title: Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a).
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).
authors.affiliation: University of Dundee, Dundee, United Kingdom.
authors.forename: Harshal A
authors.initials: HA
authors.lastname: Deshmukh
authors.affiliation: University of Dundee, Dundee, United Kingdom. Electronic address: h.colhoun@cpse.dundee.ac.uk.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Colhoun
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.affiliation: University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: McKeigue
authors.affiliation: University College London, London, United Kingdom.
authors.forename: D John
authors.initials: DJ
authors.lastname: Betteridge
authors.affiliation: University of Manchester, Manchester, United Kingdom.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Durrington
authors.affiliation: University College London, London, United Kingdom.
authors.forename: John H
authors.initials: JH
authors.lastname: Fuller
authors.affiliation: University of Dundee, Dundee, United Kingdom.
authors.forename: Shona
authors.initials: S
authors.lastname: Livingstone
authors.affiliation: University of Manchester, Manchester, United Kingdom.
authors.forename: Valentine
authors.initials: V
authors.lastname: Charlton-Menys
authors.affiliation: University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Neil
authors.affiliation: International Centre for Circulatory Health, Imperial College London, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Poulter
authors.affiliation: International Centre for Circulatory Health, Imperial College London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Sever
authors.affiliation: Complex and Adaptive Systems Laboratory, University College Dublin, Dublin, Ireland.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Shields
authors.affiliation: Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Alice V
authors.initials: AV
authors.lastname: Stanton
authors.affiliation: Pfizer Ltd., New York, NY.
authors.forename: Aurobindo
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Pfizer Ltd., New York, NY.
authors.forename: Craig
authors.initials: C
authors.lastname: Hyde
authors.affiliation: Pfizer Ltd., New York, NY.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Calle
authors.affiliation: Pfizer Ltd., New York, NY.
authors.forename: David A
authors.initials: DA
authors.lastname: DeMicco
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands and.
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.affiliation: Department of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Iris
authors.initials: I
authors.lastname: Postmus
authors.affiliation: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom; and.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands and; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D008078:Cholesterol, LDL / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D005964:Glucosyltransferases / Q000235:genetics; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D049368:Receptors, Lysophosphatidic Acid; D000069059:Atorvastatin; D005964:Glucosyltransferases