Atherosclerosis 220 (2012) 456–462 Contents lists available at SciVerse ScienceDirect Atherosclerosis journa l h omepa g e: www.elsevier.com/locate/atherosclerosis KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly  Hironobu Akao a,b,1,2 , Eliana Polisecki a,c,1,2 , Kouji Kajinami b,2 , Stella Trompet d,e,f,2 , Michele Robertson g,2 , Ian Ford g,2 , J. Wouter Jukema d,e,f,2 , Anton J.M. de Craen d,e,f,2 , Rudi G.J. Westendorp d,e,f,2 , James Shepherd h,2 , Christopher Packard h,2 , Brendan M. Buckley i,2 , Ernst J. Schaefer a,c,∗,2 a Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Tufts University School of Medicine, Boston, MA, USA b Department of Cardiology, Kanazawa Medical University, Uchinada, Japan c Boston Heart Diagnostics, Framingham, MA, USA d Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands e Department of Gerontology, Leiden University Medical Centre, Leiden, The Netherlands f Department of Geriatrics, Leiden University Medical Centre, Leiden, The Netherlands g Robertson Centre of Biostatistics, University of Glasgow, Glasgow, Scotland, UK h Department of Vascular Biochemistry, University of Glasgow, Glasgow, Scotland, UK i Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland a r t i c l e i n f o Article history: Received 20 July 2011 Received in revised form 24 November 2011 Accepted 28 November 2011 Available online 7 December 2011 Keywords: KIF6 Gene Statins Low density lipoprotein cholesterol lowering response Heart disease risk reduction a b s t r a c t Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle- associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins, coronary heart disease (CHD) at baseline, or CHD events on trial. We examined SNPs at the KIF6 (rs20455 or 719Arg), LPA (rs3798220), TAS2R50 (rs1376251) and VAMP8 (rs1010) in 5,411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No SNP was related to vascular disease at baseline. Only the KIF6 SNP was related to LDL-C lowering with homozygous Arg 719 subjects being significantly less responsive than other groups (p = 0.025, -34.2 vs. -36.1%). With regard to the primary CHD endpoint on trial (fatal or non-fatal myocardial infarction or stroke), we observed a significant relationship for KIF6 719Arg homozygotes (p = 0.03, hazards ratio 0.47, 12.8% of the population) in women on pravastatin only, and for TAS2R50 for the AA genotype (p = 0.03, hazards ratio 1.76, 8.9% of the population), also only in women on pravastatin. Our data indicate that the assessment of KIF6 rs20455 and TAS2R50 rs1376251 genotypes are not useful for predicting statin induced cardiovascular risk reduction in men, but do predict CHD risk reduction in women in this elderly population. However, these differences are no longer significant after correction for multiple comparisons, and we do not recommend the assessment of any of these SNPs in clinical practice. © 2011 Published by Elsevier Ireland Ltd.  Research support: This research was supported by grant R01 HL74753 from the National Institutes of Health, and contract 53-1950-5-003 from the Agricul- tural Research Service of the US Department of Agriculture. Dr. Akao was supported by a scholarship from Rotary International. This research was also supported by a grant to Dr. J.W. Jukema from the European Community on the Pharmacogenetics of Statins. ∗ Corresponding author at: Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Tufts Univer- sity School of Medicine, Boston, MA, USA. Tel.: +1 617 556 3100; fax: +1 617 556 3103. E-mail address: ernst.schaefer@tufts.edu (E.J. Schaefer). 1. Introduction Elevated low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) levels independently predict risk of developing coronary heart disease (CHD) [1,2]. Statins reduce LDL-C and prevent CHD events, but 1 These authors contributed equally to this research. 2 on behalf of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) Investigators. 0021-9150/$ – see front matter © 2011 Published by Elsevier Ireland Ltd. doi:10.1016/j.atherosclerosis.2011.11.037