Association between Single Nucleotide Polymorphisms of the Fibrinogen Alpha Chain (FGA) Gene and Type 2 Diabetes Mellitus in the Korean Population

  • Hwang, Joo-Yeon (Center for Genome Science, National Institute of Health) ;
  • Ryu, Min-Hyung (Center for Genome Science, National Institute of Health) ;
  • Go, Min-Jin (Center for Genome Science, National Institute of Health) ;
  • Oh, Berm-Seok (Department of Biomedical Engineering, School of Medicine, Kyung Hee University) ;
  • Cho, Yoon-Shin (Center for Genome Science, National Institute of Health)
  • Published : 2009.06.30


Fibrinogen alpha chain (FGA), a subunit of fibrinogen, might be a potential player for type 2 diabetes mellitus (T2DM), since the plasma levels of fibrinogen is known to be related to the incidence of T2DM. To elucidate the potential role of FGA in T2DM, we investigated whether FGA genetic variations are relevant in T2DM in the Korean population. Seven FGA single nucleotide polymorphisms (SNPs) were genotyped in Ansung and Ansan cohorts (474 T2DM subjects and 470 normal controls) in Korea. The association between SNPs and T2DM was determined by logistic regression analysis. Genetic relevance of SNPs to T2DM-related phenotypes was investigated by multiple linear regression analysis. Statistical analysis revealed that among seven FGA SNPs, significant associations with T2DM were observed in FGA rs2070011 (p=0.013-0.034, OR=0.72${\sim}$0.79), rs6050 (p=0.026${\sim}$0.048, OR=1.24${\sim}$1.37), and rs2070022 (p=0.016${\sim}$0.039, OR=0.70${\sim}$0.72). Two SNPs, rs2070011 and rs6050, also showed significant association with T2DM-related phenotypes such as triglyceride (p=0.005${\sim}$0.011 for rs2070011 and p=0.003${\sim}$0.008 for rs6050), total cholesterol (p=0.01 for rs2070011 and p=0.024 for rs6050) and fasting glucose (p=0.035${\sim}$0.036 for rs2070011 and p=0.048 for rs6050) in 470 normal controls. Our association study implies that FGA might be an important genetic factor in T2DM pathogenesis in the Korean population by affecting plasma lipid and glucose levels.


association;FGA;single nucleotide polymorphism (SNP);T2DM


  1. Barrett, J.C., Fry, B., Maller, J., and Daly, M.J. (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263-265
  2. Engstrom, G., Hedblad, B., Janzon, L., and Lindgarde, F. (2007). Long-term change in cholesterol in relation to inflammation- sensitive plasma proteins: a longitudinal study. Ann. Epidemiol. 17, 57-63
  3. Friedlander, Y., Kark, J.D., Sinnreich, R., Basso, F., and Humphries, S.E. (2003). Combined segregation and linkage analysis of fibrinogen variability in Israeli families: evidence for two quantitative-trait loci, one of which is linked to a functional variant (-58G > A) in the promoter of the alpha-fibrinogen gene. Ann. Hum. Genet. 67, 228-241
  4. Hotamisligil, G.S., Shargill, N.S., and Spiegelman, B.M. (1993). Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87-91
  5. Hurd, C.O., Cheetham-Wilkinson, C., and Ouwehand, W. (2000). HPA-1, -2 and -3 genotyping using the Taqman?reaction. Transfus. Med. 10, 326
  6. Kannel, W.B., D'Agostino, R.B., Wilson, P.W., Belanger, A.J., and Gagnon, D.R. (1990). Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am. Heart J. 120, 672-676
  7. Nickerson, D.A., Tobe, V.O., and Taylor, S.L. (1997). Poly-Phred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 25, 2745-275
  8. Ramensky, V., Bork, P., and Sunyaev, S. (2002). Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894-3900
  9. Rozen, S., and Skaletsky, H. (2000). Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365-386
  10. Hotamisligil, G.S., and Spiegelman, B.M. (1994). Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43, 1271-1278
  11. Mosesson, M.W., Siebenlist, K.R., and Meh, D.A. (2001). The structure and biological features of fibrinogen and fibrin. Ann. N. Y. Acad. Sci. 936, 11-30
  12. Pickup, J.C. (2006). Inflammatory markers and type 2 diabetes. Diabetes Technol. Ther. 8, 1-6
  13. Pickup, J.C., and Crook, M.A. (1998). Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41, 1241-1248
  14. Ganda, O.P., and Arkin, C.F. (1992). Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes. Diabetes Care 15, 1245-1250
  15. Hsueh, W.A., Lyon, C.J., and Quinones, M.J. (2004). Insulin resistance and the endothelium. Am. J. Med. 117, 109-117
  16. Roy, S., Overton, O., and Redman, C. (1994). Overexpression of any fibrinogen chain by Hep G2 cells specifically elevates the expression of the other two chains. J. Biol. Chem. 269, 691-695
  17. Grimble, R.F. (2002). Infammatory status and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care 5, 551-559
  18. Imperatore, G., Riccardi, G., Iovine, C., Rivellese, A.A., and Vaccaro, O. (1998). Plasma fibrinogen: a new factor of the metabolic syndrome. A population-based study. Diabetes Care 21, 649-654
  19. Jonsson, A., and Wales, J.K. (1976). Blood glycoprotein levels in diabetes mellitus. Diabetologia 12, 245-250
  20. Dunn, E.J., and Ariens, R.A. (2004). Fibrinogen and fibrin clot structure in diabetes. Herz 29, 470-479
  21. Kamath, S., and Lip, G.Y. (2003). Fibrinogen: biochemistry, epidemiology and determinants. Qjm 96, 711-729
  22. McMillan, D.E. (1989). Increased levels of acute-phase serum proteins in diabetes. Metabolism 38, 1042-1046
  23. Sakkinen, P.A., Wahl, P., Cushman, M., Lewis, M.R., and Tracy, R.P. (2000). Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am. J. Epidemiol. 152, 897-907
  24. Pauline, C., Ng, P.C., and Henikoff, S. (2002). Accounting for human polymorphisms predicted to affect protein function. Genome Res. 12, 436-446
  25. Heinrich, J., Funke, H., Rust, S., Schulte, H., Schonfeld, R., and Kohler, E. (1995). Impact of polymorphisms in the alpha- and beta-fibrinogen gene on plasma fibrinogen concentrations of coronary heart disease patients. Thromb. Res. 77, 209-215
  26. Landin, K., Tengborn, L., and Smith, U. (1990). Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J. Intern. Med. 227, 273-278
  27. Manolio, T.A., Cushman, M., Gottdiener, J.S., Dobs, A., Kuller, L.H., and Kronmal, R.A. (2004). Predictors of falling cholesterol levels in older adults: the Cardiovascular Health Study. Ann. Epidemiol. 14, 325-331
  28. Redman, C.M., and Xia, H. (2001). Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. Ann. N. Y. Acad. Sci. 936, 480-495
  29. Hamsten, A., Iselius, L., de Faire, U., and Blomback, M. (1987). Genetic and cultural inheritance of plasma fibrinogen concentration. Lancet. 2, 988-991
  30. Xu, H., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J., Sole, J., Nichols, A., Ross, J.S., Tartaglia, L.A., et al. (2003). Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821-1830
  31. Festa, A., D'Agostino, R.J., Tracy, R.P., and Haffner, S.M. (2002). Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 51, 1131-1137
  32. Spranger, J., Kroke, A., Mohlig, M., Hoffmann, K., Bergmann, M.M., and Ristow, M. (2003). Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. Technol. Ther. 52, 812-817
  33. Ernst, E., and Resch, K.L. (1993). Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann. Intern. Med. 118, 956-963
  34. Maumus, S., Marie, B., Vincent-Viry, M., Siest, G., and Visvikis-Siest, S. (2007). Analysis of the effect of multiple genetic variants of cardiovascular disease risk on insulin concentration variability in healthy adults of the STANISLAS cohort. The role of FGB -455 G/A polymorphism. Atherosclerosis 191, 369-376