ISSN 1214-0287 (on-line), ISSN 1214-021X (printed)
J Appl Biomed
Volume 10 (2012), No 1, p 19-28
DOI 10.2478/v10136-012-0001-3

Variant within CELSR2/PSRC1/SORT1, but not within CILP2/PBX4, PCSK9 and APOB genes, has a potential to influence statin treatment efficacy

Jaroslav Alois Hubacek, Vera Adamkova, Vera Lanska, Dana Dlouha, Jitka Rynekrova, Lukas Zlatohlavek, Martina Prusikova, Richard Ceska, Michal Vrablik

Address: Jaroslav Alois Hubacek, IKEM-CEM-LMG, Videnska 1958/9, 140 21 Prague 4, Czech Republic
jahb@ikem.cz

Received 29th July 2011.
Revised 20th September 2011.
Published online 25th October 2011.

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SUMMARY
Statins have become a cornerstone of cardiovascular prevention. However, their lipid lowering efficacy and, thus also, impact on event risk reduction, differ substantially between individuals. The major part of this inter-individual difference can be explained by genetic factors. Using the GWA approach, candidate genes that may modify the response to statin treatment have been detected. Variants rs646776 (CELSR2/PSRC1/SORT1), rs16996148 (CILP2/PBX4), rs11206510 (PCSK9) and rs693 (APOB) were analysed in 370 (146 males) dyslipidemic patients treated with statins (46.6% simvastatin, 41.5% atorvastatin, 11.9% lovastatin, 10 or 20 mg/day) and 470 normolipidemic controls (188 males). Lipid levels were available prior to and after 8-12 weeks of therapy. There was a significant decrease both in the total (7.36±1.28 to 5.43±1.01 mmol/l) and LDL-cholesterol (4.72±1.35 to 3.19±0.98 mmol/l) after treatment. The genotype frequencies of the three SNPs differed between patients and controls (rs646776, rs16996148, rs693). The carriers of the minor rs599838 genotype had a significantly lower response to statin treatment compared to common homozygotes (LDL-cholesterol, delta -20.3% vs. delta -32.0%). No other significant associations with lipid changes were detected. Together with variations of other, multiple gene loci the variant at CELSR2/PSRC1/SORT1 gene cluster may be useful for individualization of statin treatment leading to better outcomes of the treatment.

KEY WORDS
dyslipidemia; statins; gene variants; pharmacogenetics; treatment efficacy; CELSR2/PSRC1/SORT1; CILP2/PBX4; PCSK9; APOB

REFERENCES
Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 41: 47-55, 2009.
[CrossRef] [PubMed]

Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 376: 1670-1681, 2010.
[CrossRef]

Benn M. Apolipoprotein B levels, APOB alleles, and risk of ischemic cardiovascular disease in the general population, a review. Atherosclerosis. 206: 17-30, 2009.
[CrossRef] [PubMed]

Berger J. The age of biomedicine: current trends in traditional subjects. J Appl Biomed. 9: 57-61, 2011.
[CrossRef] [JAB]

Davignon J, Dubuc G, Seidah NG. The influence of PCSK9 polymorphisms on serum low density lipoprotein cholesterol and risk of atherosclerosis. Curr Atheroscler Rep. 12: 308-315, 2010.
[CrossRef] [PubMed]

Day IN, Humphries SE. Electrophoresis for genotyping: microtiter array diagonal gel electrophoresis on horizontal polyacrylamide gels, hydrolink, or agarose. Anal Biochem. 222: 389-395, 1994.
[CrossRef] [PubMed]

Fruchart JC, Sacks FM, Hermans MP, Assmann G, Brown WV, Ceska R, Chapman MJ, Dodson PM, Fioretto P, Ginsberg HN, Kadowaki T, Lablanche JM et al. The residual risk initiative: a call to action to reduce residual vascular risk in dyslipideamic patients. Diabetes Vasc Dis Res. 5: 319-335, 2008.
[CrossRef]

Hachem SB, Mooradian AD. Familial dyslipidaemias: an overview of genetics, pathophysiology and management. Drugs. 66: 1949-1969, 2006.
[CrossRef] [PubMed]

Hubacek JA, Vrablik M. Effect of apolipoprotein E polymorphism on statin-induced decreases in plasma lipids and cardiovascular events. Drug Metabol Drug Interact. 26: 13-20, 2011.
[CrossRef] [PubMed]

Hubacek JA, Adamkova V, Prusikova M, Snejdrlova M, Hirschfeldova K, Lanska V, Ceska R, Vrablik M. Impact of apolipoprotein A5 variants on statin treatment efficacy. Pharmacogenomics. 10: 945-950, 2009.
[CrossRef] [PubMed]

Kajinami K, Brousseau DE, Ordovas JM, Schaefer EJ. A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin. Atherosclerosis. 180: 407-415, 2005.
[CrossRef] [PubMed]

Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 40: 189-197, 2008.
[CrossRef] [PubMed]

Kjolby M, Andersen OM, Breiderhoff T, Fjorback AW, Pedersen KM, Madsen P, Jansen P, Heeren J, Willnow TE, Nykjaer A. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 12: 213-223, 2010.
[CrossRef] [PubMed]

Kooner JS, Chambers JC, Aguilar-Salinas CA, Hinds DA, Hyde CL, Warnes GR, Gomez Perez FJ, Frazer KA, Elliott P, Scott J, Milos PM, Cox DR et al. Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet. 40: 149-151, 2008.
[CrossRef] [PubMed]

Maggo SD, Kennedy MA, Clark DW. Clinical implications of pharmacogenetic variation on the effects of statins. Drug Saf. 34: 1-19, 2011.
[CrossRef] [PubMed]

Mangravite LM, Krauss RM. Pharmacogenetics of statin response, Curr Opin Lipidol. 18: 409-419, 2007.
[PubMed]

Mangravite LM, Medina MW, Cui J, Pressman S, Smith JD, Rieder MJ, Guo X, Nickerson DA, Rotter JI, Krauss RM. Combined influence of LDL and HMGCR sequence variation on lipid-lowering response to simvastatin. Arterioscler Thromb Vasc Biol. 30: 1485-1492, 2010.
[CrossRef] [PubMed]

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for DNA extraction from human nucleated cells. Nucleic Acid Res. 16: 1215, 1988.
[CrossRef] [PubMed]

Musunuru K, Kathiresan S. Genetics of coronary artery disease. Annu Rev Genomics Hum Genet. 11: 91-108, 2010.
[CrossRef] [PubMed]

Nakayama K, Bayasgalan T, Yamanaka K, Kumada M, Gotoh T, Nakayama K, Bayasgalan T, Yamanaka K, Kumada M, Gotoh T, Utsumi N, Yanagisawa Y et al. Large scale replication analysis of loci associated with lipid concentrations in a Japanese population. J Med Genet. 46: 370-374, 2009.
[CrossRef] [PubMed]

Ordovas JM, Mooser V. The APOE locus and the pharmacogenetics of the lipid response. Curr Opin Lipidol. 13: 113-117, 2002.
[CrossRef] [PubMed]

Rosenberg NA, Huang L, Jewett EM, Szpiech ZA, Jankovic I, Boehnke M. Genome-wide association studies in diverse populations. Nat Rev Genet. 11: 356-366, 2010.
[CrossRef] [PubMed]

Sadowitz B, Maier KG, Gathan V. Basic science review: Statin therapy - Part I: The pleiotropic effects of statins in cardiovascular dinase. Vasc Endovascular Surg. 44: 241-251, 2010.
[CrossRef] [PubMed]

Sandhu MS, Waterworth DM, Debenham SL, Wheeler E, Papadakis K, Zhao JH, Song K, Yuan X, Johnson T, Ashford S, Inouye M, Luben R et al. LDL-cholesterol concentrations: a genome-wide association study. Lancet. 371: 483-491, 2008.
[CrossRef]

Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, Mio F, Mori M, Miyamoto Y, Masuda I, Tsunoda T, Kamata M et al. A functional SNP in CILP, encoding the cartilage intermediate layer protein, is associated with susceptibility tolumbar disc disease. Nat Genet. 37: 607-612, 2005.
[CrossRef] [PubMed]

Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 361: 1149-1158, 2003.
[CrossRef]

Tunstall-Pedoe H (ed.). MONICA. Monograph and Multimedia Source Book. The World’s Largest Study of Heart Disease, Stroke, Risk Factors and Population Trends (1979–2002). WHO, Geneva 2003, pp. 244.

Vrablik M, Ceska R, Adamkova V, Peasey A, Pikhart H, Kubinova R, Marmot M, Bobak M, Hubacek JA. MLXIPL variant in individuals with low and high triglyceridemia in white population in Central Europe. Hum Genet. 124: 553-555, 2008.
[CrossRef] [PubMed]

Wang K, Li M, Hakonarson H. Analysing biological pathways in genome-wide association studies. Nat Rev Genet. 11: 843-854, 2010.
[CrossRef] [PubMed]

Waterworth DM, Ricketts SL, Song K, Chen L, Zhao JH, Ripatti S, Aulchenko YS, Zhang W, Yuan X, Lim N, Luan J, Ashford S et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol. 30: 2264-2276, 2010.
[CrossRef] [PubMed]

Welcome Trust Case Control Consortium, Genome wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 447: 661-678, 2007.
[CrossRef] [PubMed]
CITED

Hubacek JA, Dlouha D, Adamkova V, Lanska V, Ceska R, Vrablik M. Possible gene-gender interaction between the SLC01B1 polymorphism and statin treatment efficacy. Neuroendocrin Lett. 33(Suppl. 2): 22-25, 2012.

Vrablik M, Hubacek JA, Dlouha D, Lanska V, Rynekrova J, Zlatohlavek L, Prusikova M, Ceska R, Adamkova V. Impact of Variants Within Seven Candidate Genes on Statin Treatment Efficacy. Physiolog Res. 61: 609-617, 2012.

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