Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
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ABSTRACT:
SUBMITTER: Postmus I
PROVIDER: S-EPMC4220464 | biostudies-literature | 2014 Oct
REPOSITORIES: biostudies-literature
Publications
Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
Postmus Iris I Trompet Stella S Deshmukh Harshal A HA Barnes Michael R MR Li Xiaohui X Warren Helen R HR Chasman Daniel I DI Zhou Kaixin K Arsenault Benoit J BJ Donnelly Louise A LA Wiggins Kerri L KL Avery Christy L CL Griffin Paula P Feng QiPing Q Taylor Kent D KD Li Guo G Evans Daniel S DS Smith Albert V AV de Keyser Catherine E CE Johnson Andrew D AD de Craen Anton J M AJ Stott David J DJ Buckley Brendan M BM Ford Ian I Westendorp Rudi G J RG Slagboom P Eline PE Sattar Naveed N Munroe Patricia B PB Sever Peter P Poulter Neil N Stanton Alice A Shields Denis C DC O'Brien Eoin E Shaw-Hawkins Sue S Chen Y-D Ida YD Nickerson Deborah A DA Smith Joshua D JD Dubé Marie Pierre MP Boekholdt S Matthijs SM Hovingh G Kees GK Kastelein John J P JJ McKeigue Paul M PM Betteridge John J Neil Andrew A Durrington Paul N PN Doney Alex A Carr Fiona F Morris Andrew A McCarthy Mark I MI Groop Leif L Ahlqvist Emma E Bis Joshua C JC Rice Kenneth K Smith Nicholas L NL Lumley Thomas T Whitsel Eric A EA Stürmer Til T Boerwinkle Eric E Ngwa Julius S JS O'Donnell Christopher J CJ Vasan Ramachandran S RS Wei Wei-Qi WQ Wilke Russell A RA Liu Ching-Ti CT Sun Fangui F Guo Xiuqing X Heckbert Susan R SR Post Wendy W Sotoodehnia Nona N Arnold Alice M AM Stafford Jeanette M JM Ding Jingzhong J Herrington David M DM Kritchevsky Stephen B SB Eiriksdottir Gudny G Launer Leonore J LJ Harris Tamara B TB Chu Audrey Y AY Giulianini Franco F MacFadyen Jean G JG Barratt Bryan J BJ Nyberg Fredrik F Stricker Bruno H BH Uitterlinden André G AG Hofman Albert A Rivadeneira Fernando F Emilsson Valur V Franco Oscar H OH Ridker Paul M PM Gudnason Vilmundur V Liu Yongmei Y Denny Joshua C JC Ballantyne Christie M CM Rotter Jerome I JI Adrienne Cupples L L Psaty Bruce M BM Palmer Colin N A CN Tardif Jean-Claude JC Colhoun Helen M HM Hitman Graham G Krauss Ronald M RM Wouter Jukema J J Caulfield Mark J MJ
Nature communications 20141028
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1 ...[more]
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Project description:LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations.We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations.In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L.We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.
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