ABCMdb

PMID: 18803945

Sandhofer A, Iglseder B, Kaser S, More E, Paulweber B, Patsch JR
The influence of two variants in the adenosine triphosphate-binding cassette transporter 1 gene on plasma lipids and carotid atherosclerosis.
Metabolism. 2008 Oct;57(10):1398-404., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys We investigated the influence of the R219K and I883M variants in the ABCA1 gene on plasma lipids and carotid intima media thickness and plaque extent in 688 healthy men (40-60 years old). Login to comment 2 ABCA1 p.Arg219Lys The R219K variant showed no effect on plasma lipids, but carriers of the K allele displayed a lower intima media thickness (P = .001) and a reduced risk of advanced plaque extent (odds ratio [OR], 0.59; 0.39-0.88; P = .009) compared with noncarriers. Login to comment 4 ABCA1 p.Ile883Met The I883M variant showed no effect on plasma lipids or carotid atherosclerosis. Login to comment 5 ABCA1 p.Arg219Lys Risk of advanced plaque extent was reduced in subjects carrying the R219K variant alone (OR, 0.59; 0.38-0.94; P = .025), but not in subjects carrying both variants. Login to comment 7 ABCA1 p.Arg219Lys We conclude that smoking abrogates the protective effect of the R219K. Login to comment 24 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys We investigated and report here the role of smoking on the influence of the R219K and I883M variants in the ABCA1 gene on plasma lipid levels and ultrasonographically quantified intima media thickness (IMT) and severity of atherosclerosis of the carotid artery in a cross-sectional cohort of 688 middle-aged men. Login to comment 43 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The R219K and I883M status was determined using polymerase chain reaction-based restriction fragment length analysis, as described [5,6]. Login to comment 50 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Table 1 Clinical and laboratory characteristics R219K I883M RR (350) RK (274) KK (64) RK + KK II (522) IM (151) MM (15) IM + MM (166) Age (y) 50.0 (5.2) 49.4 (5.5) 50.9 (5.5) 49.7 (5.5) 50.1 (5.3) 49.2 (5.4) 47.9 (5.7) 49.1 (5.4) BMI (kg/m2 ) 27.2 (3.4) 27.2 (3.8) 26.9 (4.4) 27.2 (3.9) 27.2 (3.9) 27.1 (4.1) 26.3 (4.7) 27.0 (4.1) SBP (mm Hg) 130.9 (11.8) 129.4 (12.1) 130.9 (13.3) 129.7 (12.3) 130.7 (12.1 129.0 (11.9) 127.9 (12.2) 128.9 (11.9) DBP (mm Hg) 80.3 (7.4) 79.1 (7.1) 79.7 (6.5) 79.27 (7.0) 79.9 (7.1) 79.5 (7.6) 76.1 (5.2) 79.2 (7.4) Smoking (%)† 49.1 40.5 53.6 46.2 47.5 40.8 50.0 47.2 DM (%)† 4.9 4.7 0 3.8 4.4 4.0 6.7 4.2 TC (mg/dL) 230.5 (41.7) 225.5 (40.3) 228.5 (36.0) 226.1 (39.5) 226.9 (40.2) 233.0 (42.5) 234.1 (35.8) 233.1 (41.8) LDL-C (mg/dL) 148.2 (37.7) 144.2 (37.2) 150.0 (35.7) 145.3 (37.0) 145.2 (37.2) 151.5 (37.9) 155.0 (34.8) 151.8⁎ (37.5) HDL-C (mg/dL) 54.6 (13.2) 53.4 (12.9) 53.5 (11.4) 53.5 (12.7) 53.9 (13.0) 54.0 (13.0) 57.6 (11.9) 54.3 (12.9) TGs (mg/dL) 138.4 (92.0) 138.7 (81.0) 132.8 (74.5) 137.6 (79.7) 138.5 (87.2) 138.5 (85.7) 116.2 (45.6) 136.5 (83.0) Apo A-I (mg/dL) 149.0 (22.2) 148.7 (23.0) 148.8 (20.1) 148.7 (22.4) 148.8 (22.5) 148.7 (21.4) 150.9 (23.8) 148.9 (21.6) Apo B (mg/dL) 119.7 (25.4) 119.8 (25.5) 120.9 (25.7) 119.2 (25.5) 118.7 (24.8) 122.0 (18.0) 118.9 (19.5) 121.7 (27.3) LDL size (nm) 26.4 (1.11) 26.2 (1.17) 26.3 (1.28) 26.2 (1.19) 26.3 (1.14) 26.2 (1.20) 26.4 (0.88) 26.3 (1.17) Values are means (SD). Login to comment 67 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Frequencies of the R219K and I883M variants Allele frequency was 29.2% for the K allele at position 219 and 13.1% for the M allele at position 883; carrier frequency was 49.1% for the K allele and 21.9% for the M allele. Login to comment 68 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Frequencies of the R219K and I883M variants Allele frequency was 29.2% for the K allele at position 219 and 13.1% for the M allele at position 883; carrier frequency was 49.1% for the K allele and 21.9% for the M allele. Login to comment 69 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Distribution of genotypes was in Hardy-Weinberg equilibrium (P = .30 and P = .33, for R219K and I883M, respectively). Login to comment 72 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of the R219K and I883M variants on plasma lipids and IMT Table 1 illustrates the clinical characteristics and laboratory parameters of the subjects according to the genotypes. Login to comment 73 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of the R219K and I883M variants on plasma lipids and IMT Table 1 illustrates the clinical characteristics and laboratory parameters of the subjects according to the genotypes. Login to comment 74 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Carriers of the I883M variant had a higher LDL-C compared with men homozygous for the wild-type allele. Login to comment 75 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Carriers of the R219K variant had a lower IMT compared with noncarriers (781 ± 6 vs 802 ± 7 μm, P b.01), whereas the I883M variant had no effect on IMT (798 ± 9 vs 798 ± 6 μm, not significant [NS]) (Fig. 1). Login to comment 76 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of the R219K and I883M variants in combination on plasma lipids and IMT Furthermore, plasma lipids, apolipoproteins, and LDL size did not differ between the groups according to the combined carrier status of the 2 variants (Table 2). Login to comment 77 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of the R219K and I883M variants in combination on plasma lipids and IMT Furthermore, plasma lipids, apolipoproteins, and LDL size did not differ between the groups according to the combined carrier status of the 2 variants (Table 2). Login to comment 78 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The R219K and I883M variants and IMT. Login to comment 79 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The R219K and I883M variants and IMT. Login to comment 84 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of the R219K and I883M variants on risk of atherosclerosis The risk of advanced atherosclerosis-defined as a plaque score of 3 and higher-was significantly reduced in carriers of the K allele (Table 3). Login to comment 85 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of the R219K and I883M variants on risk of atherosclerosis The risk of advanced atherosclerosis-defined as a plaque score of 3 and higher-was significantly reduced in carriers of the K allele (Table 3). Login to comment 89 ABCA1 p.Ile883Met The I883M variant had no effect on the risk of carotid atherosclerosis (Table 3). Login to comment 90 ABCA1 p.Ile883Met The I883M variant had no effect on the risk of carotid atherosclerosis (Table 3). Login to comment 91 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of the R219K and I883M variants in combination on risk of atherosclerosis The reduced risk of advanced atherosclerosis observed in carriers of the K allele at position 219 was attenuated by the carrier status at position 883. Login to comment 92 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Effect of the R219K and I883M variants in combination on risk of atherosclerosis The reduced risk of advanced atherosclerosis observed in carriers of the K allele at position 219 was attenuated by the carrier status at position 883. Login to comment 93 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The unadjusted relative risk was 0.85 (95% CI, 0.72-1.00; P = .065) for carriers of the K allele alone, 1.04 (95% CI, 0.92-1.16; NS) for carriers of the M variant alone, and 0.87 (95% CI, 0.78-0.98; P b .05) for carriers of both variants, that is, R219K and I883M. Login to comment 99 ABCA1 p.Arg219Lys A positive smoking history abolished the protective effect of the R219K variant. Login to comment 100 ABCA1 p.Arg219Lys A positive smoking history abolished the protective effect of the R219K variant. Login to comment 109 ABCA1 p.Ile883Met The I883M variant had no influence irrespective of smoking history (Table 3). Login to comment 110 ABCA1 p.Ile883Met The I883M variant had no influence irrespective of smoking history (Table 3). Login to comment 113 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys We therefore used this imaging technique to investigate the influence of the R219K and I883M variants in the ABCA1 gene on the extent of carotid atherosclerosis and plasma lipids in 688 middle-aged men. Login to comment 114 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys We therefore used this imaging technique to investigate the influence of the R219K and I883M variants in the ABCA1 gene on the extent of carotid atherosclerosis and plasma lipids in 688 middle-aged men. Login to comment 115 ABCA1 p.Arg219Lys Men carrying the R219K variant had a reduced risk of carotid atherosclerosis and lower IMT values. Login to comment 116 ABCA1 p.Arg219Lys Men carrying the R219K variant had a reduced risk of carotid atherosclerosis and lower IMT values. Login to comment 118 ABCA1 p.Arg219Lys This finding is in accordance with a previous report showing, for the R219K allele, less severe CAD and slower progression of CAD in carriers of the K allele [6]; but although Clee et al [6] demonstrated increased HDL-C and reduced TG levels in carriers, we observed no effect of the K allele on plasma lipids. Login to comment 119 ABCA1 p.Arg219Lys This finding is in accordance with a previous report showing, for the R219K allele, less severe CAD and slower progression of CAD in carriers of the K allele [6]; but although Clee et al [6] demonstrated increased HDL-C and reduced TG levels in carriers, we observed no effect of the K allele on plasma lipids. Login to comment 126 ABCA1 p.Arg219Lys Previous reports suggest that the R219K variant influences HDL-C concentration only in special subpopulations, such as smokers [8] or subjects with elevated Lp(a) or apo E3 [28], indicating a gene-environment or gene-gene interaction. Login to comment 127 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Previous reports suggest that the R219K variant influences HDL-C concentration only in special subpopulations, such as smokers [8] or subjects with elevated Lp(a) or apo E3 [28], indicating a gene-environment or gene-gene interaction. Login to comment 128 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys However, in our population, the R219K variant was protective independent of Lp(a) concentration and apo E genotype (data not shown). Login to comment 129 ABCA1 p.Arg219Lys In contrast to previous reports, the R219K variant was protective in nonsmokers only, suggesting that the "genetic advantage" of carrying the K variant is abolished by the established risk factor of smoking. Login to comment 135 ABCA1 p.Arg219Lys However, this possible effect of the R219K variant needs further investigation. Login to comment 136 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys However, this possible effect of the R219K variant needs further investigation. Login to comment 137 ABCA1 p.Ile883Met ABCA1 p.Ile883Met The I883M variant had no effect on plasma lipids or carotid atherosclerosis in our study population. Login to comment 138 ABCA1 p.Ile883Met This observation contrasts with previous studies reporting either an increased progression of CAD and increased risk of cardiac events without an effect on plasma lipids [6] or an increased HDL-C [5,36] in subjects homozygous for the I883M variant. Login to comment 139 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys To further investigate if the R219K variant is the causative variant, we combined the R219K carrier status with the I883M carrier status. Login to comment 140 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys To further investigate if the R219K variant is the causative variant, we combined the R219K carrier status with the I883M carrier status. Login to comment 142 ABCA1 p.Ile883Met However, in our population, the I883M variant itself had no effect on carotid atherosclerosis. Login to comment 143 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys However, in our population, the I883M variant itself had no effect on carotid atherosclerosis. Login to comment 144 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Therefore, we suggest that the R219K variant is possibly not the causative variant. Login to comment 145 ABCA1 p.Arg219Lys In fact, the R219K variant may be in linkage disequilibrium with another variant responsible for the observed risk reduction. Login to comment 146 ABCA1 p.Arg219Lys We conclude from this study that the R219K variant in the ABCA1 gene can alter risk of atherosclerosis independently from HDL-C and TG plasma concentration in nonsmoking, healthy, middle-aged men. Login to comment 147 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys We conclude from this study that the R219K variant in the ABCA1 gene can alter risk of atherosclerosis independently from HDL-C and TG plasma concentration in nonsmoking, healthy, middle-aged men. Login to comment 148 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Because smoking abolished the protective effect of the R219K variant, we hypothesize that smoking may influence ABCA1 efficacy. Login to comment 149 ABCA1 p.Arg219Lys Considering the functions of ABCA1 other than lipid transport, the fact that the protective effect of the R219K is not dependent on plasma HDL-C or TG concentration suggests to us that another function of ABCA1 may be implicated. Login to comment