title: KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly.
abstract: 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.
authors.affiliation: Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Akao
authors.forename: Eliana
authors.initials: E
authors.lastname: Polisecki
authors.forename: Kouji
authors.initials: K
authors.lastname: Kajinami
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.forename: Michele
authors.initials: M
authors.lastname: Robertson
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: James
authors.initials: J
authors.lastname: Shepherd
authors.forename: Christopher
authors.initials: C
authors.lastname: Packard
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics* / Q000517:prevention & control*; D016009:Chi-Square Distribution; D008078:Cholesterol, LDL / Q000097:blood*; D005060:Europe; D005260:Female; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D016547:Kinesins / Q000235:genetics*; D015810:Linkage Disequilibrium; D017270:Lipoprotein(a) / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000627:therapeutic use*; D011446:Prospective Studies; D050683:R-SNARE Proteins / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D000098706:Taste Receptors, Type 2
chemical_list: D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017270:Lipoprotein(a); D050683:R-SNARE Proteins; D043562:Receptors, G-Protein-Coupled; C112938:VAMP8 protein, human; D000098706:Taste Receptors, Type 2; C526774:KIF6 protein, human; D016547:Kinesins; D017035:Pravastatin