ABCMdb

PMID: 25110219

Abd El-Aziz TA, Mohamed RH, Hagrass HA
Increased risk of premature coronary artery disease in Egyptians with ABCA1 (R219K), CETP (TaqIB), and LCAT (4886C/T) genes polymorphism.
J Clin Lipidol. 2014 Jul-Aug;8(4):381-9. doi: 10.1016/j.jacl.2014.06.001. Epub 2014 Jun 11., [PubMed]

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0 ABCA1 p.Arg219Lys Increased risk of premature coronary artery disease in Egyptians with ABCA1 (R219K), CETP (TaqIB), and LCAT (4886C/T) genes polymorphism Tarek A. Abd El-Aziz, MD, Rasha H. Mohamed, PhD*, Hoda A. Hagrass, MD Department of Cardiology, Faculty of Medicine, Zagazig University, Zagazig, Egypt (Dr Abd El-Aziz); Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt (Dr Mohamed); and Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt (Dr Hagrass) KEYWORDS: PCAD; HDLc; ABCA1; CETP; LCAT BACKGROUND: Epidemiological studies have shown a strong inverse relationship between high-density lipoprotein (HDL) cholesterol (HDLc) levels and coronary artery disease (CAD), and a low concentration of plasma HDLc is considered an independent risk factor for premature atherosclerosis. Login to comment 20 ABCA1 p.Arg219Lys The common polymorphism in the coding region is R219K (rs2230806), which lead to an arginine/lysine substitution at exon 7.6 CETP facilitates the uptake of cholesterol from peripheral tissues to the liver in an antiatherogenic process known as reverse cholesterol transport. Login to comment 34 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Amplification of ABCA1 gene R219K (rs2230806) polymorphism The ABCA1 gene polymorphism R219K was detected using polymerase chain reaction (PCR) and restricted fragment length polymorphism analysis (RFLP) as previously described.21 The oligonucleotide primers used were 50 -AAA GAC TTC AAG GACCCAGCTT-30 and 50 - CCTCACATTCCGAAAGCATTA-30 .22 PCR was subjected to 95 C for 5 minutes, 30 cycles of 95 C for 30 seconds, 55 C for 30 seconds, 72 C for 30 seconds, and final extension to 72 C for 7 minutes, producing a fragment of 309 bp. Login to comment 36 ABCA1 p.Arg219Lys Amplification of CETP gene TaqIB (rs708272) polymorphism The ABCA1 gene polymorphism R219K was detected using PCR and RFLP as previously described.23 Briefly, a 535-bp fragment in intron 1 of the CETP gene was amplified by PCR, with use of the following oligonucleotide primers: F-50 -CAC TAG CCC AGA GAGAGAGGAGTGCC-30 and R-50 -CTG AGC CCA GCC GCA CAC TAAC-30 at 95 C for 3 minutes followed by 30 cycles of 95 C for 30 seconds, 60 C for 30 seconds, 72 C for 45 seconds, and, last, by 1 cycle at 72 C for 5 minutes. Login to comment 58 ABCA1 p.Arg219Lys For R219K polymorphism, we observed a higher frequency of the R allele (46.6% vs 37.8%, OR 1.43; 95% CI 0.99-2.07; P 5 .03) in PCAD patients compared with control group. Login to comment 67 ABCA1 p.Arg219Lys Table 2 Genotype and allele frequencies in the study population Polymorphism Case (n 5 116) Control (n 5 119) OR 95% CI P ABCA1 (R219K) KK n (%) 36 (31.1) 50 (42.0) KR n (%) 52 (44.8) 48 (40.3) 1.50 0.84-2.69 .11 RR n (%) 28 (24.1) 21 (17.6) 1.85 0.91-3.76 .06 R allele n (%) 108 (46.6) 90 (37.8) 1.43 0.99-2.07 .03 CETP (Taq1B) B2B2 n (%) 18 (15.5) 32 (26.9) B1B2 n (%) 60 (51.7) 57 (47.9) 1.87 0.95-3.70 .05 B1B1 n (%) 38 (32.8) 30 (25.2) 2.25 1.06-4.77 .02 B1allele n (%) 136 (58.6) 117 (49.16) 1.46 1.01-2.11 .02 LCAT (4886C/T) CC n (%) 26 (22.4) 49 (41.2) CT n (%) 56 (48.3) 55 (46.2) 1.92 1.05-3.51 .02 TT n (%) 34 (29.3) 15 (12.6) 4.27 1.97-9.24 .000 T allele n (%) 124 (53.5) 85 (35.7) 2.07 1.43-2.99 .000 ABCA1, ATP-binding cassette A1 transporter; CETP, cholesteryl ester transfer protein; LCAT, lecithin: cholesterol acyltransferase. Login to comment 72 ABCA1 p.Arg219Lys The frequency of the B1 allele was also significantly increased in the combined hyperlipidemic group compared with the control group (61.1% vs Table 3 Genotypes distribution and correlation with HDLc levels Polymorphism PCAD with low HDLc (n 5 70) PCAD with normal HDLc (n 5 46) OR 95% CI P ABCA1 (R219K) K allele n (%) 46 (32.9) 78 (84.8) R allele n (%) 94 (67.1) 14 (15.2) 11.38 5.83-22.23 .000 CETP (Taq1B) B2 allele n (%) 36 (25.7) 60 (65.2) B1allele n (%) 104 (74.3) 32 (34.8) 5.41 3.05-9.60 .000 LCAT (4886C/T) C allele n (%) 42 (30.0) 66 (71.7) T allele n (%) 98 (70.0) 26 (28.3) 5.92 3.31-10.58 .000 ABCA1, ATP-binding cassette A1 transporter; CETP, cholesteryl ester transfer protein; HDLc, high-density lipoprotein cholesterol; LCAT, lecithin: cholesterol acyltransferase; PCAD, premature coronary artery disease. Login to comment 73 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Table 4 Genotypes distribution across different phenotypes Polymorphism Control (n 5 119) PCAD with high TGs (phenotype I, IV) (n 5 24) OR 95% CI P ABCA1 (R219K) K allele n (%) 148 (62.2) 24 (50.0) R allele n (%) 90 (37.8) 24 (50.0) 3.64 1.22-10.85 .009 CETP (Taq1B) B2 allele n (%) 121 (50.8) 16 (33.3) B1allele n (%) 117 (49.2) 32 (66.7) 2.06 1.07-3.96 .019 LCAT (4886C/T) C allele n (%) 153 (64.3) 24 (50.0) T allele n (%) 85 (35.7) 24 (50.0) 3.33 1.11-9.92 .016 Polymorphism Control (n 5 119) PCAD with high LDL (phenotype IIa) (n 5 2) OR 95% Cl P ABCA1 (R219K) K allele n (%) 148 (62.2) 3 (75.0) R allele n (%) 90 (37.8) 1 (25.0) 0.54 0.05-5.35 .52 CETP (Taq1B) B2 allele n (%) 121 (50.8) 2 (50.0) B1 allele n (%) 117 (49.2) 2 (50.0) 0.96 0.13-6.97 .67 LCAT (4886C/T) C allele n (%) 153 (64.3) 3 (75.0) T allele n (%) 85 (35.7) 1 (25.0) 0.60 0.06-5.85 .55 Polymorphism Control (n 5 119) PCAD with high TG 1 LDL (phenotype IIb) (n 5 72) OR 95% CI P ABCA1 (R219K) K allele n (%) 148 (62.2) 72 (50.0) R allele n (%) 90 (37.8) 72 (50.0) 1.64 1.08-2.50 .013 CETP (Taq1B) B2 allele n (%) 121 (50.8) 56 (38.9) B1 allele n (%) 117 (49.2) 88 (61.1) 1.62 1.06-2.47 .015 LCAT (4886C/T) C allele n (%) 153 (64.3) 60 (41.7) T allele n (%) 85 (35.7) 84 (58.3) 2.52 1.64-3.85 .000 ABCA1, ATP-binding cassette A1 transporter; CETP, cholesteryl ester transfer protein; HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; LCAT, lecithin: cholesterol acyltransferase; PCAD, premature coronary artery disease; TC, total cholesterol; TG, triglyceride. Login to comment 84 ABCA1 p.Arg219Lys These factors may vary depending on race and ethnic group.25 HDL Table 5 Lipid profile distribution across genotypes TC (mg/dL) TG (mg/dL) LDLc (mg/dL) HDLc (mg/dL) ABCA1 (R219K) KK 196.96 6 65.86 187.39 6 65.19 104.19 6 59.94 55.12 6 7.55 RK 215.14 6 67.66* 217.91 6 49.10** 130.88 6 70.27** 40.72 6 7.94# RR 242.14 6 55.68# 223.48 6 72.15** 168.05 6 60.54# 29.28 6 2.66# CETP (Taq1B) B2B2 197.68 6 66.84 184.22 6 74.77 110.19 6 70.34 58.90 6 7.52 B2B1 224.62 6 64.66 215.67 6 54.72** 128.87 6 57.02 44.20 6 8.18# B1B1 234.69 6 60.53* 211.95 6 61.13* 160.98 6 61.58** 31.32 6 4.19# LCAT (4886C/T) CC 200.15 6 72.52 205.07 6 62.86 104.52 6 66.62 54.43 6 8.55 CT 216.37 6 67.38 201.41 6 58.20 133.86 6 72.16** 42.23 6 9.46# TT 230.40 6 49.52* 226.95 6 67.67* 154.80 6 49.31# 30.14 6 3.45# HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride. Login to comment 92 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys R219K is the most common polymorphism of ABCA1 and the allele frequency of the K allele is 26-46% in the Caucasian population.29,30 To date, several studies have reported controversial results about the possible role of R219K in arteriosclerosis. Login to comment 94 ABCA1 p.Arg219Lys This is in line with recent meta-analysis31 involving 2730 CAD patients and 2658 controls and found that the K allele of the ABCA1 R219K gene has a protective role for CAD risk in Chinese population and is possibly associated with decreased CAD susceptibility. Login to comment 96 ABCA1 p.Arg219Lys Also, Takagi et al. concluded that the polymorphism does not seem to influence coronary atherosclerosis.35 HDLc is a major independent factor involved in the development of premature CAD The antiatherogenic function of HDL has been attributed to its role in reverse cholesterol transport, and the protein ABCA1 plays a crucial role in its initial step.36 Several studies have showed that the R allele in the R219K ABCA1gene polymorphism causes low HDLc levels, increased triglycerides, depressed levels of cholesterol efflux, and an increased risk of CAD.37,38 In agreement of this finding, we found that the frequency of the R allele of ABCA1 was significantly increased in PCAD with low HDLc levels compared with PCAD with normal HDLc levels (67.1% vs 15.2%). Login to comment