typical.⁴ Clinical presentation may be influenced by other genetic and lifestyle factors, however.

At least 150 different LDL receptor mutations have been described. In families in which the specific mutation is known, genetic testing can be used to identify additional affected individuals, including prenatally. In certain ethnic groups, FH is unusually common, and one or a few mutations predominate because of a founder effect, making it feasible to genetically screen members of these groups. These include French Canadians, Lebanese Christians, Jews of Lithuanian origin, Finns, and South African Afrikaners. At present, however, genetic testing for FH is available only from specialized laboratories, and most patients are identified on the basis of lipoprotein profile and clinical findings. Cholesterol guidelines based on genetic testing have recently been developed for identifying possible FH heterozygotes. Among first-degree relatives of known FH patients, a total cholesterol >220 mg/dL for patients <40 years old or >290 mg/dL for patients 40 years old suggests FH. In the general population, total cholesterol >270 mg/dL for age <40 years or >360 mg/dL for age 40 years suggests FH. In the past, FH has been overdiagnosed among the general population and underdiagnosed within FH families.⁶ Patients with FH should receive genetic counseling.

Drug therapy is necessary to reduce cholesterol levels in FH heterozygotes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lower LDL cholesterol by 30% to 50% by reducing cholesterol synthesis and by increasing LDL receptor synthesis from the normal gene.⁴ Although most homozygotes are treated by plasma exchange, liver transplantation has been used successfully in recent years.

Clinical trials of gene therapy for homozygous FH are in progress in a few patients. In the first reported case, hepatocytes derived from a section of the patient's liver were genetically repaired in culture and then returned to the liver via cell infusions into the portal circulation. This resulted in stable engraftment of a small number of LDL receptor–synthesizing hepatocytes.⁷ The patient's LDL cholesterol dropped from a mean of 448 mg/dL on lovastatin before gene therapy to a mean of 366 mg/dL on lovastatin after the procedure. Together with a small increase in HDL cholesterol, this resulted in a decline in the LDL:HDL cholesterol ratio from the range of 10 to 13 before gene therapy to 5 to 8 after the procedure. These modest improvements may not translate into an improved clinical outcome, but more efficient methods of gene replacement are under development, and these may result in more dramatic improvement.

A second relatively common single-gene disorder causing elevated LDL cholesterol, familial defective apo B100 (FDB), is due to a mutation in the apo B gene on chromosome 2.^{3 8} The resulting amino acid substitution disrupts apo B binding to the LDL receptor, impairing LDL uptake. Heterozygosity for this disorder increases LDL cholesterol levels by at least 50% (60 to 80 mg/dL) relative to unaffected family members. In general, FDB may be clinically milder than FH, but many patients have tendon xanthomas, and cholesterol levels may fall within the FH range. In some cases, the two disorders are distinguishable only by genetic tests, and the approach to treatment is the same.

In the general population, genetic variation in apo E accounts for 3% to 5% of the variance in LDL cholesterol levels. Apo E mediates hepatic uptake of chylomicron remnants as well as IDL particles. Whereas liver-derived VLDL particles are the primary carriers of endogenously synthesized fats, intestinally derived chylomicrons are the primary carriers of dietary fats. After synthesis, chylomicrons pass into lymph and then into plasma for transport to adipose tissue and skeletal muscle, where their core triglycerides are hydrolyzed by LPL to yield free fatty acids and chylomicron remnants. Cholesterol ester and apo E enriched remnants travel to the liver for uptake by the remnant receptor. Efficiency of apo E–mediated uptake of both IDL and chylomicron remnants is thought to influence LDL cholesterol levels.

Apo E is encoded by a gene cluster on chromosome 19 that also encodes apolipoproteins CI and CII. Apo E genotyping has revealed three common alleles in the population: E3 (Caucasian frequency, 77%), E4 (15%), and E2 (8%). Individuals with the E4/3 genotype (the E4 protein is synthesized from one parental allele and E3 from the other) have mean LDL cholesterol levels 5 to 10 mg/dL higher than subjects with the most common genotype, E3/3, whereas individuals with E3/2 have LDL cholesterol levels 10 to 20 mg/dL lower than E3/3 subjects (Table 4). Several mechanisms have been proposed to account for this.⁴ Hepatic clearance of IDL and chylomicron remnants is faster in individuals with E4/3 and slower in those with E3/2 relative to those with E3/3. This may cause E4/3 subjects to synthesize fewer LDL receptor molecules, reducing LDL clearance, whereas E3/2 subjects may synthesize more LDL receptors, increasing LDL clearance. In addition, in vitro evidence suggests that apo E is necessary for conversion of IDL to LDL and that E2 functions less well than E3 in this regard.

View this table: [in this window] [in a new window]   Table 4. Common Variation in Apolipoprotein E

Apo E genetic variation also influences the progression of atherosclerosis in the general population. In an autopsy study of more than 500 young male trauma victims, E3/2 was associated with reduced atherosclerosis relative to E3/3.⁹ This was observed in both whites and blacks and was only partially explained by apo E– associated differences in cholesterol levels. Apo E genotypes accounted for 6% to 7% of the variance in aortic lesion extent.

Familial combined hyperlipidemia (FCHL), a complex disorder of unknown cause, is the most common genetic hypercholesterolemia and one of the most frequent causes of premature CAD (Table 5). FCHL (type IIb hyperlipoproteinemia) is characterized by elevations of LDL cholesterol and VLDL triglyceride (>95th percentile for age and sex) within the same family. Affected subjects may have one or both abnormalities, and the lipid profile may vary over time. Xanthomas are uncommon. VLDL and apo B are overproduced in FCHL, and this may lead to elevated plasma VLDL and hypertriglyceridemia in some family members, whereas in others with more efficient lipolysis, the consequence is elevated LDL. Hyperlipidemia appears in 10% to 20% of patients in childhood, usually as hypertriglyceridemia.¹⁰ Patients usually have a strong family history of premature CAD, and hypertriglyceridemic family members seem to be at the same increased risk as those with hypercholesterolemia.² FCHL accounts for 10% of individuals with LDL cholesterol >95th percentile and is present in 10% of patients with MI.⁴ The disorder is exacerbated by obesity, diabetes, hypothyroidism, exogenous estrogen, and alcohol. Patients are often responsive to low-fat diet and exercise, but drug therapy may be necessary.

View this table: [in this window] [in a new window]   Table 5. Familial Combined Hyperlipidemia

When elevated cholesterol and triglycerides are considered as a single trait, an autosomal-dominant pattern is often observed for FCHL.⁴ The disorder appears to be genetically heterogeneous, however, and other patterns are also observed. There is evidence favoring a role, in some families, for a chromosome 11 region that includes the genes for apolipoproteins AI, CIII, and AIV.¹¹ Heterozygosity for mutations in the LPL gene on chromosome 8 has been documented in a few cases.¹² It is likely that as yet unknown genes responsible for increased apo B levels are also involved.

Elevated apo B levels (>130 mg/dL) are present in one third of patients with confirmed premature CAD.¹³ In one study, LDL cholesterol levels >95th percentile were present in 15% of patients with MI before age 60 years, while LDL apo B levels >95th percentile were present in 35%.¹⁴ The measurement of plasma apo B levels may be useful for patients with hypertriglyceridemia or known CAD. It has been argued that elevated apo B in such patients is an indication for more aggressive treatment.¹⁴

Frequently observed in, but not unique to, patients with FCHL are small dense LDL particles. These are associated with increased triglycerides and elevated apo B as well as with reduced HDL cholesterol.¹⁵ A single gene appears to have a major influence on LDL particle size, although this trait is also diet-responsive.¹⁶ Small dense LDL particles are highly susceptible to oxidation, which may make them highly atherogenic. In one study, this trait was found in 50% of MI victims but only 26% of control subjects, although this was not independent of triglyceride level.¹⁵

Family and twin studies indicate that half the population variance in LDL cholesterol is genetic. Approximately 7% of the variance is explained by known LDL receptor, apo B, and apo E mutations, with the preponderance unexplained.³ Individuals differ in their responses to dietary fat and cholesterol, and genes controlling diet response may explain much of the variation in LDL cholesterol. These genes may influence such processes as cholesterol absorption and synthesis, bile acid synthesis, and LDL receptor synthesis and catabolism.⁴

	Reduced HDL Cholesterol and Elevated Triglycerides

Top Introduction Elevated LDL Cholesterol Reduced HDL Cholesterol and... Elevated Chylomicron Remnants... Elevated Lp(a) Future Prospects References

 
Reduced HDL cholesterol (<35 mg/dL) has been found, in a large number of studies, to be a potent independent risk factor for CAD. In a study of patients with confirmed CAD before age 60 years, reduced HDL cholesterol was the most common lipoprotein abnormality (39% of cases).¹ Approximately half the population variance in HDL cholesterol is probably attributable to genetic factors.¹⁷

There are two major HDL particle size classes in plasma: HDL₃ and the larger HDL₂. Nascent HDL particles produced by the liver and small intestine consist primarily of complexes of phospholipid and apolipoprotein AI (apo AI), and remodeling of these particles occurs as they circulate in plasma.¹⁷ HDL particles attract excess free cholesterol from extrahepatic cells and from other types of lipoprotein particles. The cholesterol is esterified by the enzyme lecithin:cholesterol acyltransferase (LCAT), with apo AI as a cofactor, and the resulting cholesterol ester enters the HDL core, enlarging the particle. HDL particles may also become smaller as a result of the action of cholesteryl ester transfer protein (CETP), which exchanges the cholesterol ester in HDL for triglycerides in VLDL and IDL. Hepatic lipase can then hydrolyze HDL triglycerides, reducing particle size. Excess cholesterol in peripheral tissues can thus be transferred from HDL to other lipoprotein particles, which are cleared from plasma by hepatic receptors. This process, called reverse cholesterol transport, may account in part for the protective effect of HDL.

HDL cholesterol levels are strongly correlated with apo AI levels. Interindividual differences in HDL cholesterol and apo AI levels correlate best with the apo AI fractional catabolic rate rather than with the synthetic rate. Fractional catabolic rate increases with decreasing particle size, which in turn correlates with increased triglycerides.³ Thus, in many individuals, elevated triglycerides may be the driving force lowering HDL cholesterol levels. This may result from increased exchange of HDL cholesterol ester for VLDL triglycerides and from decreasing HDL size resulting from subsequent hepatic lipase action. In individuals with normal triglycerides, other mechanisms may result in reduced HDL cholesterol levels. For example, a low-fat diet, which is associated with protection against CAD, lowers HDL cholesterol by decreasing apo AI production.¹⁸

Lipoprotein transport genes have also been implicated in conditions affecting HDL cholesterol levels (Table 6). A small number of patients with defective HDL production due to mutations in the apo AI gene on chromosome 11 have been described. These mutations preclude synthesis of the protein and, in the homozygous state, are characterized by very low HDL cholesterol.¹⁷ Most of these patients develop planar xanthomas and CAD between the ages of 25 and 50 years. Deficiency of the LCAT enzyme results in abnormal lipoprotein particles of all types caused by inability to esterify free cholesterol, large quantities of which accumulate in plasma and tissues.⁸ This rare disorder is caused by homozygosity for mutations in the LCAT gene on chromosome 16. HDL cholesterol may be markedly reduced, and patients may have premature CAD as well as renal damage resulting from the lipoprotein disorder. Several other disorders have been described that result in low HDL cholesterol but not in premature CAD. These include Tangier disease, characterized by abnormally rapid HDL clearance; dyslipidemia due to certain apo AI amino acid substitutions; and homozygous LPL deficiency. Although it is clear that low HDL cholesterol is an important risk factor for CAD in the general population, whether this is a direct cause-and-effect relation or whether low HDL cholesterol exacerbates the risk of an otherwise atherogenic lipoprotein profile remains to be resolved.

View this table: [in this window] [in a new window]   Table 6. Genes Affecting HDL Cholesterol Levels

Two deficiencies of proteins involved in HDL processing have been found to raise HDL cholesterol levels.^{3 8} In hepatic lipase deficiency, there is premature CAD despite elevated HDL cholesterol. This rare disorder is characterized by a failure to remodel HDL₂ to HDL₃ because of a mutation in the hepatic lipase gene on chromosome 15. The second disorder, CETP deficiency, is due to mutations in the CETP gene on chromosome 16. These result in elevated apo AI and HDL cholesterol levels and reduced apo B and LDL cholesterol levels, a profile associated with protection against CAD and with longevity. CETP mutations occur frequently among Japanese and in this population are a common cause of high HDL cholesterol.¹⁹ Apart from cases of CETP deficiency, families with unusually high HDL cholesterol and apo AI levels have been reported. Simple mendelian inheritance is generally not observed, and the genetic factors responsible have yet to be identified.¹⁷

Single-gene syndromes probably account for a very small fraction (perhaps 1%) of the population variance in HDL cholesterol levels. A large number of studies have failed to demonstrate a major single-gene effect on HDL cholesterol in the general population.¹⁷ Based on family studies, however, a very significant proportion of the variance (40% to 60%) appears to be attributable to polygenic inheritance. This could result from common sequence variations in a small number of genes, and it seems likely that genes regulating HDL particle size, including those influencing the activity of HDL-processing proteins, may play an important role. The LPL gene was shown to influence HDL₃ cholesterol levels in a recent study of families of CAD victims.²⁰

HDL cholesterol levels are moderately responsive to exercise and weight loss, as well as to some drugs that lower LDL cholesterol and/or triglycerides. Increasing HDL cholesterol should be a therapeutic goal in patients with low HDL levels and with CAD, but treatment of otherwise normal patients with no family history of CAD is controversial.

Elevated triglycerides are generally found together with low HDL cholesterol, and these appear to be causally linked. In relatives of CAD patients with familial lipoprotein disorders, an elevated triglyceride level with reduced HDL cholesterol was nearly four times more common than reduced HDL cholesterol alone.¹ In some but not all studies, elevated triglycerides have been shown to be an independent CAD risk factor.²¹ Nearly one fourth of patients with CAD before age 60 years had hypertriglyceridemia in a recent study.¹ These cases were more often familial than sporadic and were almost always associated with low HDL cholesterol. Among diabetics, hypertriglyceridemia constitutes a major CAD risk factor.²²

Elevated triglycerides are common in the population. Of males 35 to 39 years old, for example, 10% have triglycerides >250 mg/dL.²³ Genetic hypertriglyceridemia may present as elevated triglycerides in the absence of secondary causes or as unusual triglyceride sensitivity to alcohol, exogenous estrogen, weight gain, hyperglycemia, or hypothyroidism. While moderate triglyceride elevations may be secondary to other metabolic abnormalities or to exogenous agents, severe hypertriglyceridemia (>1000 mg/dL) generally reflects a genetic propensity.

VLDL and chylomicrons are the principal triglyceride-rich lipoproteins. Type IV hyperlipoproteinemia is characterized by elevated VLDL, with triglycerides of 250 to 500 mg/dL, whereas type V hyperlipoproteinemia is characterized by elevated VLDL and fasting chylomicronemia, with triglycerides >500 mg/dL. Families with isolated hypertriglyceridemia are less common than those with FCHL, and triglycerides tend to be higher. In severe hypertriglyceridemia, cholesterol is often elevated, since it is a constituent of VLDL. This may be important, since the cholesterol ester content of triglyceride-rich lipoproteins may determine their atherogenicity. Some individuals with high VLDL levels also have markedly elevated LDL cholesterol, and these patients may be at especially high risk for CAD. Hypertriglyceridemic patients with elevated apo B appear to be substantially more likely to develop CAD than those with normal apo B levels.¹⁴

Familial hypertriglyceridemia is genetically heterogeneous, and in most cases the genetic basis is unknown. In some families, the disorder appears to be inherited in an autosomal-dominant manner, whereas in others, recessive or non-mendelian patterns are observed. Hypertriglyceridemia is strongly associated with hyperinsulinemia, hyperglycemia, and hypertension, a constellation of features called syndrome X.²⁴ Hypertriglyceridemia may be due to VLDL overproduction, impaired catabolism, or both. A genetic defect in the ability to catabolize VLDL triglycerides may be expressed in the presence of exacerbating factors. When VLDL is overproduced, as in obesity or diabetes or as a result of alcohol or estrogen use, affected patients may be unable to increase VLDL catabolism proportionately.⁴

Severe fasting chylomicronemia (type I hyperlipoproteinemia) is due to homozygosity for mutations in the gene for LPL (chromosome 8) or for the LPL cofactor apo CII (chromosome 19). Type I disease is characterized by very low or undetectable LPL activity and very high triglycerides but not by premature CAD. This suggests that elevated triglycerides are not inherently atherogenic but are a feature of several different metabolic disorders, only some of which are atherogenic.

In Caucasians, hypertriglyceridemia is strongly associated with the minor (less common) allele of a two-allele polymorphism near the coding sequence for apolipoprotein CIII (apo CIII) on chromosome 11.²⁵ In one study, this marker was present in 44% of patients with severe hypertriglyceridemia and in 17% of control subjects.²⁶ Association of this and other polymorphisms in the apo AI/CIII/AIV gene cluster with CAD among subjects with a family history of CAD has been reported.²⁷ Genetic factors conferring protection against hypertriglyceridemia also reside in this region.²⁶ Apo CIII is a major protein constituent of chylomicrons and VLDL particles. Normolipidemic subjects carrying the minor allele of the apo CIII polymorphism have higher apo CIII levels than noncarriers,²⁸ and apo CIII and triglyceride levels are strongly correlated. Apo CIII inhibits LPL in vitro and may also inhibit hepatic uptake of triglyceride-rich particles and their remnants. Transgenic mice that overexpress the human apo CIII gene have severe hypertriglyceridemia,²⁹ which makes this the strongest candidate gene in this region with respect to regulation of triglycerides. Apo E4 carriers and heterozygotes for LPL mutations are also at increased risk of hypertriglyceridemia.^{12 30 31}

Triglycerides should be measured in patients with CAD or a family history of CAD, as well as those with diabetes, hypertension, obesity, chronic renal disease, or peripheral vascular disease. Moderate hypertriglyceridemia (250 to 750 mg/dL) that persists after secondary causes have been eliminated may respond to low-fat diet, exercise, and weight loss, whereas severe hypertriglyceridemia often requires drug therapy. Triglycerides >1500 mg/dL may lead to pancreatitis and require immediate treatment with a low-fat diet.

	Elevated Chylomicron Remnants and IDL Cholesterol

Top Introduction Elevated LDL Cholesterol Reduced HDL Cholesterol and... Elevated Chylomicron Remnants... Elevated Lp(a) Future Prospects References

 
Type III hyperlipoproteinemia is characterized by plasma accumulation of chylomicron remnants and IDL particles due to impaired catabolism. Both cholesterol and triglycerides are elevated, with mean levels of 450 and 700 mg/dL, respectively.³² LDL cholesterol is generally low because of reduced conversion of VLDL to LDL and/or upregulation of LDL receptors. Patients are susceptible to severe premature CAD, strokes, and peripheral vascular disease.

Chylomicron remnants and IDL particles are normally cleared by hepatic remnant and LDL receptors, which recognize apo E on the surface of these particles, as described previously. A common impairment of this pathway is due to the apo E2 allele, which encodes a protein with only 1% to 2% of normal receptor binding activity. One percent of the population is homozygous for E2 (E2/2 genotype). These individuals do not generally exhibit fasting hyperlipidemia but have difficulty clearing chylomicron remnants from plasma postprandially.⁴ Approximately 1 in 50 E2/2 individuals is unable to compensate for the defective apo E protein and develops the fasting lipid elevations characteristic of type III hyperlipoproteinemia. Xanthoma striata palmaris, orange or yellow discoloration of the palmar and digital creases, is pathognomonic of type III disease.³² The difference between E2/2 individuals with and without fasting hyperlipidemia is presumably due to factors that affect IDL metabolism. These may include aging, exogenous estrogen, obesity, glucose intolerance, and hypothyroidism, as well as heterozygosity for another genetic defect, such as FH.^{4 32} Type III hyperlipoproteinemia has been reported in several patients with the apo E2/2 genotype who are also heterozygous for an LPL mutation,³³ and there are almost certainly other mutant genes that can serve as a "second hit," resulting in type III disease. Recently, dominantly inherited forms of type III with almost full penetrance have been reported to be due to mutant apo E alleles aside from the common E2 variant.^{8 32} Type III patients are highly responsive to diet and weight loss, but drug therapy is often required.

Homozygous apo E mutations resulting in very low to undetectable levels of plasma apo E have recently been described.⁸ Apo E deficiency is associated with very high plasma levels of VLDL plus IDL cholesterol and with atherosclerosis. In mice, germ-line ablation of both copies of the apo E gene results in advanced atherosclerotic lesions similar to those observed in human CAD.²⁹

	Elevated Lp(a)

Top Introduction Elevated LDL Cholesterol Reduced HDL Cholesterol and... Elevated Chylomicron Remnants... Elevated Lp(a) Future Prospects References

 
In case-control studies, elevated plasma levels of Lp(a) have been found to be an independent risk factor for CAD.³⁴ Levels of Lp(a), an LDL-like particle, vary greatly in the population (from <0.1 to >200 mg/dL) and are almost entirely genetically determined. Plasma Lp(a) concentrations >20 mg/dL have been reported to confer increased risk of CAD, as well as cerebrovascular and peripheral vascular disease. Lp(a) >39 mg/dL was the most common familial dyslipidemia in a study of patients with confirmed CAD before age 60 years, accounting for 19% of patients with a familial dyslipidemia.¹ Among Hawaiian men of Japanese ancestry, 14% of all cases of MI and 28% of cases before age 60 years were attributed to elevated Lp(a).³⁵ In contrast to case-control studies, prospective studies of Lp(a) and CAD have produced inconsistent results. Although two small Swedish studies detected an association,³⁴ a prospective analysis of Helsinki Heart Study participants found no relation between Lp(a) levels and future coronary events.³⁶ Similarly, no association between Lp(a) levels and future MI in men was detected in the Physicians' Health Study (296 cases, 296 controls).³⁷ Blacks have higher Lp(a) levels than Caucasians, but this does not appear to translate into increased CAD risk.³⁸

The protein component of the Lp(a) particle consists of one molecule of apo B disulfide-bonded to one molecule of apolipoprotein(a) [apo(a)], a very large protein of unknown function. Apo(a) bears a striking resemblance to the fibrinolytic enzyme precursor plasminogen, and the genes for these two proteins are closely linked on chromosome 6.³⁴ Plasminogen consists of five pretzel-shaped domains, called kringles, and a protease domain, whereas apo(a) consists of multiple tandem copies of a sequence resembling the plasminogen kringle IV domain plus single copies of plasminogen-like kringle V and protease domains. The protease domain of apo(a) is unable to degrade fibrin. Both the apo(a) gene and protein vary widely in size within the population because of differing numbers of copies of the kringle IV sequence.³⁴

Approximately 90% of the variability in Lp(a) levels in the population is attributable to the apo(a) gene.³⁹ Lp(a) levels are inversely correlated with apo(a) size, and individuals with smaller apo(a) isoforms are therefore presumed to be at greater risk of CAD.³⁴ Size polymorphisms account for nearly 70% of the variance in Lp(a) levels.³⁹ Apo(a) alleles of the same size are heterogeneous at the DNA sequence level, and it has been estimated that there may be more than 100 alleles in total.⁴⁰ Alleles of the same size but differing sequence are coinherited with different Lp(a) levels in families,⁴⁰ and variation in regions of the apo(a) gene that regulate messenger RNA levels are likely to make an independent contribution to variability in Lp(a) levels. Sequence heterogeneity in the apo(a) gene may contribute to genetic variation in CAD risk not only via effects on Lp(a) levels but also via qualitative differences in the apo(a) molecule.

Lp(a) may participate in both thrombogenic and atherogenic processes because of the plasminogen-like properties of apo(a) and the LDL-like properties of Lp(a).⁴¹ Fibrinolysis by plasmin requires the conversion of plasminogen to plasmin by tissue-type plasminogen activator. In vitro studies suggest that Lp(a) may interfere with this process. In addition, apo(a) can compete with plasminogen for binding to fibrin and to plasminogen receptors on cultured endothelial cells, preventing assembly of the fibrinolytic system on cell surfaces.³⁴ A relation between elevated plasma Lp(a) and increased thrombosis or reduced thrombolysis has not been established in humans but has been demonstrated in primates after arterial injury.⁴² Apo(a), much of it in the form of cholesterol-rich Lp(a), is a tightly bound constituent of human atherosclerotic plaques,³⁴ and transgenic mice expressing human apo(a) develop early atherosclerotic lesions on a high-fat diet.²⁹

Measurement of Lp(a) levels has been recommended in patients with premature CAD, and elevated levels may warrant testing and counseling of first-degree relatives.³⁴ Since known treatments fail to normalize Lp(a), intervention focuses on reduction of coexisting risk factors, especially elevated LDL cholesterol. Further studies are required to reconcile the results of the prospective and case-control studies.

	Future Prospects

Top Introduction Elevated LDL Cholesterol Reduced HDL Cholesterol and... Elevated Chylomicron Remnants... Elevated Lp(a) Future Prospects References

 
As this review shows, considerable progress has been made in understanding the genetic basis of lipoprotein disorders through the study of candidate genes that code for proteins known to be involved in lipoprotein metabolism. However, further study of these genes and others yet to be identified will be necessary before knowledge of the genetic basis for variation in lipoprotein levels is complete.

The genetic complexity of the heritable lipoprotein phenotypes associated with heart disease suggests that important advances are likely to result from the development of new animal models based on transgenic techniques. The ability to express a human gene in transgenic mice or to ablate an endogenous gene in "knockout" mice affords an unprecedented opportunity to establish the functions of specific genes and the role they might play in lipoprotein disorders and susceptibility to atherosclerosis.²⁹ In addition, new strategies have recently been developed for identifying rodent genes controlling quantitative traits such as plasma cholesterol and triglycerides. In many cases, this is likely to lead to the identification of corresponding human genes. Improved understanding of the genetic processes underlying lipoprotein disorders will suggest new interventions to inhibit or reverse these processes.

Our growing awareness of the strongly familial nature of CAD and predisposing metabolic disorders should encourage cardiologists to focus additional attention on the younger members of affected families, particularly the families of patients with MI before age 55 years. This should take the form of patient education and follow-up with respect to hygienic measures of proven efficacy and aggressive treatment of metabolic disorders that prove resistant to changes in lifestyle.

Received August 10, 1994; accepted November 2, 1994.

	References

Top Introduction Elevated LDL Cholesterol Reduced HDL Cholesterol and... Elevated Chylomicron Remnants... Elevated Lp(a) Future Prospects References

 
1. Genest JJ Jr, Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH, Silberman SR, Wilson PWF, Salem DN, Schaefer EJ. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992;85:2025-2033. [Abstract/Free Full Text]

2. Bierman EL. Atherosclerosis and other forms of arteriosclerosis. In: Wilson JD, Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci AS, Root R, eds. Harrison's Principles of Internal Medicine. 12th ed. New York, NY: McGraw-Hill; 1991:992-1001.

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