Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2011 Oct 6:12:131.
doi: 10.1186/1471-2350-12-131.

Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

Stella Trompet  1 , Anton J M de Craen, Iris Postmus, Ian Ford, Naveed Sattar, Muriel Caslake, David J Stott, Brendan M Buckley, Frank Sacks, James J Devlin, P Eline Slagboom, Rudi G J Westendorp, J Wouter Jukema; PROSPER Study Group
Affiliations
Randomized Controlled Trial

Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

Stella Trompet et al. BMC Med Genet. .

Abstract

Background: The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.

Methods: The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.

Results: Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.

Conclusion: With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Flow chart of the Quality Control of the PROSPER/PHASE study.
Figure 2
Figure 2
QQ-plot for the GWAS on baseline LDL cholesterol in the PROSPER/PHASE study.
Figure 3
Figure 3
Manhattan plot for the GWAS on baseline LDL cholesterol in the PROSPER/PHASE study.
See this image and copyright information in PMC

References

    1. McGovern PG, Pankow JS, Shahar E, Doliszny KM, Folsom AR, Blackburn H, Luepker RV. Recent trends in acute coronary heart disease--mortality, morbidity, medical care, and risk factors. The Minnesota Heart Survey Investigators. N Engl J Med. 1996;334(14):884–90. doi: 10.1056/NEJM199604043341403. - DOI - PubMed
    1. Kalantzi KJ, Milionis HJ, Mikhailidis DP, Goudevenos JA. Lipid lowering therapy in the elderly: is there a benefit? Curr Pharm Des. 2006;12(30):3945–60. doi: 10.2174/138161206778559669. - DOI - PubMed
    1. Kreisberg RA, Oberman A. Clinical review 141: lipids and atherosclerosis: lessons learned from randomized controlled trials of lipid lowering and other relevant studies. J Clin Endocrinol Metab. 2002;87(2):423–37. doi: 10.1210/jc.87.2.423. - DOI - PubMed
    1. Johnson JA, Cavallari LH. Cardiovascular pharmacogenomics. Exp Physiol. 2005;90(3):283–9. doi: 10.1113/expphysiol.2004.028506. - DOI - PubMed
    1. Goldstein DB, Tate SK, Sisodiya SM. Pharmacogenetics goes genomic. Nat Rev Genet. 2003;4(12):937–47. - PubMed

Publication types

LinkOut - more resources