Objective. Previous studies have confirmed that GCKR rs780093 polymorphism is associated with triglyceride (TG), a known risk factor of coronary heart disease (CHD). The goal of our study is to explore the association of GCKR rs780093 polymorphism with CHD in Han Chinese population. Methods and Results. A total of 568 CHD cases and 494 non-CHD controls were enrolled in the current case-control study. Genotyping was done using melting temperature shift (Tm-shift) approach. Our results also showed that GCKR rs780093 polymorphism was significantly associated with TG level ( ). Although there was no significant association between cases and controls ( ), a breakdown analysis by age yielded a significant association of GCKR rs780093 polymorphism with CHD in individuals aged 65 and older (genotype: ; df？=？2; ; allele: ; df？=？1; ). Conclusion. Our findings confirmed the contribution of GCKR rs780093 polymorphism to TG metabolism and demonstrated GCKR rs780093 as a risk factor of CHD in individuals aged 65 and older. 1. Introduction Coronary heart disease (CHD) is one of the leading causes of morbidity and death in the developed countries, and its prevalence is increasing rapidly in the developing countries [1]. CHD has become a major health burden in the world [2]. CHD is a type of complex disease caused by both environmental and genetic factors, as well as interactions among these factors [3]. CHD may lead to severe events, including sudden cardiac death (SCD) or acute myocardial infarction (AMI). CHD is heritable [4–6]. Although genetic factors are estimated to account for about 30–60% of the CHD risk [7, 8], the pathogenesis of CHD is still not fully understood. Aberrant levels of blood lipids and glucose are risk factors of CHD [9, 10]. Elevated triglyceride (TG) levels were shown to be associated with increased risk of CHD and other cardiovascular events [11]. The GCKR locus is the strongest completely novel locus implicated in TG metabolism [12]. Interestingly, GCKR is also associated with the risk of cardiovascular disease [13]. Located on chromosome 2p23, GCKR gene consists of 19 exons and encodes a protein comprising 625 amino acids [14]. GCKR is a susceptibility gene for type 2 diabetes mellitus [15]. GCKR gene product inhibits glucokinase in liver and pancreatic islet cells by binding noncovalently to form an inactive complex with glucokinase and thus plays a pivotal role in glucose homeostasis [16, 17]. Recent genome-wide association studies (GWAS) have identified that GCKR is important for modulating serum TG [18] or fasting blood glucose levels.
References
[1]
“WHO publishes definitive atlas on global heart disease and stroke epidemic,” Indian Journal of Medical Sciences, vol. 58, pp. 405–406, 2004.
[2]
V. L. Roger, A. S. Go, D. M. Lloyd-Jones et al., “Executive summary: heart disease and stroke statistics-2012 update: a report from the American heart association,” Circulation, vol. 125, no. 1, pp. 188–197, 2012.
[3]
S. Maouche and H. Schunkert, “Strategies beyond genome-wide association studies for atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 2, pp. 170–181, 2012.
[4]
I. J. Kullo and K. Ding, “Mechanisms of disease: the genetic basis of coronary heart disease,” Nature Clinical Practice Cardiovascular Medicine, vol. 4, no. 10, pp. 558–569, 2007.
[5]
B. Mayer, J. Erdmann, and H. Schunkert, “Genetics and heritability of coronary artery disease and myocardial infarction,” Clinical Research in Cardiology, vol. 96, no. 1, pp. 1–7, 2007.
[6]
G. Pilia, W. Chen, A. Scuteri et al., “Heritability of cardiovascular and personality traits in 6,148 Sardinians,” PLoS Genetics, vol. 2, no. 8, article e132, 2006.
[7]
S. Zdravkovic, A. Wienke, N. L. Pedersen, M. E. Marenberg, A. I. Yashin, and U. de Faire, “Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins,” Journal of Internal Medicine, vol. 252, no. 3, pp. 247–254, 2002.
[8]
M. E. Marenberg, N. Risch, L. F. Berkman, B. Floderus, and U. De Faire, “Genetic susceptibility to death from coronary heart disease in a study of twins,” The New England Journal of Medicine, vol. 330, no. 15, pp. 1041–1046, 1994.
[9]
J. I. Cleeman, “Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III),” Journal of the American Medical Association, vol. 285, no. 19, pp. 2486–2497, 2001.
[10]
K. G. Alberti and P. Z. Zimmet, “Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation,” Diabetic Medicine, vol. 15, pp. 539–553, 1998.
[11]
A. Patel, “Serum triglycerides as a risk factor for cardiovascular diseases in the Asia-Pacific region,” Circulation, vol. 110, no. 17, pp. 2678–2686, 2004.
[12]
R. Saxena, B. F. Voight, V. Lyssenko et al., “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels,” Science, vol. 316, no. 5829, pp. 1331–1336, 2007.
[13]
C. T. Johansen, S. Kathiresan, and R. A. Hegele, “Genetic determinants of plasma triglycerides,” Journal of Lipid Research, vol. 52, no. 2, pp. 189–206, 2011.
[14]
E. van Schaftingen, “A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate,” European Journal of Biochemistry, vol. 179, no. 1, pp. 179–184, 1989.
[15]
A. T. Kraja, D. Vaidya, J. S. Pankow et al., “A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium,” Diabetes, vol. 60, no. 4, pp. 1329–1339, 2011.
[16]
J. Grimsby, J. W. Coffey, M. T. Dvorozniak et al., “Characterization of glucokinase regulatory protein-deficient mice,” The Journal of Biological Chemistry, vol. 275, no. 11, pp. 7826–7831, 2000.
[17]
D. Farrelly, K. S. Brown, A. Tieman et al., “Mice mutant for glucokinase regulatory protein exhibit decreased liver glucokinase: a sequestration mechanism in metabolic regulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 25, pp. 14511–14516, 1999.
[18]
J. Dupuis, C. Langenberg, I. Prokopenko, et al., “New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk,” Nature Genetics, vol. 42, pp. 105–116, 2010.
[19]
K. Shaye, T. Amir, S. Shlomo, and S. Yechezkel, “Fasting glucose levels within the high normal range predict cardiovascular outcome,” American Heart Journal, vol. 164, pp. 111–116, 2012.
[20]
M. Li, B. McCulloch, and R. McDermott, “Metabolic syndrome and incident coronary heart disease in Australian indigenous populations,” Obesity, vol. 20, pp. 1308–1312, 2012.
[21]
R. M. O'Doherty, D. L. Lehman, S. Télémaque-Potts, and C. B. Newgard, “Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia,” Diabetes, vol. 48, no. 10, pp. 2022–2027, 1999.
[22]
T. Ferre, E. Riu, F. Bosch, and A. Valera, “Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver,” The FASEB Journal, vol. 10, no. 10, pp. 1213–1218, 1996.
[23]
Z. C. J. Higgs, D. A. L. Macafee, B. D. Braithwaite, and C. A. Maxwell-Armstrong, “The Seldinger technique: 50 years on,” The Lancet, vol. 366, no. 9494, pp. 1407–1409, 2005.
[24]
S. Germer and R. Higuchi, “Single-tube genotyping without oligonucleotide probes,” Genome Research, vol. 9, no. 1, pp. 72–78, 1999.
[25]
L. Excoffier and H. E. L. Lischer, “Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows,” Molecular Ecology Resources, vol. 10, no. 3, pp. 564–567, 2010.
[26]
P. C. Sham and D. Curtis, “Monte Carlo tests for associations between disease and alleles at highly polymorphic loci,” Annals of Human Genetics, vol. 59, no. 1, pp. 97–105, 1995.
[27]
W. D. Dupont and W. D. Plummer Jr., “Power and sample size calculations. A review and computer program,” Controlled Clinical Trials, vol. 11, no. 2, pp. 116–128, 1990.
[28]
M. A. Williams, J. L. Fleg, P. A. Ades et al., “Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ≥75 years of age): an american heart association scientific statement from the council on clinical cardiology subcommittee on exercise, cardiac rehabilitation, and prevention,” Circulation, vol. 105, no. 14, pp. 1735–1743, 2002.
[29]
S. Kathiresan, A. K. Manning, S. Demissie et al., “A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study,” BMC Medical Genetics, vol. 8, supplement 1, article S17, 2007.
[30]
E. Warensj？, J. Sundstr？m, B. Vessby, T. Cederholm, and U. Risérus, “Markers of dietary fat quality and fatty acid desaturation as predictors of total and cardiovascular mortality: a population-based prospective study,” American Journal of Clinical Nutrition, vol. 88, no. 1, pp. 203–209, 2008.
[31]
J. A. Simon, M. L. Hodgkins, W. S. Browner, J. M. Neuhaus, J. T. Bernert Jr., and S. B. Hulley, “Serum fatty acids and the risk of coronary heart disease,” American Journal of Epidemiology, vol. 142, no. 5, pp. 469–476, 1995.
[32]
J. H. Wu, R. N. Lemaitre, A. Manichaikul, et al., “Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium,” Circulation, vol. 6, pp. 171–183, 2013.
[33]
S. Kathiresan, C. J. Willer, G. M. Peloso et al., “Common variants at 30 loci contribute to polygenic dyslipidemia,” Nature Genetics, vol. 41, no. 1, pp. 56–65, 2009.
[34]
M. E. Keebler, R. C. Deo, A. Surti et al., “Fine-mapping in African Americans of 8 recently discovered genetic loci for plasma lipids: the Jackson Heart Study,” Circulation, vol. 3, no. 4, pp. 358–364, 2010.
[35]
M. Orho-Melander, O. Melander, C. Guiducci et al., “Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations,” Diabetes, vol. 57, no. 11, pp. 3112–3121, 2008.
[36]
N. L. Beer, N. D. Tribble, L. J. McCulloch et al., “The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver,” Human Molecular Genetics, vol. 18, no. 21, pp. 4081–4088, 2009.
[37]
C. Ward-Caviness, C. Haynes, C. Blach, E. Dowdy, S. G. Gregory, S. H. Shah, et al., “Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort,” Human Genetics, vol. 132, no. 12, pp. 1371–1382, 2013.
