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

被引：97

作者：

Deshmukh, Harshal A. ^{[1
]}

Colhoun, Helen M. ^{[1
]}

Johnson, Toby ^{[2
]}

McKeigue, Paul M. ^{[3
]}

Betteridge, D. John ^{[4
]}

Durrington, Paul N. ^{[5
]}

Fuller, John H. ^{[4
]}

Livingstone, Shona ^{[1
]}

Charlton-Menys, Valentine ^{[5
]}

Neil, Andrew ^{[6
]}

Poulter, Neil ^{[7
]}

Sever, Peter ^{[7
]}

Shields, Denis C. ^{[8
]}

Stanton, Alice V. ^{[9
]}

Chatterjee, Aurobindo ^{[10
]}

Hyde, Craig ^{[10
]}

Calle, Roberto A. ^{[10
]}

DeMicco, David A. ^{[10
]}

Trompet, Stella ^{[11
]}

Postmus, Iris ^{[12
]}

Ford, Ian ^{[13
]}

Jukema, J. Wouter ^{[8
,14
]}

Caulfield, Mark ^{[2
]}

Hitman, Graham A. ^{[2
]}

机构：

[1] Univ Dundee, Dundee, Scotland

[2] Queen Mary Univ London, Barts & London Sch Med & Dent, London, England

[3] Univ Edinburgh, Edinburgh, Midlothian, Scotland

[4] UCL, London, England

[5] Univ Manchester, Manchester, Lancs, England

[6] Univ Oxford, Oxford, England

[7] Imperial Coll London, Int Ctr Circulatory Hlth, London, England

[8] Univ Coll Dublin, Complex & Adapt Syst Lab, Dublin 2, Ireland

[9] Royal Coll Surgeons Ireland, Dublin 2, Ireland

[10] Pfizer Ltd, New York, NY USA

[11] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands

[12] Leiden Univ, Med Ctr, Dept Geriatr & Gerontol, Leiden, Netherlands

[13] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland

[14] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands

来源：

JOURNAL OF LIPID RESEARCH | 2012年 / 53卷 / 05期

关键词：

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;

D O I：

10.1194/jlr.P021113

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1000 / 1011

页数：12

共 37 条

[1] ProbABEL package for genome-wide association analysis of imputed data [J].

Aulchenko, Yurii S. ;

Struchalin, Maksim V. ;

van Duijn, Cornelia M. .

BMC BIOINFORMATICS, 2010, 11

[2] Genome-Wide Association of Lipid-Lowering Response to Statins in Combined Study Populations [J].

Barber, Mathew J. ;

Mangravite, Lara M. ;

Hyde, Craig L. ;

Chasman, Daniel I. ;

Smith, Joshua D. ;

McCarty, Catherine A. ;

Li, Xiaohui ;

Wilke, Russell A. ;

Rieder, Mark J. ;

Williams, Paul T. ;

Ridker, Paul M. ;

Chatterjee, Aurobindo ;

Rotter, Jerome I. ;

Nickerson, Deborah A. ;

Stephens, Matthew ;

Krauss, Ronald M. .

PLOS ONE, 2010, 5 (03)

[3]

Becker ML, 2009, PHARMACOGENOMICS, V10, P1743, DOI [10.2217/pgs.09.105, 10.2217/PGS.09.105]

[4]

BENZEEV O, 1994, J LIPID RES, V35, P1511

[5] Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease [J].

Clarke, Robert ;

Peden, John F. ;

Hopewell, Jemma C. ;

Kyriakou, Theodosios ;

Goel, Anuj ;

Heath, Simon C. ;

Parish, Sarah ;

Barlera, Simona ;

Franzosi, Maria Grazia ;

Rust, Stephan ;

Bennett, Derrick ;

Silveira, Angela ;

Malarstig, Anders ;

Green, Fiona R. ;

Lathrop, Mark ;

Gigante, Bruna ;

Leander, Karin ;

de Faire, Ulf ;

Seedorf, Udo ;

Hamsten, Anders ;

Collins, Rory ;

Watkins, Hugh ;

Farrall, Martin .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (26) :2518-2528

[6] Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial [J].

Colhoun, HM ;

Betteridge, DJ ;

Durrington, PN ;

Hitman, GA ;

Neil, HAW ;

Livingstone, SJ ;

Thomason, MJ ;

Mackness, MI ;

Charlton-Menys, V ;

Fuller, JH .

LANCET, 2004, 364 (9435) :685-696

[7] Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes:: a Go-DARTS study [J].

Donnelly, Louise A. ;

Palmer, Colin N. A. ;

Whitley, Adrian L. ;

Lang, Chim Choy ;

Doney, Alex S. F. ;

Morris, Andrew D. ;

Donnan, Peter T. .

PHARMACOGENETICS AND GENOMICS, 2008, 18 (04) :279-287

[8] A paucimorphic variant in the HMO-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study [J].

Donnelly, Louise A. ;

Doney, Alex S. F. ;

Dannfald, Jennifer ;

Whitley, Adrian L. ;

Lang, Chim C. ;

Morris, Andrew D. ;

Donnan, Peter T. ;

Palmer, Colin N. A. .

PHARMACOGENETICS AND GENOMICS, 2008, 18 (12) :1021-1026

[9]

Erqou S, 2009, JAMA-J AM MED ASSOC, V302, P412, DOI 10.1001/jama.2009.1063

[10]

FRIEDEWALD WT, 1972, CLIN CHEM, V18, P499

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