Top

Published in:

Open Access 01-12-2011 | Research article

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

Authors: Stella Trompet, Anton JM 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 GJ Westendorp, J Wouter Jukema, the PROSPER study group

Published in: BMC Medical Genetics | Issue 1/2011

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.

Available only for authorised users

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. 10.1056/NEJM199604043341403.CrossRefPubMed

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. 10.2174/138161206778559669.CrossRefPubMed

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. 10.1210/jc.87.2.423.CrossRefPubMed

Johnson JA, Cavallari LH: Cardiovascular pharmacogenomics. Exp Physiol. 2005, 90 (3): 283-9. 10.1113/expphysiol.2004.028506.CrossRefPubMed

Goldstein DB, Tate SK, Sisodiya SM: Pharmacogenetics goes genomic. Nat Rev Genet. 2003, 4 (12): 937-47.CrossRefPubMed

Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG: Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002, 360 (9346): 1623-30. 10.1016/S0140-6736(02)11600-X.CrossRefPubMed

Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, et al: Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010, 466 (7307): 707-13. 10.1038/nature09270.CrossRefPubMedPubMedCentral

Shepherd J, Blauw GJ, Murphy MB, Cobbe SM, Bollen EL, Buckley BM, Ford I, Jukema JW, Hyland M, Gaw A, Lagaay AM, Perry IJ, Macfarlane PW, Meinders AE, Sweeney BJ, Packard CJ, Westendorp RG, Twomey C, Stott DJ: The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk. Am J Cardiol. 1999, 84 (10): 1192-7. 10.1016/S0002-9149(99)00533-0.CrossRefPubMed

Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995, 333 (20): 1301-7. 10.1056/NEJM199511163332001.CrossRefPubMed

10.

Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996, 335 (14): 1001-9. 10.1056/NEJM199610033351401.CrossRefPubMed

11.

Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, et al: Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2009, 41 (1): 47-55. 10.1038/ng.269.CrossRefPubMed

12.

Barber MJ, Mangravite LM, Hyde CL, Chasman DI, Smith JD, McCarty CA, Li X, Wilke RA, Rieder MJ, Williams PT, Ridker PM, Chatterjee A, Rotter JI, Nickerson DA, Stephens M, Krauss RM: Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS One. 2010, 5 (3): e9763.-CrossRefPubMedPubMedCentral

13.

Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008, 40 (2): 189-97. 10.1038/ng.75.CrossRefPubMedPubMedCentral

14.

Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, et al: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009, 41 (1): 56-65. 10.1038/ng.291.CrossRefPubMed

15.

Ma L, Yang J, Runesha HB, Tanaka T, Ferrucci L, Bandinelli S, Da Y: Genome-wide association analysis of total cholesterol and high-density lipoprotein cholesterol levels using the Framingham heart study data. BMC Med Genet. 2010, 11: 55-CrossRefPubMedPubMedCentral

16.

Sandhu MS, Waterworth DM, Debenham SL, Wheeler E, Papadakis K, Zhao JH, Song K, Yuan X, Johnson T, Ashford S, Inouye M, Luben R, Sims M, Hadley D, McArdle W, Barter P, Kesäniemi YA, Mahley RW, McPherson R, Grundy SM, Wellcome Trust Case Control Consortium, Bingham SA, Khaw KT, Loos RJ, Waeber G, Barroso I, Strachan DP, Deloukas P, Vollenweider P, Wareham NJ, Mooser V: LDL-cholesterol concentrations: a genome-wide association study. Lancet. 2008, 371 (9611): 483-91. 10.1016/S0140-6736(08)60208-1.CrossRefPubMedPubMedCentral

17.

Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M Ahmadi K, Dobson RJ, Marçano AC, Hajat C, Burton P, Deloukas P, Brown M, Connell JM, Dominiczak A, Lathrop GM, Webster J, Farrall M, Spector T, Samani NJ, Caulfield MJ, Munroe PB: Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet. 2008, 82 (1): 139-49. 10.1016/j.ajhg.2007.11.001.CrossRefPubMedPubMedCentral

18.

Waterworth DM, Ricketts SL, Song K, Chen L, Zhao JH, Ripatti S, Aulchenko YS, Zhang W, Yuan X, Lim N, Luan J, Ashford S, Wheeler E, Young EH, Hadley D, Thompson JR, Braund PS, Johnson T, Struchalin M, Surakka I, Luben R, Khaw KT, Rodwell SA, Loos RJ, Boekholdt SM, Inouye M, Deloukas P, Elliott P, Schlessinger D, Sanna S, et al: Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol. 2010, 30 (11): 2264-76. 10.1161/ATVBAHA.109.201020.CrossRefPubMedPubMedCentral

19.

Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen WM, Li Y, Scott LJ, Scheet PA, et al: Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008, 40 (2): 161-9. 10.1038/ng.76.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/12/131/prepub

Title: Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses
Authors: Stella Trompet
Anton JM 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 GJ Westendorp
J Wouter Jukema
the PROSPER study group
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2011
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-12-131

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2011

Association of the MAOA promoter uVNTR polymorphism with suicide attempts in patients with major depressive disorder

New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women

Interactions between genetic admixture, ethnic identity, APOE genotype and dementia prevalence in an admixed Cuban sample; a cross-sectional population survey and nested case-control study

Molecular diagnosis of hereditary inclusion body myopathy by linkage analysis and identification of a novel splice site mutation in GNE

Melatonin receptor 1 B polymorphisms associated with the risk of gestational diabetes mellitus

UGT1A1 sequence variants and bilirubin levels in early postnatal life: a quantitative approach