ABCMdb

PMID: 21310416

Ma XY, Liu JP, Song ZY
Associations of the ATP-binding cassette transporter A1 R219K polymorphism with HDL-C level and coronary artery disease risk: a meta-analysis.
Atherosclerosis. 2011 Apr;215(2):428-34. Epub 2011 Jan 21., [PubMed]

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0 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Atherosclerosis 215 (2011) 428-434 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Associations of the ATP-binding cassette transporter A1 R219K polymorphism with HDL-C level and coronary artery disease risk: A meta-analysis Xiang-yu Maa,b,1 , Jian-ping Liua,1 , Zhi-yuan Songa,* a Department of Cardiology, Southwest Hospital, Third Military Medical University, Gaotanyan Street 30, Chongqing 400038, China b Department of Epidemiology, Faculty of Preventive Medicine, Third Military Medical University, Gaotanyan Street 30, Chongqing 400038, China a r t i c l e i n f o Article history: Received 2 July 2010 Received in revised form 16 December 2010 Accepted 7 January 2011 Available online 21 January 2011 Keywords: Meta-analysis Coronary artery disease ATP-binding cassette transporter A1 HDL-C a b s t r a c t Objective: Previous studies have evaluated the associations of the ATP-binding cassette transporter A1 (ABCA1) R219K polymorphism (rs2230806) with the level of high-density lipoprotein cholesterol (HDL-C) and the risk of developing coronary artery disease (CAD), but results from many small, underpowered studies are conflicting. Login to comment 2 ABCA1 p.Arg219Lys Methods: We conducted a systematic review and meta-analysis of available studies to clarify the associations of the ABCA1 R219K polymorphism with HDL-C level and CAD risk. Login to comment 3 ABCA1 p.Arg219Lys Results: Through retrieving PubMed, Embase, Web of Science, CBM and CNKI, we identified a total of 22 studies with 6597 cases and 15,369 controls for the association between the ABCA1 R219K polymorphism and CAD risk. Login to comment 4 ABCA1 p.Arg219Lys The carriers of allele 219K were found to have a lower risk of CAD than the non-carriers: OR = 0.76, 95% CI = 0.68-0.85, P = 3.78E-07, Pheterogeneity = 3.59E-08; meanwhile, 18 studies from 17 papers with 12,869 subjects were included in the association between the ABCA1 R219K polymorphism and the level of HDL-C. Login to comment 9 ABCA1 p.Arg219Lys Conclusions: The synthesis of available evidence demonstrates that the ABCA1 R219K polymorphism is associated with a higher HDL-C level in Asians and a protective role for CAD risk both in Asians and Caucasians. Login to comment 29 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys The results showed that only the R219K polymorphism (G1051A, rs2230806), which resulted from the substitution of a lysine for arginine at amino acid 219 of the ABCA1 protein, was associated with increased HDL-C and a reduced risk of CAD. Login to comment 31 ABCA1 p.Arg219Lys However, there have been few studies focusing on other genetic variants in the ABCA1 gene with the exception of R219K. Login to comment 32 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Considering R219K being the most focused polymorphic site and the limited number of studies about other genetic variants in the ABCA1 gene, we conducted this meta-analysis to clarify the role of the ABCA1 R219K polymorphism in the synthesis of HDL-C and CAD risk. Login to comment 40 ABCA1 p.Arg219Lys Selection criteria We selected the studies that met the following criteria: (1) the publication examined the associations of the ABCA1 R219K polymorphism with CAD or HDL-C level; (2) all CAD cases were diagnosed as myocardial infarction (defined by World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease [MONICA] criteria [7]) or angiographic coronary stenosis (generally defined as at least 50% stenosis of one major coronary artery); (3) for CAD association, the papers must offer the total number of cases and controls, distribution of genotypes or other information that can help us infer the results; for HDL-C level association, the number of population, the mean of HDL-C level and the standard deviations (SD) by genotypes should be available; (4) when multiple publications reported on the same or overlapping data, we used the most recent or largest population as recommended by Little et al. [8]; (5) publication language was limited to English and Chinese. Login to comment 49 ABCA1 p.Arg219Lys Summary odds ratios (ORs) with their 95% confidence intervals (CIs) for alleles and genotypes were used to assess the strength of the association between the ABCA1 R219K polymorphism and CAD risk. Login to comment 51 ABCA1 p.Arg219Lys A pooled standardized mean difference (SMD) and its 95% CIs were used for the meta-analysis of HDL-C level and the ABCA1 R219K polymorphism. Login to comment 61 ABCA1 p.Arg219Lys Selection and characteristics of studies Through a comprehensive retrieval and evaluation, 22 studies with 6597 cases and 15,369 controls were identified with data on the ABCA1 R219K polymorphism and CAD [5,12-32]. Login to comment 65 ABCA1 p.Arg219Lys Table 2 describes the characteristics and data of the studies which were included in the association between the ABCA1 R219K polymorphism and HDL-C level. Login to comment 70 ABCA1 p.Arg219Lys Association between the ABCA1 R219K polymorphism and CAD risk The result of all 22 comparisons showed that the carriers of allele 219K had a lower risk of CAD than the non-carriers: OR = 0.76, 95% CI = 0.68-0.85, P = 3.78E-07, Pheterogeneity = 3.59E-08 (Fig. 1). Login to comment 71 ABCA1 p.Arg219Lys Additive genetic model, recessive genetic model and dominant genetic model were also included in the analysis of the association between the ABCA1 R219K polymorphism and CAD risk (Supplementary Figs. 1-3) and the results were similar with allele comparison. Login to comment 73 ABCA1 p.Arg219Lys There was significant heterogeneity among the available studies and this Table 1 Characteristics of individual studies included in the meta-analysis of CAD and the ABCA1 R219K polymorphism. First author Year Country Ethnicity Source of controls Number (case/control) MAF Cases Controls RR RK KK RR RK KK Porchay-Balderelli et al. [14] 2009 France Caucasian Population-based 482/2647 0.28 270 175 37 1326 1109 212 Frikke-Schmidt et al. [19] 2008 Denmark Caucasian Population-based 1107/7858 0.26 603 429 75 4260 3032 566 Balcerzyk et al. [20] 2008 Poland Caucasian Population-based 178/180 0.29 90 68 20 91 78 11 Nebel et al. [21] 2007 Germany Caucasian Population-based 1090/728 0.36 b Cases: 578-1602; control: 376-1080 Andrikovics et al. [24] 2006 Germany Caucasian Population-based 150/193 0.29 84 55 11 97 73 23 Martin et al. [23] 2006 Spain Caucasian Hospital-based 100/100 0.31 48 42 10 49 40 11 Bertolini et al. [29] 2004 Italy Caucasian Hospital-based 97/97 NA c Cases: 65-32; control:47-50 Cenarro et al. [32] 2003 Spain Caucasian Hospital-based 216/158 0.28 123 78 15 72 71 15 Evans and Beil [31] 2003 Germany Caucasian Hospital-based 114/629 0.26 72 35 7 337 245 47 Clee et al. [5] 2001 Canada Caucasian Hospital-based 432/358 0.25 248 170 14 176 160 22 Li et al. [15] 2009 China Asian Population-based 365/246 0.39 140 170 55 92 116 38 Li et al. [26] 2005 China Asian Population-based 396/417 0.42 158 174 64 124 198 95 Zhao and Xiao [27] 2004 China Asian Population-based 236/251 0.40 96 111 29 80 123 48 Wang and Zhang [13]a 2009 China Asian Hospital-based 150/139 0.42 61 69 20 47 53 39 Zhang et al. [16] 2008 China Asian Hospital-based 162/186 0.43 71 65 26 49 93 44 Yu and Deng [17] 2008 China Asian Hospital-based 49/72 0.34 29 18 2 24 35 13 Liu et al. [18] 2008 China Asian Hospital-based 113/155 0.32 71 39 3 57 70 28 Wang et al. [22] 2006 China Asian Hospital-based 234/198 0.36 108 105 21 67 101 30 Sun et al. [25] 2005 China Asian Hospital-based 224/248 0.42 105 85 34 62 129 57 Wang et al. [28] 2004 China Asian Hospital-based 222/278 0.47 79 94 49 76 125 77 Harada et al. [30] 2003 Japan Asian Hospital-based 273/137 0.49 73 139 61 31 73 33 Doosti et al. [12]a 2010 Iran - Hospital-based 207/94 0.47 77 71 59 38 17 39 MAF = minor allele frequency; NA = not available. Login to comment 77 ABCA1 p.Arg219Lys Meta-analysis of CAD and the ABCA1 R219K polymorphism (allele comparison). Login to comment 78 ABCA1 p.Arg219Lys Table 2 Characteristics of individual studies included in the meta-analysis of HDL-C level and the ABCA1 R219K polymorphism. First author Year Country Ethnicity MAF RR RK KK n Mean SD n Mean SD n Mean SD Porchay-Balderelli et al. [14] 2009 France Caucasian 0.28 1596 1.31 0.36 1284 1.32 0.35 249 1.33 0.36 Sandhofer et al. [33] 2008 Austria Caucasian 0.29 350 1.41 0.34 274 1.38 0.33 64 1.38 0.29 Boekholdt et al. [36]a 2006 Holland Caucasian 0.24 302 0.92 0.21 223 0.92 0.22 21 0.92 0.20 Hodoglugil et al. [37] 2005 Turkey Caucasian 0.39 364 1.06 0.24 480 1.06 0.22 152 1.06 0.26 Hodoglugil et al. [37] 2005 Turkey Caucasian 0.37 574 0.91 0.19 688 0.91 0.19 204 0.91 0.20 Evans and Beil [31] 2003 Germany Caucasian 0.26 279 1.32 0.03 206 1.34 0.03 30 1.27 0.31 Clee et al. [5]a 2001 Canada Caucasian 0.25 424 0.92 0.22 330 0.93 0.23 36 0.92 0.20 Wang and Zhang [13]a 2009 China Asian 0.42 108 0.96 0.26 122 1.03 0.30 59 1.07 0.25 Li et al. [15] 2009 China Asian 0.38 140 1.06 0.15 170 1.09 0.13 55 1.12 0.17 Liu et al. [18]a 2008 China Asian 0.32 29 1.22 0.18 39 1.26 0.19 3 1.48 0.11 Wu and Bai [35] 2007 China Asian 0.47 52 1.27 0.29 107 1.41 0.54 41 1.48 0.45 Wang et al. [22] 2006 China Asian 0.36 175 1.09 0.18 206 1.11 0.23 51 1.34 0.35 Li et al. [26] 2005 China Asian 0.38 158 1.12 0.33 174 1.16 0.30 64 1.15 0.38 Wang et al. [28]a 2004 China Asian 0.43 79 0.96 0.14 94 0.95 0.14 49 1.01 0.12 Zhao and Xiao [27] 2004 China Asian 0.40 176 1.32 0.33 234 1.36 0.39 77 1.44 0.32 Zhao et al. [38] 2004 China Asian 0.40 394 1.3 0.4 470 1.4 0.4 179 1.4 0.4 Harada et al. [30] 2003 Japan Asian 0.48 68 1.25 0.41 140 1.24 0.40 57 1.24 0.35 Benton et al. [34]a 2007 USA Mixed 0.39 388 1.33 0.38 409 1.29 0.35 172 1.37 0.39 MAF = minor allele frequency; NA = not available; HDL-C = HDL cholesterol; 1 mmol/l HDL-C = 38.73 mg/dl HDL-C. Login to comment 83 ABCA1 p.Arg219Lys However, the significant association between the ABCA1 R219K polymorphism and CAD risk was unchanged. Login to comment 85 ABCA1 p.Arg219Lys The results suggested a significant association between the ABCA1 R219K polymorphism and CAD risk, but the existence of heterogeneity was not influenced. Login to comment 87 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Association between the ABCA1 R219K polymorphism and HDL-C level Fig. 2 describes the result of the meta-analysis of HDL-C level and the ABCA1 R219K polymorphism (KK vs RR) and it strongly suggested that the carriers of KK genotype had higher level of HDL-C than those of RR genotype: SMD = 0.19, 95% CI = 0.06-0.32, P = 0.005, Pheterogeneity = 3.19E-09. Login to comment 97 ABCA1 p.Arg219Lys For the ABCA1 R219K polymorphism and CAD risk, the shape of the funnel plot (Fig. 3 and Supplementary Fig. 9) did not reveal obvious asymmetry which means no publication bias. Login to comment 98 ABCA1 p.Arg219Lys Then, it was confirmed by Egger`s test (P value for allele contrast: 0.200; P value for dominant model: 0.494); for the ABCA1 R219K polymorphism and HDL-C level, both of the shape of the funnel plot (Fig. 4 and Supplementary Fig. 10) and Egger`s test (P value for KK vs RR: 0.646; P value for RK vs RR: 0.714) confirmed the absence of publication bias. Login to comment 101 ABCA1 p.Arg219Lys Additionally, a total of 18 studies from 17 papers with 12,869 subjects were included in the analysis of association between the ABCA1 R219K polymorphism and HDL-C level. Login to comment 103 ABCA1 p.Arg219Lys After the associations of the ABCA1 polymorphisms with HDL-C level and CAD were reported by Clee et al. [5] in 2001, serial of studies evaluated the association of the ABCA1 R219K polymorphism with HDL-C level and CAD risk in different races, and the results manifested inconclusive and underpowered. Login to comment 104 ABCA1 p.Arg219Lys We calculated the MAFs of the ABCA1 R219K polymorphism in all studies and found that MAFs of Asian were higher than those of Caucasian through t test (P < 0.01). Login to comment 106 ABCA1 p.Arg219Lys To date, several well-designed genome-wide association studies (GWAS) of coronary heart disease have been performed [39-47], but the R219K variant was not tested by these GWAS because of the limited SNP coverage rate of the existing SNP microarray platforms on the ABCA1 gene. Login to comment 109 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys In this meta-analysis, we found that the ABCA1 R219K polymorphism was significantly associated with a higher level of HDL-C in Asians, not in Caucasians; we also confirmed the protective role of ABCA1 R219K polymorphism for CAD risk both in Asians and Caucasians (allele contrast: OR = 0.76, 95% CI = 0.68-0.85, P = 3.78E-07, Pheterogeneity = 3.59E-08), though the association in Caucasians was less consistent than that in Asians. Login to comment 111 ABCA1 p.Arg219Lys Meta-analysis of HDL-C level and the ABCA1 R219K polymorphism (KK vs RR). Login to comment 115 ABCA1 p.Arg219Lys Funnel plot for allele comparison of CAD and the ABCA1 R219K polymorphism. Login to comment 121 ABCA1 p.Arg219Lys Funnel plot of HDL-C level and the ABCA1 R219K polymorphism (KK vs RR). Login to comment 129 ABCA1 p.Arg219Lys By excluding these outlier studies, the heterogeneity among Asian subjects and Caucasian studies was effectively removed, but the significant association between the ABCA1 R219K polymorphism and CAD risk or HDL-C level was not changed. Login to comment 132 ABCA1 p.Arg219Lys The results suggested a significant association between the ABCA1 R219K polymorphism and CAD risk or HDL-C level. Login to comment 134 ABCA1 p.Arg219Lys The functional analysis of the ABCA1 R219K polymorphism was done by SIFT and Polyphen, which predicted not only damaging variants, but also gain-of-function mutations. Login to comment 140 ABCA1 p.Arg219Lys During these studies, cases were all survivors of CAD, as we could not evaluate those that did not survive; second, the sample sizes of some included studies were rather small and they did not have adequate power to detect the possible risk for the R219K polymorphism. Login to comment 143 ABCA1 p.Arg219Lys Conclusion The synthesis of available evidence supports the fact that the ABCA1 R219K polymorphism is associated with a higher level of HDL-C in Asians and a protective role for CAD risk both in Asians and Caucasians. Login to comment