ABCMdb

PMID: 12700893

Evans D, Beil FU
The association of the R219K polymorphism in the ATP-binding cassette transporter 1 ( ABCA1) gene with coronary heart disease and hyperlipidaemia.
J Mol Med (Berl). 2003 Apr;81(4):264-70. Epub 2003 Mar 26., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA1 p.Arg219Lys Abstract The R219K polymorphism in the ATP-binding cassette transporter 1 gene (ABCA1) has been associated with reduced severity of atherosclerosis, fewer coronary events, decreased triglycerides and a trend to increased HDL in men with coronary heart disease (CHD). Login to comment 7 ABCA1 p.Arg219Lys In conclusion, we provide additional evidence that the R219K polymorphism in the ABCA1 gene either directly or as a result of linkage disequilibrium with additional functional variant(s), has a protective effect against CHD and is associated with lower plasma triglycerides in sub-groups of patients with hyperlipidaemia. Login to comment 10 ABCA1 p.Arg219Lys Evans (✉) · F. U. Beil Klinik und Poliklinik für Innere Medizin, Medizinische Klinik I, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany e-mail: evans@uke.uni-hamburg.de Tel.: +49-40-428036978, Fax: +49-40-428038290 J Mol Med (2003) 81:264-270 DOI 10.1007/s00109-003-0426-y O R I G I N A L A RT I C L E David Evans · F. Ulrich Beil The association of the R219K polymorphism in the ATP-binding cassette transporter 1 (ABCA1) gene with coronary heart disease and hyperlipidaemia Received: 31 October 2002 / Accepted: 16 January 2003 / Published online: 26 March 2003 (c) Springer-Verlag 2003 DAVID EVANS received his Ph.D. in virology in 1979 from the University of Glasgow, UK. Login to comment 22 ABCA1 p.Arg219Lys Clee et al. [15] investigated the phenotypic effects of the R219K polymorphism in 804 Dutch subjects with confirmed coronary artery disease. Login to comment 31 ABCA1 p.Arg219Lys The aim of this study was to investigate the role of the R219K polymorphism in CHD and plasma lipid levels in patients attending a lipid out-patient clinic. Login to comment 44 ABCA1 p.Arg219Lys Genotyping DNA was extracted using standard methods and the frequency of the R219K polymorphism in ABCA1 was determined as described by Clee et al. [15], apoE and lipoprotein lipase LPL polymorphisms were determined as described [19, 20, 21]. Login to comment 60 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Carriers of the K allele had lower triglycerides and, although not statistically significant, the P value Table 2 R219K polymorphism in the ABCA1 gene and coronary heart disease (CHD) All Men Women* Lp(a)>20 mg/dl n Age (years) n Age (years) n Age (years) All** Men Women CHD present RR 72 56.1±1.5 49 54.7±1.9 23 59.2±2 33 22 11 RK+KK 35+7 54.5±1.8 25+7 53.1±1.9 10+0 59.2±3.9 13+1 9+1 4+0 K frequency 0.21 0.24 0.15 0.16 0.19 0.10 CHD absent RR 337 43.2±0.7 178 42.8±0.8 159 43.7±1.2 78 32 46 RK+KK 245+47 43.7±0.8 128+29 44.2±0.9 117+18 43.1±1.3 66+12 31+8 35+4 K frequency 0.27 0.28 0.26 0.29 0.31 0.24 *P=0.05, difference in allele frequency between the presence and absence of CHD in women (Fisher`s exact test) **P=0.007, combined difference in allele frequency between the presence and absence of CHD (Fisher's exact test) Table 3 R219K polymorphism in the ABCA1 gene and plasma lipids (HDL-c high-density lipoprotein cholesterol, LDL-c low-density lipoprotein cholesterol) Before treatment After diet advice RR (n=279) RK (n=206) KK (n=30) RR (n=338) RK (n=229) KK (n=43) Age (years) 45.8±0.6 45.3±0.7 45.6±2.2 45.9±1 46.2±1 43.7±2 Body mass index 26.4±0.2 26.2±0.3 25.9±0.7 26.5±0.2 26.1±0.3 24.4±1.6 Total cholesterol (mg/dl) 285±4.9 284±6.1 280±10 278±5 284±6 274±8 Triglycerides (mg/dl) 328±30 288±32 236±49 317±26 297±30 216±27 HDL-c (mg/dl) 51±1 52±1 49±12 47±1 48±1 45±2 LDL-c (mg/dl) 188±4 188±5 194±12 190±5 192±5 195±10 ApoB (mg/dl) 135±2 130±3 142±8 - - - ApoAI (mg/dl) 131±2 133±2 127±5 - - - Fig. 1 ABCA1 R219K genotype frequencies and coronary heart disease in patients with elevated (>20 mg/dl) lipoprotein(a) Table 4 R219K polymorphism in the ABCA1 gene and plasma triglycerides before treatment: successive exclusion of factors associated with elevated triglycerides and interaction with apoE genotype (DM2, triglycerides >1000 mg/dl, apoE 2/2, LPL D9N, N291S carriers excluded) Patients excluded RR RK KK Pb apoE genotype None 0.17 n 279 206 30 Triglycerides 328±30 288±32 236±49 DM2, triglycerides >1000 mg/dl 0.13 n 258 191 29 Triglycerides 232±11 207±13 195±27 DM2, triglycerides >1000 mg/dl, apoE 2/2 0.09 ns 255 188 29 Triglycerides 232±12 203±13 195±27 DM2, triglycerides >1000 mg/dl, apoE 2/2, 0.07 LPL D9N, N291S carriers n 194 141 22 Triglycerides 234±14 200±15 158±17 3/3 0.035 n 113 76 11 Triglycerides 200±15 152±14 148±14 */4a 0.24 n 70 53 8 Triglycerides 270±28 249±30 140±28 3/4 0.23 n 59 44 7 Triglycerides 250±28 256±34 125±27 2/3 0.87 n 15 12 3 Triglycerides 321±55 290±54 243±86 was lower (P=0.13 vs. 0.17) despite the lower number of patients. Login to comment 76 ABCA1 p.Arg219Lys Discussion In this communication we confirm in patients of both sexes with hyperlipidaemia the findings of Clee et al. [15] in men with CHD that the K allele of the R219K polymorphism in the ABCA1 gene has a protective effect against CHD and is associated with reduced plasma tri- glyceride levels. Login to comment 80 ABCA1 p.Arg219Lys Unlike Clee et al. [15] we did not find an association between the R219K polymorphism and HDL, nor did we find that the age of the patient affected the influence of the polymorphism; however, we did find an association with plasma triglycerides. Login to comment 87 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Lys776Asn ABCA1 p.Val771Met Clee et al. [15] found that the R219K polymorphism was in linkage disequilibrium with two less frequent variants, V771M and K776N; however, excluding patients who were also carriers of these polymorphisms did not alter the results they obtained for the R219K polymorphism. Login to comment 88 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Similarly they observed that the R219K effects were independent of the I883M and R1587K variants. Login to comment 90 ABCA1 p.Arg219Lys Although there is considerable amount of linkage disequilibrium between the polymorphisms, they did not report the extent of disequilibrium with the R219K polymorphism. Login to comment 91 ABCA1 p.Arg219Lys Neither Brousseau et al. [16] nor Wang et al. [13] report on linkage disequilibrium between the R219K and other polymorphisms. Login to comment 92 ABCA1 p.Arg219Lys Lutucuta et al. [17] also reported the effect of polymorphisms in the promoter of the ABCA1 gene on coronary atherosclerosis but did not determine whether this was due to disequilibrium with the R219K polymorphism. Login to comment 93 ABCA1 p.Arg219Lys Therefore given the large number of polymorphisms described to date in the ABCA1 gene we cannot in this communication conclude that the effects which we see of the K allele of the R219K polymorphism are the direct result of the polymorphism, or whether it is a marker for functional variation elsewhere in the gene. Login to comment 95 ABCA1 p.Arg219Lys In conclusion here we provide evidence that the R219K polymorphism in the ABCA1 gene has a protective effect against CHD in patients at high risk due to hyperlipidaemia and especially those with concomitantly elevated Lp(a). Login to comment