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

Harshal A. Deshmukh, Helen Colhoun, Toby Johnson, Paul M. McKeigue, D. John Betteridge, Paul N. Durrington, John H. Fuller, Shona Livingstone, Valentine Charlton-Menys, Andrew Neil, Neil Poulter, Peter Sever, Denis C. Shields, Alice V. Stanton, Aurobindo Chatterjee, Craig Hyde, Roberto A. Calle, David A. DeMicco, Stella Trompet, Iris PostmusIan Ford, J. Wouter Jukema, Mark Caulfield, Graham A. Hitman, CARDS, ASCOT, PROSPER Investigators

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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 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.

Original languageEnglish
Pages (from-to)1000-1011
Number of pages12
JournalJournal of lipid research
Volume53
Issue number5
DOIs
Publication statusPublished - May 2012

Keywords

  • STATIN TREATMENT
  • statins
  • CARDIOVASCULAR-DISEASE
  • LPA LOCUS
  • LIPID-LOWERING RESPONSE
  • low density lipoprotein
  • genetics
  • META ANALYSIS
  • DENSITY-LIPOPROTEIN CHOLESTEROL
  • lipoprotein(a)
  • CONTROLLED-TRIAL
  • WHOLE-GENOME
  • LDL/metabolism
  • PLASMA LIPOPROTEIN(A)
  • CORONARY-HEART-DISEASE

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