Apolipoprotein A-I_Zavalla (Leu₁₅₉Pro)

HDL Cholesterol Deficiency in a Kindred Associated With Premature Coronary Artery Disease

From the Department of Medicine at the University of Maryland School of Medicine (M.M., D.A., G.F., K.Z.), and the Veterans Affairs Medical Center (M.M., K.Z.), Baltimore, Md, and the Department of Pathology, University of British Columbia, Vancouver, Canada (H.P.).

Correspondence to Michael Miller, MD, Division of Cardiovascular Medicine, S3BO6, University of Maryland Hospital, 22 S Greene St, Baltimore, MD 21201-1595. E-mail mmiller{at}heart.ab.umd.edu

	Abstract

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Abstract—We investigated the molecular defect causing high density lipoprotein cholesterol (HDL-C) deficiency in a male proband and his family members. Amplification and sequencing of genomic DNA disclosed a novel base-pair substitution at residue 159 in the apolipoprotein (apo) A-I gene. This substitution resulted in the loss of an AviII restriction site and a predicted substitution of leucine with proline at residue 159. Restriction enzyme analysis demonstrated absence of the AviII site in 19 of 40 biological family members. Compared with familial controls, subjects with the apoA-I_Zavalla variant had reduced HDL-C (1.16 versus 0.27 mmol/L, P<0.0001), apoA-I (38.7 versus 124.4 mg/dL, P<0.0001), and apoA-II (14.3 versus 19.0 mg/dL, P<0.0001) levels. Two subjects who have developed coronary artery disease to date possess additional cardiovascular risk factors. Other heterozygotes for apoA-I_Zavalla are presently without symptomatic coronary artery disease. This study identifies a monogenic cause of hypoalphalipoproteinemia, with the single base-pair substitution having a dominant effect on the low HDL-C phenotype. In addition, it extends recent observations that HDL-C deficiency states may be more prone to the development of premature coronary artery disease when accompanied by additional cardiovascular risk factors.

Key Words: HDL cholesterol • coronary artery disease • apolipoprotein A-I • genetics

	Introduction

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Epidemiological studies have demonstrated an inverse association between HDL cholesterol (HDL-C) levels and coronary artery disease (CAD),^{1 2} even when total cholesterol levels are not elevated.³ An important mechanism subserving the antiatherogenic role of HDL-C is reverse cholesterol transport. Extrahepatic cholesterol, esterified by lecithin:cholesterol acyltransferase (LCAT) and incorporated in HDL-C, may be transferred to lower density lipoproteins (LDL-C)⁴ or incorporated by steroidogenic tissues.⁵ The latter process is mediated by the scavenger receptor BI, an HDL-C–binding protein that also participates in the early stages of reverse cholesterol transport by promoting cellular cholesterol efflux.⁶

Genetic deficiency of HDL-C has been associated with premature CAD in several families. These cases have ranged from single point mutations in the apoA-I gene to large deletions or chromosomal aberrations in the apoA-I/C-III/A-IV gene complex.^{7 8 9 10} However, HDL-C deficiency states resulting from structural apoA-I changes do not inevitably result in premature CAD.¹¹ Recently, severe HDL-C deficiency was associated with premature CAD only when accompanied by additional CAD risk factors.^{12 13}

We now report a novel point mutation in the apoA-I gene that in the heterozygous state causes very low HDL-C. The structural variant occurs at the same residue as apoA-I_Fin,¹⁴ but the base-pair substitution involves proline rather than arginine. To our knowledge, the affected family represents the largest related cohort in the United States reported to date with HDL-C deficiency.

	Methods

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Subjects
Index Patient
In 1984, the 35-year-old proband (T.L.) of Zavalla, Tex, suffered a myocardial infarction due to complete occlusion of the right coronary artery. Five years later, the frequency of angina increased; coronary arteriography revealed a 90% stenosis of the midportion of the right coronary artery. The lesion was successfully dilated by percutaneous transluminal angioplasty, and he has remained free of symptomatic disease. A reduced level of HDL-C (0.16 mmol/L; 6 mg/dL) was initially identified in 1986. In addition to low HDL-C, the only other identifiable risk factor for premature CAD was a history of cigarette smoking (20 to 30 cigarettes daily beginning at age 15 years).

Family Studies
Forty biological family members have been screened; the pedigree is illustrated in Figure 1. The proband's mother (J.L.) has the genetic mutation (see below). There is no history of symptomatic CAD, and no other coronary risk factors, except for low HDL-C, are present. Neither of J.L.'s 2 sisters with apoA-I_Zavalla (M.B.R. and B.B.B.) have clinically manifest CAD. The only coronary risk factor among them was cigarette smoking; M.B.R. had smoked 5 to 10 cigarettes daily for 40 years but quit in 1996.

View larger version (18K): [in this window] [in a new window]   Figure 1. Pedigree of 40 biological family members screened for the apoA-IZavalla mutation. Arrow indicates the proband; partially shaded circles (women) and squares (men) indicate heterozygotes for the apoA-I structural variant.

The proband has 7 siblings. His eldest sister (R.A.) developed severe angina at age 41; coronary arteriography revealed a 75% to 85% osteal narrowing of the left main coronary artery and significant narrowing in the proximal left anterior descending artery, circumflex artery, and right coronary artery. She underwent successful coronary artery bypass grafting. Her HDL-C levels varied from 0.05 to 0.31 mmol/L (2 to 12 mg/dL). Additional CAD risk factors included an elevated LDL-C level and 32 years of cigarette smoking (as many as 40 cigarettes daily beginning at age 14 years).

None of the other siblings has symptomatic CAD. Affected sister B.J.H. has smoked 20 cigarettes daily for the past 26 years. Thallium scintigraphy in 1995 did not demonstrate reversible myocardial ischemia. Two additional brothers have the mutation. M.L. has adult-onset diabetes mellitus and had a negative thallium scintigraphy study in 1996. J.A.L. has no other cardiac risk factors. Two affected cousins, P.R.M. and D.J.K., have hypertension as an additional risk factor; exercise stress testing was negative in both individuals. The other affected first cousin (N.K.F.) has no other cardiovascular risk factors, and no further cardiac work-up has been performed to date. Third-generation family members heterozygous for apoA-I_Zavalla are young (<40 years) and have also not been tested noninvasively for CAD. All study subjects signed consent forms approved by the Institutional Review Board at the University of Maryland School of Medicine.

Laboratory Methods: Quantification of Lipids and Apolipoproteins
Blood samples, collected in tubes containing EDTA, were drawn after an overnight fast. Whole blood was centrifuged, with the plasma and buffy coats dispensed into vials and shipped in wet ice by overnight express. Plasma concentrations of total cholesterol (TC) and triglyceride (TG) were measured enzymatically with a Hitachi 704 clinical chemistry analyzer (Boehringer Mannheim). HDL-C was measured after precipitation of apoB-containing lipoproteins as previously described.¹⁵ LDL-C was estimated by the Friedewald formula.¹⁶ ApoA-I and apoB concentrations were quantified by using commercially available immunodiffusion plates (apo A-I, Tago, Inc; apoB, Behring Diagnostics). ApoA-II levels were quantified by an ELISA.¹⁷ The activity of LCAT was measured by established methods.¹⁸

DNA Analyses
Polymerase Chain Reaction (PCR) Amplification
Genomic DNA obtained from the proband and biological family members was isolated from leukocytes of 30 mL of whole blood by using a DNA extraction kit (Stratagene). PCR¹⁹ was used to amplify the apoA-I gene promotor and coding regions by utilizing oligonucleotide primers designed in accordance with the known genomic sequence of the apoA-I gene.^{20 21} The sequence and position of the oligonucleotide primers used are shown in Table 1. Each PCR was performed with 25 ng of genomic DNA in the presence of 0.67 mmol/L MgCl₂, 100 µmol/L of each dNTP, 67 mmol/L Tris-HCl (pH 8.0), 10% DMSO, 10 mmol/L DTT, 17 mmol/L (NH₄)₂SO₄, and 0.17 mg/mL BSA in a total volume of 100 µL. DNA was denatured at 95°C for 5 minutes and then cooled to annealing temperature before the enzyme was added. Thirty amplification cycles were performed as follows: 95°C for 45 seconds, 58°C to 65°C for 1 minute (annealing), and 72°C for 1 minute (extension).

Sequencing of PCR-Amplified DNA
PCR products were isolated by using the Qiagen PCR purification kit. DNA was eluted in water and sequenced by using the fluorescent dye terminator cycle sequencing method. Reactions were analyzed on an ABI automated sequencer. The PCR primers (Table 1) were also used for sequencing.

Restriction Enzyme Analysis
To examine polymorphic restriction sites created by the identified mutation, sequencing primers 9 and 10 (Table 1) were used to amplify exon 4 under the PCR conditions employed above. Approximately 500 ng of each PCR product was digested for 2 hours with 5 U of AviII (Stratagene). The restriction fragments were separated by polyacrylamide gel (8%) electrophoresis. DNA was visualized after ethidium bromide staining.

	Results

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Analysis of Lipids: Lipoproteins, Apolipoproteins, and LCAT Activity
Levels of lipids, lipoproteins, and apolipoproteins for the 40 biological members of this family are presented in Table 2. The age range of the family studied was 8 to 72 years. Similarly, there was a wide range of lipid and lipoprotein values obtained. Subjects with the apoA-I_Zavalla mutation (see also below) had variable reductions in HDL-C and apo A-I levels: whereas the majority of first-generation subjects had an 50% reduction in apoA-I, subsequent generations evidenced greater decrements in apoA-I levels (nearly 75%). Overall, the mean levels of HDL-C, apoA-I, and apo A-II were significantly reduced in affected subjects compared with biological controls; TC, TG, LDL-C, and apoB levels were not different between the groups (Table 3). Measurement of LCAT activity was performed in the proband (T.L.), his sister (R.A.), and his mother (J.L.). Compared with controls (24.6±3.6 nmol · mL^-1 · h^-1), LCAT activity was slightly lower in R.A. (16.8) but normal in T.L. (25.9) and J.L. (30.4). Moreover, the cholesterol esterification rate was not different between controls (123±32 nmol · mL^-1 · h^-1) and the subjects tested (R.A., 86.0; T.L., 78.7; and J.L., 72.2 nmol · mL^-1 · h^-1). This excluded the LCAT gene as a potential cause for the low HDL-C.

Analysis of the ApoA-I Mutation
After PCR amplification of genomic DNA, direct sequencing of the coding region of the apoA-I gene revealed that the proband was heterozygous for a base-pair substitution in exon 4, leading to an amino acid change (Leu ₁₅₉ Pro) (Figure 2). Sequencing of the other coding regions and the apoA-I promotor did not disclose any additional mutations.

View larger version (153K): [in this window] [in a new window]   Figure 2. Single base-pair change (TC) in codon 159 of the apoA-I gene. Compared with the sequence of control DNA (left), the sequence on the right demonstrates a heterozygous subject with 1 normal (CTG) and 1 mutant (CCG) allele. Base-pair substitution changes a LeuPro.

Because the TC transition abolished an AviII restriction site, restriction enzyme analysis was used to determine the prevalence of the genomic variant in biological family members. On amplification and AviII digestion, the normal allele revealed 2 fragments, 76 and 253 bp long (Figure 3). The proband and affected relatives exhibited 3 fragments: an uncut full-length product and the 2 smaller digested fragments. This finding is consistent with a heterozygous state of 1 normal and 1 mutant allele.

View larger version (47K): [in this window] [in a new window]   Figure 3. AviII-digested PCR products. The 329-bp product contains the 5' portion of exon 4 of apoA-I. Normal allele contains an AviII site that produces 2 fragments, 253 and 76 bp, after digestion with this restriction endonuclease. Single base-pair substitution in codon 159 destroys the AviII site. AviII digests from several family members are illustrated.

	Discussion

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We have identified a novel mutation in the apoA-I gene in a large US family primarily residing in Texas and Ohio. The 19 affected subjects are heterozygotes for the mutation, consistent with an autosomal dominant mode of inheritance. Highly polymorphic genetic markers (eg, variable nucleotide repeat elements) previously disclosed that the apoA-I_Zavalla mutation is linked to the low HDL-C phenotype.²²

As anticipated, first-generation heterozygotes (M.B.R., B.B.B., and J.L.) evidenced an 50% reduction in apoA-I levels. However, with few exceptions (eg, P.R.M. and C.M.J.), successive-generation heterozygotes had an 80% reduction in apoA-I levels. A similar dominant effect on the HDL-C phenotype was recently reported with ApoA-I_Fin, a TG substitution at residue 159, resulting in a leucinearginine change. In subjects who were heterozygous for apoA-I_Fin, HDL-C and apoA-I concentrations were 20% of normal. In vivo kinetic studies disclosed hypercatabolism of the mutant apoA-I protein. In the present study, there was a TC substitution at residue 159, resulting in a leucineproline change, and marked reductions in HDL-C and apoA-I were observed in many affected subjects. Based on the predicted structural analysis of apoA-I,²³ the conversion of leucine to proline significantly enhances hydrophilicity, decreases the -helix–forming potential, and increases the ß-turn–forming potential; these structural alterations predict an unstable protein susceptible to posttranslational degradation.^{24 25} In addition to apoA-I_Fin, apoA-I_Seattle is also associated with apoA-I levels that are 15% of normal. The latter mutation results from a 45-bp deletion in exon 4 of the apoA-I gene, corresponding to a protein product lacking amino acids Glu₁₄₆Arg₁₆₀.²⁶ Although this region appears to be important for LCAT activation,²³ cholesterol esterification in plasma was only mildly reduced in apoA-I_Fin but normal in the apoA-I_Seattle heterozygotes. Similarly, our heterozygous subjects with apoA-I_Zavalla manifested normal or only mildly reduced LCAT activity, suggesting that the disproportionate reduction in apoA-I mass was likely not a consequence of marked inhibition of LCAT. Thus, it is unlikely that the variability in apoA-I levels observed in some apoA-I_Zavalla heterozygotes (eg, T.L. and J.L.) can be explained by differences in LCAT activity. Whether additional factors such as DNA instability²⁷ or alterations in other HDL-C–regulating genes (eg, lipoprotein lipase) account for the variability in apoA-I levels is presently unknown and requires further study. Nevertheless, the marked reductions in HDL-C and apoA-I identified in the majority of apoA-I_Zavalla heterozygotes extends previous observations in apoA-I_Fin and apoA-I_Seattle that alteration of the domain containing residue 159 appears particularly unstable and vulnerable to catabolism. Comparative kinetic studies may further assess the relative impact of this region compared with other domains that also enhance apoA-I catabolism but do not reduce levels as dramatically.²⁸

Despite reduced HDL-C in all of the affected family members, symptomatic CAD has thus far developed only in the proband (T.L.) and 1 sister (R.A.). Both subjects evidenced additional coronary risk factors, including cigarette smoking (T.L. and R.A.) and hypercholesterolemia (R.A.). Of the other 5 apoA-I_Zavalla heterozygotes >40 years old, 3 had CAD risk factors and 2 had negative noninvasive cardiovascular studies.

However, this does not rule out the possibility that occult CAD may exist, because the majority of myocardial infarctions occur in lesions previously identified as non–flow limiting.²⁹ The evaluation of additional noninvasive modalities (eg, carotid ß-mode ultrasound) may therefore provide an opportunity to further evaluate atherosclerosis in a subgroup of individuals at potentially increased risk of CAD.

That low HDL-C increases the likelihood of premature CAD has been well described in observational studies.^{1 2 30} Subjects at highest risk include those with apoA-I/C-III/A-IV deficiency,^{7 8} reduced apoA-I synthesis,⁹ or the presence of additional cardiovascular risk factors.^{12 13} There are several mechanisms whereby HDL-C deficiency may enhance CAD risk. First, reverse cholesterol transport may be impaired.³¹ HDL-C may also inhibit modification of LDL-C,³² a known prerequisite of atherothrombosis. Recent studies indicate that paraoxonase, an enzyme residing on the surface of HDL-C particles, inhibits LDL-C oxidation.^{33 34} Thus, reduced HDL-C mass and concomitantly less circulating paraoxonase may intensify lipid peroxidation and internalization by the macrophage scavenger receptor despite normal circulating levels of LDL-C. Indeed, CAD patients with "desirable" TC levels evidence significantly higher coronary event rates if accompanied by low HDL-C.³⁵ Moreover, the addition of risk factors that facilitate LDL-C modification (eg, cigarette smoking)³⁶ may markedly augment this process.

Notwithstanding, not all subjects with HDL-C reduction or deficiency evidence symptomatic CAD. In addition to apoA-I_Zavalla, this trend was observed in apoA-I_Fin¹⁴ and in studies of young (<40 years)^{10 11 31 37} or hypocholesterolemic (TC 3.88 mmol/L) individuals.³⁸ Moreover, screening healthy populations³⁹ for genomic variants in HDL-C candidate genes may be less informative than focusing on families with premature CAD. Because in vitro studies have demonstrated that cholesterol efflux is maintained in HDL-C–deficient states,⁴⁰ our study extends recent observations that mechanisms imposed by additional CAD risk factors may be necessary to augment atherothrombosis. In the absence of these factors, however, the overall risk of CAD with HDL-C deficiency remains to be established.

	Acknowledgments

 
This study was supported by NIH grant HL-52663. We thank Dr Daniel J. Harmon for identifying the proband. The authors also gratefully knowledge Dr John Collins for computer analysis of the altered apoA-I protein.

Received November 19, 1997; accepted February 23, 1998.

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