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Lack of association between increased carotid intima-media thickening and decreased HDL-cholesterol in a family with a novel ABCA1 variant, G2265T.

HDL particles play a pivotal role in reverse cholesterol transport (RCT) [3] by transporting free cholesterol from peripheral tissues to the liver. Inherently, molecular abnormalities in any of the proteins regulating HDL metabolism may therefore potentially impair RCT or advance atherothrombosis. Observational studies have identified an inverse relationship between coronary artery disease (CAD) and the HDL-cholesterol (HDL-C) concentration, even when total cholesterol concentrations are desirable (1). The recent identification of the ATP-binding cassette transporter, ABCA1, as an important regulator of HDL metabolism and RCT has demonstrated that variations in this gene appear to be a noteworthy contributor to HDL deficiency states.

Despite the recent characterization of ABCA1 mutations as the cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (2-5), there have been little data evaluating clinical measures of atherosclerosis in individuals with identified defects in ABCA1. This is an important issue to resolve because low-HDL syndromes are heterogeneous and may not necessarily be linked to premature vascular disease (6). For example, CAD has been reported in individuals with TD before age 60 years, although premature, symptomatic CAD at <40 years has not been reported (7). As such, identifying individuals at potentially high risk of CAD would seemingly have important clinical implications.

In view of the burgeoning evidence invoking ABCA1 in HDL metabolism and RCT, we identified a novel ABCA1 mutation in a kindred with moderately low HDL-C but without a history of TD. In addition, a noninvasive surrogate of atherosclerosis was used to evaluate the impact of low HDL-C concentrations on premature vascular disease.

Materials and Methods

STUDY PARTICIPANTS

The proband (II-3), a Caucasian resident of Jacksonville, FL, had decreased HDL-C (0.34 mmol/L) and apolipoprotein AI (apoA-I; 0.49 g/L) concentrations (Fig. 1, arrow). When he was 44 years of age, he was diagnosed with CAD and underwent coronary artery bypass grafting. Before the development of symptomatic CAD, the proband had smoked heavily (40 cigarettes daily) for 25 years. The proband's father (I-1) evidenced no history of premature CAD and died of a brain tumor at the age of 74 years. The proband's paternal uncle (I-3) had no history of symptomatic CAD and died in 1999 of an alcohol-related illness. At present, there is no history of symptomatic CAD in other biological family members, whose risk factors include hypertension (II-2) and cigarette smoking (III-5). A total of 17 biological family members were evaluated in this kindred, and all participants gave their informed consent before participation.

PCR AMPLIFICATION AND SINGLE-STRAND CONFORMATION POLYMORPHISM ANALYSIS

Genomic DNA was isolated from the peripheral whole blood of study participants. Templates for single-strand conformation polymorphism (SSCP) analysis were enzymatically amplified from genomic DNA of the participants by PCR, using each pair of primers and reaction conditions described previously (3, 8-11). The primers were made to amplify all coding regions and splice site junctions. PCR products were mixed with 6x loading dye (950 mL/L formamide, 20 mmol/L EDTA, 0.5 g/L bromphenol blue, 0.5 g/L xylene cyanol FF), denatured for 10 min at 96[degrees]C, and placed on ice. SSCP analysis was performed by electrophoresis using 6% or 8% nondenatured polyacrylamide gels at 5-10 W for ~24 h at room temperature.

SEQUENCING OF PCR-AMPLIFIED DNA

PCR products showing SSCP shifts were purified by use of a PCR purification reagent set from Qiagen and sequenced manually with a thermo sequenase [sup.33]P-labeled terminator cycle sequencing reagent set (Amersham). To identify variants of other primary HDL candidate genes as well as ABCA1 in the proband, all exon regions and splice site junctions of the apoA-I (APOAI), lecithin cholesterol acyl transferase (LCAT), lipoprotein lipase (LPL), phospholipid transfer protein (PLTP), and scavenger receptor class B type I (SR-BI) genes were amplified and sequenced (12-15). Evaluation for PLTP mutations was conducted in the laboratory of Dr. X-C. Jiang.

[FIGURE 1 OMITTED]

DETERMINATION OF CONCENTRATIONS OF PLASMA LIPIDS AND LIPOPROTEIN SUBCLASSES

Blood samples were collected from all participants after an overnight fast. The concentrations of plasma total cholesterol and triglycerides were measured by enzymatic methods. HDL-C was determined by the heparin-manganese precipitation method. The concentrations of apoA-I and apoB were measured by use of single radial immunodiffusion plates. LDL-cholesterol was calculated by the formula of Friedewald et al. (16).

MEASUREMENT OF CAROTID ARTERY INTIMA-MEDIA THICKNESS

A standardized B-mode ultrasound examination (17) was performed to identify the mean intima-media thickness (IMT) of the common carotid artery in predefined 10-mm segments of the near and far walls located between 10 and 20 mm proximal to the flow divider tip of the carotid bifurcation, on the left and right sides of the neck. Sonographers used a high-resolution 5- to 10-MHz Acuson Aspen ultrasound system to obtain B-mode images on S-VHS videotapes. All images were read at the Wake Forest School of Medicine, and carotid IMT measurement were recorded by readers blinded to HDL variant status. Each value represents the mean of up to 20 mean IMT measurements obtained from multiple interrogation angles.

STATISTICAL ANALYSIS

The lipid concentrations between two groups were compared by the Student t-test. The data are expressed as mean [+ or -] SD. Statistical significance was defined as P <0.05.

Results

SSCP analysis of the intron-exon boundaries led to the identification of a novel ABCA1 mutation. The affected individuals in the kindred were heterozygous for a G2265T substitution (Fig. 2, arrow) with predicted conversion of Trp to Leu (W590L). Although this mutation did not alter a restriction enzyme site, it was detected by SSCP analysis and confirmed by direct sequencing of the affected individuals. The point mutation was not detected during the screening of >200 chromosomes of healthy Caucasians.

Lipid, lipoprotein, and apolipoprotein concentrations of the proband (shown in bold) and family members of the kindred are shown in Table 1. Mean lipid concentrations were compared between carriers (+) and noncarriers (-) of the ABCA1 variant. Significant differences between (+) and (-) individuals for the W590L mutation were noted for HDL-C (P = 0.009) and apoA-I (P = 0.036). Affected family members with the ABCA1 mutant exhibited decreased HDL-C and apoA-I. HDL-C and apoA-I concentrations were lowest in the proband (II-3), his son (III-3), and the proband's youngest sibling (II-8), whereas the other heterozygotes for G2265T (I-3, II-5, and III-4), evidenced only mildly decreased HDL-C without decreased apoA-I. Finally, four individuals (III-1, III-6, III-8, and III-10) had low HDL-C (<1.03 mmol/L, or < 40 mg/dL) in the absence of the G2265T variant.

[FIGURE 2 OMITTED]

B-Mode ultrasound studies were performed in 30 participants, including 5 of the 6 participants with the ABCA1 variant (I-3 died before testing), unaffected biological family members (n = 10), and age- and sex-matched controls (n = 15; Table 2). The mean carotid IMT in affected individuals was 0.6192 cm compared with 0.689 cm (P, not significant) for age- and sex-matched controls. Biological family members without the mutation evidenced slightly lower carotid IMT compared with individuals with the ABCA1 variant, G2265T (0.588 cm), but these measurements were not significantly different compared with age- and sex-matched controls (0.576 cm). We were also unable to identify a significant correlation between HDL-C and carotid IMT in the small subset of individuals tested.

Discussion

We identified a novel ABCA1 variant, G2265T, associated with decreased HDL-C but not with increased carotid IMT thickness. Although the proband developed premature CAD, he also had a long-standing history of cigarette smoking, which may have played an important contributory role. In addition to the proband, the genetic variant was also present in five additional family members. Although three of these family members are relatively young (<50 years of age), neither of the two oldest affected family members, sibling II-5 (57 years of age) and paternal uncle I-3 (who died at age 81 years), had manifested symptomatic CAD, emphasizing the complexity inherent in interpreting the clinical relevance of low HDL-C. That is, although some low-HDL-C syndromes coincide with premature CAD, others do not (6, 7, 18, 19). In fact, individuals with apoA-[I.sub.Milano], a disorder characterized by very low HDL-C but without premature CAD, have also been shown to have decreased carotid IMT (20). Although the proband in the present study evidenced premature CAD, there was no evidence of increased carotid IMT among the five individuals studied with the ABCA1 variant G2265T, suggesting that this ABCA1 variant may be insufficient for promoting early atherosclerosis unless environmental triggers (e.g., cigarette smoking) intervene. In contrast, increased carotid IMT and premature CAD have been reported in association with defective ABCA1 alleles (21, 22), although the extent and severity of concomitant CAD risk factors were not identified (23).

The W590L mutation site in ABCA1 resides in a highly conserved hydrophobic region within the extracellular segment of the NH2 terminus (24, 25) and is identical to amino acid 605 of ABCR. Two mutations in amino acids 602 and 608 of ABCR have been reported in association with Stargardt disease (26), a recessive childhood retinal degeneration syndrome. Other mutations in ABCA1 associated with TD and in close proximity to W590S have been identified in amino acids 587 and 597 (3, 27). Finally, Bodzioch et al. (4) reported a mutation in an individual with TD at the same nucleotide (2265) that led to a predicted conversion of Trp to Ser (W590S). Thus, the mutation reported here at amino acid 590 in ABCA1 identifies an important region with predicted physiologic relevance.

The mean HDL-C concentrations were significantly different between affected and unaffected biological family members with ABCA1 variant G2265T. However, only four of the six affected individuals displayed low HDL-C ([less than or equal to] 1.03 mmol/L). To rule out the possibility of additional variants causing HDL-C deficiency in the proband, all coding regions and splice site junctions for the following HDL candidate genes were sequenced: APOAI, LCAT, LPL, PLTP, and SR-BI. However, no other mutations were identified, indicating that a single defective ABCA1 allele may lead to familial HDL deficiency, as has been demonstrated previously (3, 8, 28). Alternatively, fluctuation in HDL-C among family members may have resulted, in part, from linkage disequilibrium between G2265T and other common variants in exons or promoter regulatory factors of ABCA1.

In conclusion, affected individuals with G2265T evidenced decreased HDL-C. However, despite the resulting low HDL-C and history of premature CAD in the proband, there was no evidence of increased carotid IMT in the proband or affected individuals. The lack of an association between the mutation and carotid IMT may have reflected the small number of individuals studied. Alternatively, despite reduced activity from defective ABCA1, other regulators of cholesterol efflux (29) may have compensated sufficiently to preserve RCT and limit early plaque deposition. Regardless, these data do not implicate the ABCA1 variant G2265T as promoting early atherosclerosis despite its association with isolated low HDL-C.

This study was supported by an American Heart Association Grant-In-Aid (Mid Atlantic Region), Veterans Affair Merit Award, and NIH award (HL-61369). The carotid ultrasound examinations were performed by Teresa Crotts, Lois Hoots, and Mitzie Spainhour from the Wake Forest University School of Medicine. We acknowledge Dr. X-C Jiang (SUNY-Downstate Medical Center, Brooklyn, NY) for evaluation of genetic variants in PLTP.

Received May 21, 2002; accepted August 1, 2002.

References

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(2.) Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, et al. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest 1999;104:R25-31.

(3.) Brook-Wilson A, Marcil M, Clee SM, Zhang L-H, Roomp K, van Dam M, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 1999;22:336-45.

(4.) Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999;22:347-51.

(5.) Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999;22:352-5.

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(12.) Miller M, Aiello D, Pritchard H, Friel G, Zeller K. Apolipoprotein A-I (Zavalla) (Leu1593Pro): HDL cholesterol deficiency in a kindred associated with premature coronary artery disease. Arterioscler Thromb Vasc Biol 1998;18:1242-7.

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(16.) Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.

(17.) Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 2000;102:1503-10.

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(20.) Sirtori CR, Calabresi L, Franceschini G, Baldassarre D, Amato M, Johansson J, et al. Cardiovascular status of carriers of the apolipoprotein A-[I.sub.Milano] mutant: The Limone sul Garda Study. Circulation 2001;103:1949-54.

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(23.) Attie AD, Kastelein JP, Hayden MR. Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J Lipid Res 2001;42:1717-26.

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(27.) Bertolini S, Pisciotta L, Seri M, Cusano R, Cantafora A, Calabresi L, et al. A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of Tangier disease. Atherosclerosis 2001;154:599-605.

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(29.) Schmitz G, Langmann T, Heimer S. Role of ABCG1 and other ABCG family members in lipid metabolism. J Lipid Res 2001;42:1513-20.

Seung Ho Hong, [1] * Ward Riley, [2] Jeffrey Rhyne, [1] Gina Friel, [1] and Michael Miller [1] [[dagger]]

[3] Nonstandard abbreviations: RCT, reverse cholesterol transport; CAD, coronary artery disease; HDL-C, HDL-cholesterol; TD, Tangier disease; apoA-I, apolipoprotein AI; SSCP, single-strand conformation polymorphism; and IMT, intima-media thickness.

[1] Department of Medicine, University of Maryland and Veterans Administration Medical Center, Baltimore, MD 21201.

[2] Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC 27104.

* Current address: Department of Science Education, Jeju National University, Jeju 690-061, Korea.

[[dagger]] Address correspondence to this author at: Department of Medicine, University of Maryland, 22 S. Greene St., S3B06, Baltimore, MD 21201. Fax 410-328-4382; e-mail mmiller@heart.umaryland.edu.
Table 1. Plasma lipids, lipoprotein, and apolipoprotein
concentrations for the kindred.

 Individual (a) Sex Age, years

I-2(-) F 88
I-3(+)# M# 81#
II-1 (-) M 48
II-2 (-) F 47
II-3 (+)# M# 52#
II-4 (-) F 54
II-5 (+)# M# 57#
II-6 (-) F 54
II-7 (-) M 54
II-8 (+)# F# 40#
III-1 (-) F 19
III-2 (-) M 27
III-3 (+)# M# 31#
III-4 (+)# F# 28#
III-5 (-) F 33
III-6 (-) F 19
III-7 (-) F 27
III-8 (-) M 10
III-9 (-) M 13
III-10 (-) F 17
Mean [+ or -] SD
 (+), n=6 41.60 [+ or -] 12.70
 (-), n=14 36.40 [+ or -] 21.90

 Individual (a) TC, (b) mmol/L TG, mmol/L

I-2(-) 5.43 3.28
I-3(+)# 4.63# 2.20#
II-1 (-) 4.88 4.34
II-2 (-) 5.53 3.54
II-3 (+)# 3.10# 2.97#
II-4 (-) 3.95 1.63
II-5 (+)# 5.19# 2.38#
II-6 (-) 3.67 1.24
II-7 (-) 7.13 4.91
II-8 (+)# 3.80# 2.45#
III-1 (-) 4.16 2.48
III-2 (-) 3.10 2.43
III-3 (+)# 3.70# 2.74#
III-4 (+)# 3.80# 2.35#
III-5 (-) 3.98 1.52
III-6 (-) 3.95 2.74
III-7 (-) 5.37 2.07
III-8 (-) 3.64 2.25
III-9 (-) 3.70 1.60
III-10 (-) 3.23 3.75
Mean [+ or -] SD
 (+), n=6 4.04 [+ or -] 0.75 2.52 [+ or -] 0.29
 (-), n=14 4.41 [+ or -] 1.12 2.70 [+ or -] 1.12

 Individual (a) HDL-C, mmol/L LDL-C, mmol/L

I-2(-) 1.40 3.39
I-3(+)# 1.06# 3.13#
II-1 (-) 1.14 2.87
II-2 (-) 1.65 3.18
II-3 (+)# 0.34# 2.17#
II-4 (-) 1.65 1.96
II-5 (+)# 1.14# 3.59#
II-6 (-) 1.14 2.17
II-7 (-) 1.94 4.21
II-8 (+)# 0.88# 2.43#
III-1 (-) 0.96 2.71
III-2 (-) 1.27 1.34
III-3 (+)# 0.54# 2.61#
III-4 (+)# 1.03# 2.30#
III-5 (-) 1.40 2.27
III-6 (-) 0.96 2.45
III-7 (-) 1.96 2.89
III-8 (-) 1.01 2.20
III-9 (-) 1.24 2.14
III-10 (-) 0.88 1.60
Mean [+ or -] SD
 (+), n=6 0.83 [+ or -] 0.32 (c) 2.71 [+ or -] 0.55
 (-), n=14 1.33 [+ or -] 0.36 (c) 2.53 [+ or -] 0.75

 Individual (a) apoA-I, g/L apoB, g/L

I-2 (-) 1.67 1.10
I-3 (+)# 1.21# 0.95#
II-1 (-) 1.32 1.00
II-2 (-) 2.00 1.11
II-3 (+)# 0.49# 0.93#
II-4 (-) 1.54 0.60
II-5 (+)# 1.39# 1.18#
II-6 (-) 1.18 0.64
II-7 (-) 2.05 1.26
II-8 (+)# 1.06# 0.86#
III-1 (-) 1.01 0.79
III-2 (-) 1.51 0.54
III-3 (+)# 0.85# 0.98#
III-4 (+)# 1.29# 0.80#
III-5 (-) 1.34 0.68
III-6 (-) 1.10 0.75
III-7 (-) 1.90 0.93
III-8 (-) 1.15 0.77
III-9 (-) 1.24 0.68
III-10 (-) 1.09 0.62
Mean [+ or -] SD
 (+), n=6 1.016 [+ or -] 0.361 (d) 0.950 [+ or -] 0.146
 (-), n=14 1.435 [+ or -] 0.351 (d) 0.819 [+ or -] 0.223

(a) (-) and (-) indicate individuals with and without the ABCA1 W590L
mutation, respectively. Values for (+) individuals are indicated in
bold.

(b) TC, total cholesterol; TG, triglycerides; LDL-C, LDL-cholesterol.

(c,d) Significant differences between (+) and (-) individuals:
(c) P = 0.009; (d) P = 0.036

Note: Values for (+) individuals are indicated with #.

Table 2. B-Mode ultrasound assessment of carotid IMT in
individuals with the ABCA1 variant, G2265T, unaffected
biological family members, and age- and sex-matched
controls.

 Common carotid artery IMT, cm

 G2265T variant

Individuals Mean SD

G2265T(+)
 II-3 0.692 0.186
 II-5 0.689 0.147
 II-8 0.600 0.105
 III-3 0.577 0.092
 III-4 0.538 0.088
G2265T(-)
 I-2 0.695 0.084
 11-2 0.581 0.081
 II-4 0.804 0.084
 II-9 0.615 0.089
 III-1 0.597 0.075
 III-2 0.517 0.064
 III-5 0.487 0.060
 III-8 0.519 0.071
 III-9 0.597 0.068
 III-10 0.465 0.070
Group
 G2265T (+), n = 5 (a) 0.619 0.07
 G2265T (-), n = 10 (b) 0.588 0.10

 Common carotid artery IMT, cm

 Age-matched controls

Individuals Mean SD

G2265T(+)
 II-3 0.848 0.103
 II-5 0.912 0.331
 II-8 0.505 0.084
 III-3 0.610 0.113
 III-4 0.569 0.093
G2265T(-)
 I-2 0.754 0.119
 11-2 0.621 0.105
 II-4 0.644 0.084
 II-9 0.584 0.050
 III-1 0.530 0.115
 III-2 0.574 0.063
 III-5 0.499 0.050
 III-8 0.561 0.076
 III-9 0.545 0.078
 III-10 0.448 0.038
Group
 G2265T (+), n = 5 (a) 0.689 0.18
 G2265T (-), n = 10 (b) 0.576 0.08

(a) n = 5 for both G2265T (+) group and matched controls.

(b) n = 10 for both G2265T (-) group and matched controls.
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Title Annotation:Case Report
Author:Hong, Seung Ho; Riley, Ward; Rhyne, Jeffrey; Friel, Gina; Miller, Michael
Publication:Clinical Chemistry
Date:Nov 1, 2002
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