Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importnace of Lp(a)

Deshmukh, H.A. et al. (2012) Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importnace of Lp(a). Journal of Lipid Research, 53, pp. 1000-1011. (doi: 10.1194/jlr.P021113)

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We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 x 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 x 10(-16) and rs4420638; P = 1.01 x 10(-11)) that are proxies for the epsilon 2 and epsilon 4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response.jlr Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).-Deshmukh, H. A., H. M. Colhoun, T. Johnson, P. M. McKeigue, D. J. Betteridge, P. N. Durrington, J. H. Fuller, S. Livingstone, V. Charlton-Menys, A. Neil, N. Poulter, P. Sever, D. C. Shields, A. V. Stanton, A. Chatterjee, C. Hyde, R. A. Calle, D. A. DeMicco, S. Trompet, I. Postmus, I. Ford, J. W. Jukema, M. Caulfield, and G. A. Hitman on behalf of the CARDS, ASCOT, and PROSPER investigators. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). J. Lipid Res. 2012. 53: 1000-1011.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Ford, Professor Ian
Authors: Deshmukh, H.A., Colhoun, H.M., Johnson, T., McKeigue, P.M., Betteridge, D.J., Durrington, P.N., Fuller, J.H., Livingstone, S., Charlton-Menys, V., Neil, A., Poulter, N., Sever, P., Shields, D.C., Stanton, A.V., Chatterjee, A., Hyde, C., Calle, R.A., DeMicco, D.A., Trompet, S., Postmus, I., Ford, I., Jukema, J.W., Caulfield, M., and Hitman, G.A.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
Journal Name:Journal of Lipid Research
ISSN (Online):1539-7262
Published Online:24 February 2012
Copyright Holders:Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.
First Published:First published in Journal of Lipid Research 2012 53:1000-1011
Publisher Policy:Reproduced with the permission of the publisher, distributed under the terms of the Creative Commons Attribution Non-Commercial License

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