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

Deshmukh, H.A. et al. (2012) Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). Journal of Lipid Research, 53(5), pp. 1000-1011. (doi: 10.1194/jlr.P021113)

Abstract

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 × 10−9) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 × 10−16 and rs4420638; P = 1.01 × 10−11) that are proxies for the ϵ2 and ϵ4 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. 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).

• Item Type: Articles
• Status: Published
• Refereed: Yes
• 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
• Publisher: American Society for Biochemistry and Molecular Biology, Inc
• ISSN: 0022-2275
• ISSN (Online): 1539-7262
• Copyright Holders: Copyright © 2012 American Society for Biochemistry and Molecular Biology, Inc
• First Published: First published in Journal of Lipid Research 53(5) : 1000-1011
• Publisher Policy: Reproduced under a Creative Commons License