(Circulation. 1996;94:1622-1628.)
© 1996 American Heart Association, Inc.
Articles |
Compound Heterozygosity for a Structural Apolipoprotein A-I Variant, Apo A-I(L141R)Pisa, and an Apolipoprotein A-I Null Allele in Patients With Absence of HDL Cholesterol, Corneal Opacifications, and Coronary Heart Disease
the Cattedra di Malattie del Metabolismo, Istituto di Clinica Medica II, Universita degli Studi di Pisa, Italy (R.M., A. Bertolotto, R.N.); Unita Operativa di Malattie Cardiovascolari, Ospedale di Lucca, Italy (L.O.); Centro Medico Alba, Lucca, Italy (A. Boni); Institut fur Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfalische Wilhelms-Universitat, Munster, Germany (J.W., H.F., A.v.E., G.A.); and Institut fur Arterioskleroseforschung an der Universitat Munster, Germany (H.W., G.A.).
Correspondence to Dr Arnold von Eckardstein, Institut fur Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfalische Wilhelms-Universitat, Albert-Schweitzer-Str 33, D-48129 Munster, FRG.
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Abstract |
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Background The concentration of HDL cholesterol is inversely correlated with the risk of coronary heart disease (CHD). Some rare mutations in the apolipoprotein (apo) A-I gene are associated with low levels of HDL cholesterol. Their association with cardiovascular risk is controversial.
Methods and Results We studied the molecular defects underlying corneal opacities and absence of HDL cholesterol in three brothers and a sister. In a family study, the importance of these defects for lipid metabolism and manifestation of coronary heart disease was investigated. The frequency of these apo A-I defects was assessed by genotype and phenotype analysis of 477 DNA- and plasma samples, respectively, from the population. The four patients were compound heterozygotes for a null allele and a missense mutation in the apo A-I gene that leads to a leucine
arginine substitution at residue 141 [apo A-I(L141R)Pisa]. Heterozygotes for either the null allele or the structural variant had half-normal concentrations of HDL cholesterol and apo A-I compared with unaffected family members. Apo A-I(L141R)Pisa was detected in one more unrelated subject. Coronary angiography of the four compound heterozygotes revealed the presence of CHD in all male patients, whose ages ranged between 45 and 52 years. They presented with additional risk factors, including elevated LDL cholesterol levels, obesity, and arterial hypertension. Despite complete HDL deficiency and hypercholesterolemia, CHD was absent in the 51-year-old premenopausal sister.
Conclusions Apo A-I deficiency may lead to premature atherosclerosis if present in conjunction with additional cardiovascular risk factors.
Key Words: lipoproteins • apolipoproteins • genetics • coronary disease
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Introduction |
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Numerous epidemiological and clinical studies have demonstrated the inverse relationship between the concentration of HDL cholesterol and the risk of myocardial infarction (reviewed in Reference 1). The antiatherogenic role of HDLs has usually been attributed to their ability to remove cholesterol from cells of the arterial wall and to transfer this cholesterol to the liver (reviewed in Reference 2). Family and twin studies have put the influence of genes on HDL cholesterol at 35% to 50%.3 Twenty percent of patients <60 years old with myocardial infarction have familial hypoalphalipoproteinemia.4 The genetic basis of low HDL cholesterol is little understood. Only rare mutations in the genes of the major protein component in HDL, apo A-I,5 6 and of the cholesterol-esterifying plasma enzyme LCAT (reviewed in References 5 and 7) have been identified as the basis of low HDL cholesterol levels. Another, as yet unknown defect causes HDL deficiency in patients with Tangier disease.8 Moreover, the association of these conditions with cardiovascular risk is inconsistent.5 6 7 8 9 Here, we investigated the effect of two mutations in the apo A-I gene on lipid metabolism and CHD in four HDL-deficient patients and their large Italian family.
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Subjects
Index Patient
The proband (subject IIf in the pedigree, Fig 1
) is a 47-year-old Italian man originating from a small village in Tuscany. He was referred to us because of the bilateral presence of corneal opacities (Fig 2) and complete HDL deficiency. He suffered an ischemic heart attack at the age of 43 years. He underwent three-vessel aortocoronary bypass surgery 3 months thereafter. He had no history of hypertension, diabetes mellitus, or smoking. Physical examination of the patient revealed the bilateral presence of diffuse corneal cloudings that totally covered the iris and were surrounded by a grayish arcus 1 mm wide (Fig 2, top). By slit lamp examination, the clouding appeared as grayish dots in the cornea (Fig 2, bottom). Only the cornea was clouded, not the lens. Despite the massive cloudings, vision was normal. Further examination did not reveal other symptoms typical for various familial HDL-deficiency syndromes, such as xanthomas, abnormal tonsils, hepatosplenomegaly, peripheral neuropathy, or lymphadenopathy. The man's body mass index was 26.6 kg/m2, and blood pressure was 115/80 mm Hg. Except for hypercholesterolemia and absence of HDL cholesterol (Table 1), all routine laboratory tests yielded results within the normal ranges. ECG showed a previous inferior myocardial infarction.
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Family Studies
The proband's 78-year-old mother and 86-year-old father are still alive. The patient had four sisters and six brothers. Two of these siblings died of infectious diseases at the ages of 4 months and 6 years, respectively. Among his eight living siblings, two brothers and one sister also presented with bilateral corneal opacities that resembled in all respects those described for the index patient. Clinical and biochemical data of the siblings as well as of other family members are described in the "Results" section.
Population Studies
To assess the frequency of the two apo A-I gene defects in the population and to compare the biochemical data of the mutant carriers with those from the population in their environment, we screened 477 inhabitants of the area in Tuscany from which the proband originated. The study was performed during the morning hours of 3 days in autumn 1994 and 2 days in spring 1995. The study was announced in local newspapers as a primary prevention study to monitor cardiovascular risk factors in the population. Participation was voluntary and free of charge. The examination included case history by standardized questionnaires, measurement of blood pressure and body weight, collection of blood samples after a 12-hour fast for the determination of lipoprotein profiles and glucose levels, and phenotypic and genotypic analyses of apo A-I. All findings were reported to the participant's general practitioner, and the volunteer was told whether the results of the examination were normal or whether a checkup by the general practitioner might be necessary. The investigators neither carried out nor arranged for any intervention.
Laboratory Methods
Blood Sampling
Venous blood samples were drawn after overnight fasting. Serum was taken for the quantification of lipids, lipoproteins, and apolipoproteins. After centrifugation at 4°C for 15 minutes at 2000g, sera and plasmas were divided into aliquots and immediately frozen at -70°C. EDTA-treated blood was taken to separate leukocytes for the isolation of DNA. Frozen sera and EDTA-treated whole blood were sent to the laboratory in Munster for biochemical and genetic analyses.
Measurements of Lipids, Lipoproteins, and Apolipoproteins
Serum concentrations of triglycerides and cholesterol were quantified with an autoanalyzer (Hitachi/Boehringer Mannheim). HDL cholesterol concentrations were measured after precipitation of apo B–containing lipoproteins with phosphotungstic acid/MgCl2 (Boehringer Mannheim). LDL cholesterol was calculated by the Friedewald formula.10 Concentrations of apos A-I, A-II, and B were determined with immunoturbidimetric assays (Boehringer Mannheim). Lp A-I was determined by immunoelectrophoresis (Sebia). Lp A-I,A-II levels were calculated as the difference between the concentrations of apo A-I and Lp A-I. Lp(a) was measured by ELISA (Immuno).
Phenotyping of Apo A-I Isoforms
Isoforms of apo A-I were separated by IEF of plasma.11 They were visualized after electroblotting onto nitrocellulose with a polyclonal goat anti–apo A-I antiserum (Boehringer Mannheim), a biotinylated anti–goat IgG antiserum from rabbit, and a streptavidin–biotinylated horseradish peroxidase complex.
DNA Amplification and Sequencing
Genomic DNA was extracted from peripheral blood cells according to standard procedures.12 Four DNA segments harboring each of the four exons of the apo A-I gene were amplified by PCR and sequenced as reported previously.13 For determination of the presence or absence of the null allele in the family members and the control population, a simple PCR procedure was used. Accordingly, a PCR fragment of exon 3 containing the expected deletion mutation was amplified by use of the primers 5'-AGCCCACAGCTGGCCTGATCTG-3' and biotin-5'-TCATCCCACAGGCCTCTGCCCCCTG-3'. The PCR fragments were electrophoresed on a standard sequencing gel with a GATC 1500 direct blotting electrophoresis system. Visualization was done with a streptavidin–alkaline-phosphatase–conjugated antibody ELISA with colorimetric detection on a nylon filter (Nonradioactive DNA Labeling and Detection Kit, Boehringer Mannheim). The heterozygosity for the null allele was indicated by the presence of 257- and 256-bp-long DNA fragments, reflecting the wild-type and the mutant alleles, respectively. The missense mutation in codon 141 was analyzed by a PCR-based restriction fragment length polymorphism assay, using Desulfovibrio desulfuricans endonuclease I (DdeI; Biolabs) as the restriction endonuclease (Biolabs).
Cardiological Examinations
The index patient's siblings were evaluated for the presence of CHD by stress ECG,14 two-dimensional echocardiography at rest and after application of dipyridamole (when indicated), and thallium scintigraphy of the heart.
In addition, coronary angiography was performed in all compound heterozygotes and in one heterozygote (subject IIa in the pedigree). Coronary angiograms were obtained by the Judkins technique.15 A patient was identified as affected by manifest CHD if he or she had a documented myocardial infarction or if angiography revealed a >50% stenosis of at least one coronary vessel.
Statistical Analysis
Data are expressed as mean±SD. Statistical comparisons were done by Student's t test.
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Results |
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Description of the Defects
IEF of the index patient's plasma revealed the presence of an abnormal anti–apo A-I immunoreactive banding pattern (Fig 3
). Two anti–apo A-I immunoreactive bands occurred cathodic from the position of apo A-I isoforms in normal plasma. In normal plasma, the more cathodic apo A-I isoform, which corresponds to the zymogen proapo A-I,8 is present at a much lower concentration than the more acidic isoform, which corresponds to mature apo A-I. In contrast, both isoforms are present at equal concentrations in the patient's plasma. This phenotype was observed in three siblings of the patient as well (subjects IIc, IId, and IIg in Fig 1
and Table 1), who also presented clinically with corneal cloudings and biochemically with complete HDL deficiency. The patient's mother and six other family members had five instead of the three apo A-I isoforms found in normal control subjects: three with the normal isoelectric points and two isoforms with the more cathodic isoelectric points that have been observed in the four HDL-deficient subjects (Fig 3). This suggested the presence of an apo A-I defect that was vertically transmitted in the family. Sequence analysis of the patient's apo A-I gene identified two mutant alleles. A deletion of a cytosine within a stretch of seven adjacent cytosines in codons 3, 4, and 5 changes the reading frame and terminates translation in codon 12 (Fig 4A) and thus prevents the synthesis and secretion of apo A-I into plasma. We call this null allele apo A-I(5fs)Pisa. A thymidineguanosine transversion in codon 141 leads to a substitution of a leucine by an arginine (Fig 4B) in the encoded protein and hence to the synthesis and secretion of a structural apo A-I variant, called apo A-I(L141R)Pisa. Compound heterozygosity for the apo A-I null allele and the structural apo A-I variant was also found in the three siblings who presented with complete HDL deficiency and corneal opacities. Genotype analysis of the apo A-I gene in other family members identified several heterozygotes for either apo A-I(5fs)Pisa or apo A-I(L141R)Pisa (Fig 1). The apo A-I null allele was inherited from the father, the structural variant from the mother.
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IEF and subsequent anti–apo A-I immunoblotting of blood samples from 477 individuals from this family's homeland helped to identify one more male individual whose apo A-I presented with an abnormal banding pattern. Desulfovibrio desulfuricans endonuclease I digestion of his PCR-amplified DNA revealed heterozygosity for apo A-I(L141R)Pisa. A recall of his family history did not identify common relatives with the index family over the past three generations. Direct sequencing of exon 3 of the apo A-I gene in all samples from the population did not lead to the identification of another carrier of the apo A-I null allele.
Biochemical Consequences
Table 1 summarizes results of analysis of lipid metabolism in the index patient as well as in his three compound heterozygous siblings. These four individuals presented with absence of HDL cholesterol and severely reduced serum concentrations of apo A-I. Most of the residual apo A-I appeared to reside on particles that also contain apo A-II (Lp A-I,A-II) (Table 2). Moreover, in contrast to other family members, these four individuals presented with elevated levels of LDL cholesterol that surpassed the 70th percentile in the population (Fig 5, bottom). Both heterozygotes for the apo A-I null allele and heterozygotes for the structural apo A-I variant presented with approximately half-normal values for HDL cholesterol and apo A-I compared with unaffected family members (Table 2). Compared with the population in Tuscany, these values were below the 10th percentiles of sex-matched controls (Fig 5, top). In heterozygotes for apo A-I(L141R)Pisa and heterozygotes for the apo A-I null allele, the two major HDL subclasses Lp A-I and Lp A-I,A-II were decreased (Table 2). In male heterozygotes for apo A-I(L141R), the decrease in Lp A-I was more pronounced than in male heterozygotes for the apo A-I Pisa null allele (21.0±5.3 mg/dL [n=4] versus 29.7±2.3 mg/dL [n=3], P<.05, Student's t test).
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Association of Apo A-I Defects With CHD
At the age of 43 years and after an ischemic heart attack, the index patient underwent three-vessel aortocoronary bypass surgery. To assess the association of CHD with HDL deficiency, all members of generations I and II underwent cardiological examinations, although none of them reported clinical symptoms (Table 3). Coronary angiography identified two 44- and 51-year-old brothers with compound heterozygosity for apo A-I(L141R) and the apo A-I null allele (subjects IIc and IIg) as being affected with significantly stenosed coronary vessels (Table 3). In addition to HDL deficiency, both were hypertensive, obese, and hypercholesterolemic (Table 1). Coronary angiography did not identify significant coronary stenoses in the 50-year-old sister with compound heterozygosity and HDL deficiency (subject IId). She has not yet entered menopause. Two of nine heterozygotes for either the apo A-I null allele or the structural apo A-I variant suffered from CHD. The patient's father suffered a myocardial infarction at the age of 85 years. Coronary angiography identified a 57-year-old male heterozygote for apo A-I(L141R)Pisa (subject IIa) as being affected with 90% and 75% stenoses of the first and second diagonal branches of the left coronary artery, respectively. In addition to low HDL cholesterol, he also presented with profound hypercholesterolemia (Table 1). The past family history of the patients' parents was not indicative for any increased prevalence of myocardial infarctions.
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Discussion |
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Several mutations in the apo A-I gene have been described that cause an absence of HDL cholesterol and normal apo A-I in homozygous patients. All but two defects prevent the secretion of apo A-I into the plasma compartment.16 17 18 19 20 21 Exceptions are a single base deletion in codon 202 of the apo A-I gene that leads to the synthesis of an apo A-I variant with a grossly changed and truncated carboxy terminal22 and a terminating mutation in codon 31 that, for reasons not yet understood, does not prevent the synthesis of small amounts of full-length apo A-I.23 In this study, we demonstrate that compound heterozygosity for a null allele, which prevents the secretion of apo A-I, and a missense mutation, which causes a single amino acid substitution in apo A-I(L141R)Pisa, cause complete HDL deficiency. The structural apo A-I variant occurs in Tuscany with a carrier frequency of
1 in 500. Heterozygosity for either the null allele or apo A-I(L141R)Pisa severely decreases levels of HDL cholesterol and apo A-I and thereby resembles heterozygosity for other nonsense and frameshift mutations in the apo A-I gene16 17 18 19 20 21 22 23 and heterozygosity for apo A-I(R173C)Milano,24 apo A-I(P165R),25 and apo A-I(R26G)Iowa,26 respectively. Thus, the single amino acid substitution in apo A-I(L141R)Pisa exerts the same negative effect on HDL cholesterol levels as the apo A-I null allele. This suggests that this defect affects crucial functions of apo A-I in HDL metabolism.2 Our data do not allow any conclusions about the mechanism by which apo A-I(L141R)Pisa causes HDL deficiency. The relatively increased concentration of proapo A-I in compound heterozygotes for apo A-I(L141R)Pisa and the apo A-I null allele may indicate enhanced catabolism of the variant protein.8 27 Moreover, and interestingly, the defect in apo A-I(L141R)Pisa is located within epitopes of monoclonal anti-apo A-I antibodies, which inhibit the ability of apo A-I to promote cholesterol efflux from cells.28 29 30 Studies on cholesterol efflux stimulation by apo A-I(L141R)Pisa are currently being performed in our laboratory.
For several reasons, controversy exists as to whether or not apo A-I deficiency causes premature manifestation of CHD. First, apo A-I deficiency is a very rare condition, and the age of affected patients ranges from 5 to 70 years. Second, some patients with apo A-I deficiency had premature CHD,16 17 18 19 and others did not.19 20 21 22 23 This is unlike familial hypercholesterolemia,31 in which most untreated homozygotes have died of myocardial infarction at <20 years old. Also, unlike in familial hypercholesterolemia, heterozygotes for apo A-I variants or apo A-I null alleles are not affected with premature CHD (Table 3, and see References 16 to 26). Third, patients with both apo A-I deficiency and CHD came to medical attention because of coronary events.16 17 18 19 20 Since CHD is highly prevalent in most industrialized countries and is multifactorial in origin, the association between complete HDL deficiency and atherosclerosis in these cases is biased. In the family reported here, we identified the index patient because of myocardial infarction. However, we also assessed CHD in two brothers who have undergone coronary angiography because of complete HDL deficiency, although they had no clinical symptoms. This indicates that apo A-I deficiency may well confer a risk for premature atherosclerosis. However, the HDL-deficient sister, who has not yet entered menopause, did not present with CHD. Moreover, all compound heterozygous siblings presented with additional risk factors (Table 3). Among cardiovascular risk factors leading to premature atherosclerosis in HDL-deficient patients, hypercholesterolemia may be of special importance, because this risk factor was present in all four compound heterozygotes for apo A-I(L141R)Pisa as well as in some other patients with hereditary apo A-I deficiency.19 20 23 The important role of hypercholesterolemia for precipitating atherosclerosis in patients with very low HDL cholesterol is indicated by our observation that the only heterozygous sibling with CHD also had elevated LDL cholesterol concentration (subject IIa, Table 3). Premature manifestation of CHD in some patients with apo A-I deficiency16 17 18 19 may therefore be a consequence of the presence of such additional risk factors as sex, menopausal status, and other lipoprotein anomalies. This is in agreement with observations in transgenic animals. Apo A-I–deficient mice are not more susceptible to atherosclerosis than control animals.32 However, high expression of apo A-I prevents vessel disease in apo E–deficient mice, which are highly susceptible to atherosclerosis.33
It has been argued that nonsynthetic forms of HDL deficiency caused by apo A-I null alleles are atherogenic.34 By contrast, some structural apo A-I variants, such as apo A-I(R173C)Milano35 and apo A-I(R26G)Iowa,26 as well as Tangier disease27 and LCAT deficiency,7 cause HDL deficiency by the enhanced catabolism of HDL. It has been proposed that these hypercatabolic forms of HDL deficiency do not cause premature atherosclerosis.34 Like patients with Tangier disease and LCAT deficiency,7 8 27 36 compound heterozygotes for apo A-I(L141R)Pisa and the apo A-I null allele contain the precursor of apo A-I, ie, proapo A-I, in their plasma at increased concentration relative to mature apo A-I (Fig 3). This phenomenon indirectly indicates that apo A-I(L141R)Pisa undergoes enhanced catabolism and thereby contributes to HDL deficiency. Presence of premature CHD in three compound heterozygotes for apo A-I(L141R)Pisa hence provides an example that apo A-I deficiency, because of structural apo A-I variants, may well confer a risk for premature atherosclerosis. Conversely, not all patients with apo A-I null alleles were affected by CHD at a young age.19 20 21 22 Neither do transgenic mice develop atherosclerosis in which expression of the apo A-I gene has been prevented by gene targeting.32
Conclusions
We analyzed an Italian family with a nucleotide deletion and a missense mutation in the apo A-I gene that both decrease HDL cholesterol levels. Compound heterozygosity for these defects causes absence of HDL cholesterol, the occurrence of massive corneal opacities, and premature CHD in male carriers. We conclude that apo A-I deficiency may lead to premature atherosclerosis if present in conjunction with additional cardiovascular risk factors. We suggest that complete HDL deficiency constitutes an indication for coronary angiography even in the absence of clinical symptoms, especially if it is present in conjunction with additional cardiovascular risk factors.
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Acknowledgments |
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This work was supported by a grant from the Consiglio Nazionale delle Ricerche (Progetto Finalizzato Invecchiamento N. 93.00425. PF40) and from the Ministero dell'Universita e della Ricerca Scientifica of Italy (Ricerca Scientifica 1992, 1993) and by grants from the Deutsche Forschungsgemeinschaft to Dr Funke (Fu179-1.2) and Dr von Eckardstein (Ec116-2,1). We are indebted to all family members for their cooperation in this study.
Received January 10, 1996; revision received March 21, 1996; accepted April 11, 1996.
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