Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)
Author(s)
Type
Journal Article
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).
Date Issued
2012-05-01
Date Acceptance
2012-05-01
Citation
Journal of Lipid Research, 2012, 53 (5), pp.1000-1011
ISSN
0022-2275
Publisher
American Society for Biochemistry and Molecular Biology
Start Page
1000
End Page
1011
Journal / Book Title
Journal of Lipid Research
Volume
53
Issue
5
Copyright Statement
© 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Free via Creative Commons: CC-BY license
License URL
Sponsor
National Institute for Health Research
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000302786800019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
NF-SI-0508-10116
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
genetics
low density lipoprotein
LDL/metabolism
lipoprotein(a)
statins
CORONARY-HEART-DISEASE
LIPID-LOWERING RESPONSE
DENSITY-LIPOPROTEIN CHOLESTEROL
CARDIOVASCULAR-DISEASE
PLASMA LIPOPROTEIN(A)
STATIN TREATMENT
CONTROLLED-TRIAL
META ANALYSIS
WHOLE-GENOME
LPA LOCUS
Publication Status
Published
Date Publish Online
2012-05