The Trp719Arg allele of KIF6 rs20455, a putative risk factor for CHD especially in those with elevated low-density lipoprotein cholesterol (LDL-C), was investigated in Filipino-American women (FAW, ) participating in health screenings in four cities. The rs20455 genotype of each subject was determined by a multiplex assay using a Luminex-OLA procedure. The risk allele Trp719Arg was present in 77% of the subjects. The genotype distribution was 23% Trp/Trp, 51% Arg/Trp, and 26% Arg/Arg. Genotype did not predict the presence of CHD risk factors. Moreover, LDL-C, HDL-C, and triglycerides mean values did not vary as a function of genotype. However, those with the Arg/Arg genotype on statin medication exhibited a significantly higher mean triglycerides level ( ). Approximately 60% of participants regardless of genotype exhibited LDL-C levels 100？mg/dL but were not taking medication. Approximately 43% of those with the Trp719Arg risk allele on statins exhibited elevated LDL-C levels. Our study suggests that the Trp719Arg allele of KIF 6 rs20455 is common among Filipino-American women; thus, even with borderline LDL-C levels would benefit from statin treatment. Secondly, many participants did not exhibit guideline recommended LDL-C levels including many who were on statin drugs. 1. Introduction Coronary heart disease is a multifactorial and complex disease resulting from the interaction of genes and environmental factors [1–5]. Genetics plays an important role in determining the inherent CHD vulnerability and in determining how a person responds to statin therapy. KIF6 is a member of the kinesin family, a class of motor proteins that are involved in the intracellular transport of membrane organelles, messenger RNA’s and other protein complexes along microtubules [6–10]. Several studies focusing on Caucasians have reported that the Trp719Arg allele of single nucleotide polymorphism (SNP) rs20455 in the KIF6 gene is associated with CHD and that carriers who carry one or two copies of the risk allele respond better to statin therapy than noncarriers [10–15]. The prevalence among Caucasians is about 59% and the risk ratio has been stated to be 1.22 (95% confidence intervals 1.12–1.32) [15]. This association with increased risk was present in African Americans, who have very high numbers (~90%) with the risk allele [15]. Chinese and Japanese also have been reported to have a high frequency (~70%) of the risk allele [15]. Other investigators were unable to detect the association of the rs20455 allele with increased CHD risk [16] even with a large sample size [17].
References
[1]
J. C. Cohen, “Genetic approaches to coronary heart disease,” Journal of the American College of Cardiology, vol. 48, no. 9, pp. A10–A14, 2006.
[2]
A. J. Lusis, A. M. Fogelman, and G. C. Fonarow, “Genetic basis of atherosclerosis: part II: clinical implications,” Circulation, vol. 110, no. 14, pp. 2066–2071, 2004.
[3]
G. H. Gibbons, C. C. Liew, M. O. Goodarzi et al., “Genetic markers: progress and potential for cardiovascular disease,” Circulation, vol. 109, no. 25, supplement 1, pp. IV47–IV58, 2004.
[4]
J. F. Peden and M. Farrall, “Thirty-five common variants for coronary artery disease: the fruits of much collaborative labour,” Human Molecular Genetics, vol. 20, no. 2, pp. R198–205, 2011.
[5]
The IBC 50K CAD Consortium, “Large-scale gene-centric analysis identifies novel variants for coronary artery disease,” PLoS Genetics, vol. 7, no. 9, Article ID e1002260, 2011.
[6]
N. Hirokawa, “Kinesin and dynein superfamily proteins and the mechanism of organelle transport,” Science, vol. 279, no. 5350, pp. 519–526, 1998.
[7]
H. Miki, M. Setou, K. Kaneshiro, and N. Hirokawa, “All kinesin superfamily protein, KIF, genes in mouse and human,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 13, pp. 7004–7011, 2001.
[8]
S. Seiler, J. Kirchner, C. Horn, A. Kallipolitou, G. Woehlke, and M. Schliwa, “Cargo binding and regulatory sites in the tail of fungal conventional kinesin,” Nature Cell Biology, vol. 2, no. 6, pp. 333–338, 2000.
[9]
P. Peng, J. Lian, R. S. Huang et al., “Meta-analyses of KIF6 rs20455 in coronary heart disease and statin therapeutic effect,” PLoS ONE, vol. 7, no. 12, Article ID e50126, 2012.
[10]
G. Wu, G. B. Li, and B. Dai, “Association of KIF6 variant with lipid level and angiographic coronary artery disease events risk in the Han Chinese population,” Molecules, vol. 17, no. 9, pp. 11269–11280, 2012.
[11]
D. Shiffman, D. I. Chasman, R. Y. L. Zee et al., “A kinesin family member 6 variant is associated with coronary heart disease in the Women's Health Study,” Journal of the American College of Cardiology, vol. 51, no. 4, pp. 444–448, 2008.
[12]
P. M. Ridker, J. G. Macfadyen, R. J. Glynn, and D. I. Chasman, “Kinesin-like protein 6 (KIF6) polymorphism and the efficacy of rosuvastatin in primary prevention,” Circulation: Cardiovascular Genetics, vol. 4, pp. 312–317, 2011.
[13]
D. Shiffman, M. S. Sabatine, J. Z. Louie et al., “Effect of pravastatin therapy on coronary events in carriers of the KIF6 719Arg allele from the cholesterol and recurrent events trial,” The American Journal of Cardiology, vol. 105, no. 9, pp. 1300–1305, 2010.
[14]
O. A. Iakoubova, C. H. Tong, C. M. Rowland et al., “Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials. The CARE and WOSCOPS trials,” Journal of the American College of Cardiology, vol. 51, no. 4, pp. 435–443, 2008.
[15]
Y. Li, O. A. Iakoubova, D. Shiffman, J. J. Devlin, J. S. Forrester, and H. R. Superko, “KIF6 polymorphism as a predictor of risk of coronary events and of clinical event reduction by statin therapy,” The American Journal of Cardiology, vol. 106, no. 7, pp. 994–998, 2010.
[16]
L. A. Bare, E. A. Ruiz-Narvaéz, C. H. Tong et al., “Investigation of KIF6 Trp719Arg in a case-control study of myocardial infarction: a Costa Rican population,” PLoS ONE, vol. 5, no. 9, Article ID e13081, 2010.
[17]
T. Assimes, H. Holm, S. Katherisan, et al., “Lack of assoaition between the rs20455 polymorphism in Kinesin-like protein-6 and coronary artery disease in 19 case-control studies,” Journal of the American College of Cardiology, vol. 56, no. 9, pp. 1552–1563, 2010.
[18]
B. A. Ference, W. Yoo, J. M. Flack, and M. Clarke, “A common KIF6 polymorphism increases vulnerability to low-density lipoprotein cholesterol: two meta-analyses and a meta-regression analysis,” PLoS ONE, vol. 6, no. 12, Article ID e28834, 2011.
[19]
L. J. Larsen, “The foreign born population in the United States: 2003,” Current Population Reports, U.S. Census Bureau, Washington, DC, USA, 2004.
[20]
R. A. Ursua, N. S. Islam, D. E. Aguilar et al., “Predictors of hypertension among Filipino immigrants in the Northeast US,” Journal of Community Health, vol. 38, no. 5, pp. 847–855, 2013.
[21]
M. R. G. Araneta, A. Grandinetti, and H. K. Chang, “A1C and diabetes diagnosis among Filipino Americans, Japanese Americans, and Native Hawaiians,” Diabetes Care, vol. 33, no. 12, pp. 2626–2628, 2010.
[22]
A. T. Holland, B. Zhao, E. C. Wong, S. E. Choi, N. D. Wong, and L. P. Palaniappan, “Racial/ethnic differences in control of cardiovascular risk factors among type 2 diabetes patients in an insured, ambulatory care population,” Journal of Diabetes and Its Complications, vol. 27, no. 1, pp. 34–40, 2013.
[23]
I. B. Ancheta, C. A. Battie, T. Tuason, and C. V. Ancheta, “A comparison of metabolic syndrome (MetS) risk factors in Filipino women and Filipino American women: A Pilot Study,” Ethnicity & Disease, vol. 22, no. 4, pp. 404–409, 2012.
[24]
L. P. Palaniappan, M. R. Araneta, T. L. Assimes et al., “Call to action: cardiovascular disease in Asian Americans: a science advisory from the American Heart Association,” Circulation, vol. 122, pp. 1242–1252, 2010.
[25]
M. Iannone, J. Taylor, J. Chen, et al., “Multiplexed single nucleotide polymorphism genotyping by oligonucleotide ligation and flow cytometry,” Cytometry, vol. 39, pp. 131–140, 2000.
[26]
Y. S. Kim, S. Sunwoo, H. R. Lee et al., “Determinants of non-compliance with lipid-lowering therapy in hyperlipidemic patients,” Pharmacoepidemiology and Drug Safety, vol. 11, no. 7, pp. 593–600, 2002.
[27]
A. M. Peterson and W. F. McGhan, “Pharmacoeconomic impact of non-compliance with statins,” PharmacoEconomics, vol. 23, no. 1, pp. 13–25, 2005.
[28]
K. O. Bonsu, A. Kadirvelu, and D. D. Reidpath, “Lipophilic versus hydrophilic statin therapy for heart failure: a protocol for an adjusted indirect comparison meta-analysis,” Systematic Reviews, vol. 2, article 22, 2013.
[29]
S. Ganesan and M. K. Ito, “Coenzyme Q10 ameliorates the reduction in GLUT4 transporter expression induced by simvastatin in 3T3-L1 adipocytes,” Metabolic Syndrome and Related Disorders, vol. 11, no. 4, pp. 251–255, 2013.
[30]
U. S. Food and Drug Administration, FDA Public Health Advisory for Crestor (Rosuvastatin), 2013, http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm051756.htm.
[31]
F. M. Sacks, M. A. Pfeffer, L. A. Moye et al., “The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels,” The New England Journal of Medicine, vol. 335, no. 14, pp. 1001–1009, 1996.
[32]
J. Shepherd, S. M. Cobbe, I. Ford et al., “Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia,” The New England Journal of Medicine, vol. 333, no. 20, pp. 1301–1307, 1995.
[33]
J. Shepherd, G. J. Blauw, M. B. Murphy et al., “Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial,” The Lancet, vol. 360, no. 9346, pp. 1623–1630, 2002.
[34]
M. Cushman, E. S. Cornell, P. R. Howard, E. G. Bovill, and R. P. Tracy, “Laboratory methods and quality assurance in the Cardiovascular Health Study,” Clinical Chemistry, vol. 41, no. 2, pp. 264–270, 1995.
[35]
L. P. Fried, N. O. Borhani, P. Enright et al., “The Cardiovascular Health Study: design and rationale,” Annals of Epidemiology, vol. 1, no. 3, pp. 263–276, 1991.
[36]
M. Szklo, R. Barnes, A. Folsom et al., “The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators,” American Journal of Epidemiology, vol. 129, no. 4, pp. 687–702, 1989.
[37]
A. D. White, A. R. Folsom, L. E. Chambless et al., “Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) Study: methods and initial two years' experience,” Journal of Clinical Epidemiology, vol. 49, no. 2, pp. 223–233, 1996.
[38]
P. M. Ridker, N. R. Cook, I.-M. Lee et al., “A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women,” The New England Journal of Medicine, vol. 352, no. 13, pp. 1293–1304, 2005.
[39]
J. C. Hopewell, S. Parish, R. Clarke et al., “No impact of KIF6 Genotype on vascular risk and statin response among 18,348 randomized patients in the heart protection study,” Journal of the American College of Cardiology, vol. 57, no. 20, pp. 2000–2007, 2011.
[40]
J. C. Hopewell, S. Parish, A. Offer et al., “Impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection Study,” European Heart Journal, vol. 34, pp. 982–992, 2013.
