KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly

Authors: AKAO, HIRONOBU - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; POLISECKI, ELIANA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KAJINAMI, KOUJI - Kanazawa University; TROMPET, STELLA - Leiden University Medical Center; ROBERTSON, MICHELE - University Of Glasgow; FORD, IAN - University Of Glasgow; JUKEMA, J. WOUTER - Leiden University Medical Center; DE CRAEN, ANTON J. M. - Leiden University Medical Center; WESTENDORP, RUDI G. J. - Leiden University Medical Center; SHEPHERD, JAMES - University Of Glasgow; PACKARD, CHRISTOPHER - University Of Glasgow; BUCKLEY, BRENDAN M. - University College Cork; SCHAEFER, ERNST J. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/28/2011
Publication Date: 2/1/2012
Citation: Akao, H., Polisecki, E., Kajinami, K., Trompet, S., Robertson, M., Ford, I., Jukema, J., De Craen, A., Westendorp, R., Shepherd, J., Packard, C., Buckley, B., Schaefer, E. 2012. KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly. Atherosclerosis. 220(2):456-462.

Interpretive Summary: In addition to lifestyle change, the use of cholesterol lowering medications, especially statins which inhibit cholesterol production in the body, have been shown to significantly reduce the risk of heart disease. It is known that the response to statins, in this case pravastatin, can be very different in terms of lowering total blood cholesterol and low density lipoprotein (LDL) cholesterol (the ‘bad’ cholesterol particle). Our goal was to look at various genetic markers to see if any of these markers predicted lowering of LDL cholesterol and heart disease risk reduction in an elderly population of 5,411 people. We examined genetic variants at four different gene loci and while some differences were noted our conclusions were that assessing these variants (kinesin like protein 6, lipoprotein(a), taste receptor 2, and vesicle associated membrane protein 8) would not be useful in the clinical setting. These variants were selected because other groups have reported that they might be useful in this setting. However our studies in a much larger number of subjects do not support their conclusions and recommendations. This research is of importance to people who are interested in the prevention and treatment of heart disease, the leading cause of death and disability in our society.

Technical 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.