ABCMdb

PMID: 24854628

Akao H, Polisecki E, Schaefer EJ, Trompet S, Robertson M, Ford I, Jukema JW, de Craen AJ, Packard C, Buckley BM, Kajinami K
ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment.
Atherosclerosis. 2014 Jul;235(1):176-81. doi: 10.1016/j.atherosclerosis.2014.04.030. Epub 2014 May 8., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA1 p.Arg219Lys ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatmentq Hironobu Akao a,b,1 , Eliana Polisecki a,c,1 , Ernst J. Schaefer a,c , Stella Trompet d,e , Michele Robertson f , Ian Ford f , J. Wouter Jukema d,e , Anton J.M. de Craen d,e , Christopher Packard g , Brendan M. Buckley h , Kouji Kajinami b,*, on behalf of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) Investigator a Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Tufts University School of Medicine, Boston, MA, USA b Department of Cardiology, Kanazawa Medical University, Uchinada, Japan c Boston Heart Diagnostics, Framingham, MA, USA d Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands e Department of Gerontology, and Geriatrics, Leiden University Medical Centre, Leiden, The Netherlands f Robertson Centre of Biostatistics, University of Glasgow, Glasgow, Scotland, UK g Department of Vascular Biochemistry, University of Glasgow, Glasgow, Scotland, UK h Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland a r t i c l e i n f o Article history: Received 17 January 2014 Received in revised form 17 April 2014 Accepted 25 April 2014 Available online 8 May 2014 Keywords: ABCA1 gene Statins Low-density lipoprotein cholesterol lowering response Heart disease risk reduction a b s t r a c t Aims: Our goals were to examine the relationships of a specific ATP-binding cassette transporter A1 (ABCA1) variant, rs2230806 (R219K), on baseline lipids, low-density lipoprotein cholesterol (LDL-C) lowering due to pravastatin, baseline heart disease, and cardiac endpoints on trial. Login to comment 1 ABCA1 p.Arg219Lys Methods and results: The ABCA1 R219K variant was assessed in 5414 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Login to comment 6 ABCA1 p.Arg219Lys Conclusion: Our data indicate that subjects with the ABCA1 R219K variant may get significantly less heart disease risk reduction from pravastatin treatment than those without the variant. Login to comment 29 ABCA1 p.Arg219Lys The most studied variant at the ABCA1 gene locus is the R219K variant which causes an amino substitution in which an arginine is replaced by a lysine at amino acid position 219 in the ABCA1 protein [11]. Login to comment 30 ABCA1 p.Arg219Lys It has been previously reported that individuals carrying the R219K variant (found in 46% of a population of 790 subjects) had significantly lower triglyceride levels, slightly higher HDL-C levels, and significantly reduced severity of CHD as compared to non-carriers [12]. Login to comment 32 ABCA1 p.Arg219Lys Subsequently it was reported that the presence of the R219K ABCA1 variant in patients with familial hypercholesterolemia (n &#bc; 374) was associated with a markedly reduced risk of CHD (hazards ratio 0.32, p < 0.001) as compared to non-carriers [13]. Login to comment 33 ABCA1 p.Arg219Lys A recent meta-analysis based on an examination of 6597 CHD cases and 15,369 controls concluded that the presence of the R219K ABCA1 variant was associated with a lower risk of CHD (hazards ratio 0.76, p < 0.0001), and modestly higher HDL-C levels [14]. Login to comment 34 ABCA1 p.Arg219Lys However, there are no studies to our knowledge that have assessed whether the R219K ABCA1 genetic variant affects responses to statin treatment in terms of lipid modification or CHD risk reduction. Login to comment 35 ABCA1 p.Arg219Lys Our goals in this study were to determine whether the ABCA1 variant rs2230806 or R219K in PROSPER participants would affect baseline lipids, CHD prevalence at baseline, pravastatin induced LDL-C lowering, and pravastatin mediated CHD risk reduction. Login to comment 48 ABCA1 p.Arg219Lys For DNA analysis the single nucleotide polymorphism (SNP), R219K (rs2230806) of the ABCA1 gene was genotyped using Taq Man&#d2; SNPs genotyping assays (Applied Biosystems, Foster City, CA). Login to comment 63 ABCA1 p.Arg219Lys There was no interaction between R219K and apoE phenotype. Login to comment 78 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Associations with lipid response to treatment To determine whether the R219K variant affected lipid responses to pravastatin, the association between the R219K variant under study and 6 month and 12 month changes in TC, LDL-C, HDL-C, and triglyceride levels in individuals treated with pravastatin or placebo were examined. Login to comment 81 ABCA1 p.Arg219Lys Associations with history and within trial incidence of cardiovascular disease There were no significant associations between the prevalence of various forms of vascular disease at baseline and the presence of the R219K variant (data not shown). Login to comment 85 ABCA1 p.Arg219Lys For all subjects, there was a significantly increased risk of new cardiovascular disease (fatal CHD, non-fatal myocardial infarction, or fatal or non-fatal stroke) on trial for those who carried the ABCA1 R219K variant as compared to those who did not. Login to comment 89 ABCA1 p.Arg219Lys ABCA1 SNP rs2230806 R219K pa GG GA AA All (n) 2834 2167 413 TC (mmol/L) 5.69 0.91 5.68 0.89 5.75 0.93 0.463 LDL-C (mmol/L) 3.81 0.80 3.79 0.80 3.80 0.80 0.655 HDL-C (mmol/L) 1.27 0.34 1.28 0.35 1.30 0.34 0.024 TG (mmol/L) 1.56 0.72 1.53 0.69 1.52 0.64 0.140 apoA-I (g/L) 1.32 0.24 1.33 0.25 1.35 0.23 0.066 apoB (g/L) 1.15 0.23 1.15 0.23 1.15 0.22 0.222 Men (n) 1395 1040 184 TC (mmol/L) 5.36 0.80 5.36 0.80 5.31 0.71 0.819 LDL-C (mmol/L) 3.59 0.72 3.58 0.73 3.54 0.62 0.820 HDL-C (mmol/L) 1.17 0.31 1.18 0.33 1.21 0.30 0.133 TG (mmol/L) 1.50 0.74 1.50 0.74 1.44 0.59 0.568 apoA-I (g/L) 1.24 0.21 1.25 0.24 1.26 0.22 0.166 apoB (g/L) 1.11 0.22 1.10 0.21 1.09 0.19 0.227 Women (n) 1439 1127 229 TC (mmol/L) 6.00 0.89 5.97 0.88 6.11 0.93 0.110 LDL-C (mmol/L) 4.01 0.81 3.99 0.81 4.07 0.82 0.281 HDL-C (mmol/L) 1.36 0.35 1.38 0.35 1.40 0.34 0.091 TG (mmol/L) 1.61 0.69 1.55 0.64 1.60 0.68 0.127 apoA-I (g/L) 1.39 0.25 1.40 0.24 1.42 0.21 0.221 apoB (g/L) 1.20 0.23 1.18 0.22 1.20 0.23 0.577 a p values using the three genotypes, men and women combined; adjusted for gender, body mass index, age, alcohol, smoking, diabetes, apoE phenotype, and country. As for Bonferroni correction of multiple testing, p-value threshold divided by independent tests would be 0.05/12 &#bc; 0.004. Login to comment 98 ABCA1 p.Arg219Lys Discussion We examined the association of a prevalent genetic polymorphism, R219K, at the ABCA1 gene locus with baseline lipids and vascular disease, pravastatin induced LDL-C lowering response, and cardiovascular endpoints on trial in PROSPER, in which participants who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years [8]. Login to comment 104 ABCA1 p.Arg219Lys To date, the association between ABCA1 R219K variant and increased HDL-C level remains controversial. Login to comment 105 ABCA1 p.Arg219Lys To our knowledge, only one small study examined potential effects of the R219K variant on statin induced lipid responses [28]. Login to comment 108 ABCA1 p.Arg219Lys Our study did not provide direct evidence for the mechanism by which the R219K variant affect the statin effects in cardiovascular event reduction. Login to comment 111 ABCA1 p.Arg219Lys Another possible mechanism is that R219K variant plays a novel role in lipid metabolism. Login to comment 112 ABCA1 p.Arg219Lys Supporting this is a recent study suggesting that the R219K variant not only affects apoA-I and HDL metabolism, but may also significant influence postprandial lipid metabolism [29]. Login to comment 115 ABCA1 p.Arg219Lys As for R219K variant, a meta-analysis including 5388 participants reported opposite genotype effects, K-variant as a protective allele, in Chinese population [30]. Login to comment 117 ABCA1 p.Arg219Lys Another meta-analysis including 42 studies for R219K variant reported a potential protective role of K-allele, but again suggested limited interpretation of results because of significant heterogeneity among enrolled studies [31]. Login to comment 119 ABCA1 p.Arg219Lys This pharmacogenetic study enrolled 1686 patients with familial hypercholesterolemia without history of coronary heart disease and analyzed statin-ABCA1 C69T, not R219K, polymorphism interaction by comparing treated and untreated patients. Login to comment 130 ABCA1 p.Arg219Lys In conclusion, ABCA1 R219K variant might be a novel genetic determinant for pravastatin treatment response in heart disease risk reduction in the elderly. Login to comment