Novel Promoter Polymorphism in RUNX2 Is Associated with Serum Triglyceride Level

  • Shin, Hyoung Doo (Department of Life Science, Sogang University) ;
  • Jeon, Jae-Pil (National Genome Research Institute, National Institute of Health) ;
  • Park, Byung Lae (Department of Genetic Epidemiology, SNP Genetics) ;
  • Bae, Joon Seol (Department of Genetic Epidemiology, SNP Genetics) ;
  • Nam, Hye-Young (National Genome Research Institute, National Institute of Health) ;
  • Shim, Sung-Mi (National Genome Research Institute, National Institute of Health) ;
  • Park, Kyong Soo (Genome Research Center for Diabetes and Endocrine Disease, Clinical Research Institute, Seoul National University Hospital, Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Han, Bok-Ghee (National Genome Research Institute, National Institute of Health)
  • Received : 2008.04.14
  • Accepted : 2008.07.09
  • Published : 2008.11.30

Abstract

Much research evidence supports the hypothesis that chronic, low-grade inflammation related to innate immunity may play an important role in the pathophysiology of type 2 diabetes mellitus (T2DM). Runt-related transcription factor 2 (RUNX2; MIM# 600211) acts as a scaffold that controls the integration, organization, and assembly of nucleic acids. To examine whether the novel promoter variant in RUNX2 is associated with the risk of T2DM and related phenotypes, RUNX2-742G > T was genotyped in 378 T2DM patients and 382 normal controls recruited in the Korean T2DM Study. Statistical analysis revealed that RUNX2-742G > T was associated with serum triglyceride level (TG) in nondiabetic controls, although it was not associated with the risk of T2DM. Individuals who carry T/T, T/G, and G/G genotypes had the highest ($2.061{\pm}0.20$), intermediate ($2.01{\pm}0.19$), and the lowest ($1.97{\pm}0.18$) levels of log [TG (mmol/l)] (P = 0.007), respectively. Our data on this important variant of RUNX2 suggest that lipid metabolism might be affected by genetic polymorphisms in the promoter region.

Keywords

polymorphism;promoter;RUNX2;triglyceride;type 2 diabetes mellitus

Acknowledgement

Supported by : National Institute of Health, Ministry of Health and Welfare

References

  1. Committee, E. (1997). Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20,1183-1197 https://doi.org/10.2337/diacare.20.7.1183
  2. Livak, K.J. (1999). Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal. 14, 143-149 https://doi.org/10.1016/S1050-3862(98)00019-9
  3. Min, W.K., Lim, H., Lee, Y.P., Sung, S.K., Kim, B.D., and Kim, S. (2008). Identification of a third haplotype of the sequence linked to the Restorer-of-fertility (Rf) gene and its implications for malesterility phenotypes in peppers (Capsicum annuum L.). Mol. Cells 25, 20-29
  4. Goseki-Sone, M., Orimo, H., Watanabe, A., Hamatani, R., Yokozeki, M., Ohyama, K., Kuroda, T., Watanabe, H., Miyazaki, H., Shimada, T., et al. (2001). Identification of a novel frameshift mutation (383insT) in the RUNX2 (PEBP2 alpha/CBFA1/AML3) gene in a Japanese patient with cleidocranial dysplasia. J. Bone Miner. Metab. 19, 263-266 https://doi.org/10.1007/s007740170030
  5. Otto, F., Kanegane, H., and Mundlos, S. (2002). Mutations in the RUNX2 gene in patients with cleidocranial dysplasia. Hum. Mutat. 19, 209-216 https://doi.org/10.1002/humu.10043
  6. Doecke, J.D., Day, C.J., Stephens, A.S., Carter, S.L., van Daal, A., Kotowicz, M.A., Nicholson, G.C., and Morrison, N.A. (2006). Association of functionally different RUNX2 P2 promoter alleles with BMD. J. Bone Miner. Res. 21, 265-273 https://doi.org/10.1359/JBMR.051013
  7. Ermakov, S., Malkin, I., Kobyliansky, E., and Livshits, G. (2006). Variation in femoral length is associated with polymorphisms in RUNX2 gene. Bone 38, 199-205 https://doi.org/10.1016/j.bone.2005.08.008
  8. Vaughan, T., Pasco, J.A., Kotowicz, M.A., Nicholson, G.C., and Morrison, N.A. (2002). Alleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fracture. J. Bone Miner. Res. 17, 1527-1534 https://doi.org/10.1359/jbmr.2002.17.8.1527
  9. Terry, A., Kilbey, A., Vaillant, F., Stewart, M., Jenkins, A., Cameron, E., and Neil, J.C. (2004). Conservation and expression of an alternative 3' exon of Runx2 encoding a novel proline-rich Cterminal domain. Gene 336, 115-125 https://doi.org/10.1016/j.gene.2004.04.015
  10. Mundlos, S., Otto, F., Mundlos, C., Mulliken, J.B., Aylsworth, A.S., Albright, S., Lindhout, D., Cole, W.G., Henn, W., Knoll, J.H., et al. (1997). Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773-779 https://doi.org/10.1016/S0092-8674(00)80260-3
  11. Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., and Turner, R.C. (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412-419 https://doi.org/10.1007/BF00280883
  12. Stein, G.S., Lian, J. B., van Wijnen, A.J., Stein, J.L., Montecino, M., Javed, A., Zaidi, S.K., Young, D.W., Choi, J.Y., and Pockwinse, S.M. (2004). Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene 23, 4315-4329 https://doi.org/10.1038/sj.onc.1207676
  13. Young, D.W., Hassan, M.Q., Yang, X.Q., Galindo, M., Javed, A., Zaidi, S.K., Furcinitti, P., Lapointe, D., Montecino, M., Lian, J.B., et al. (2007). Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2. Proc. Natl. Acad. Sci. USA 104, 3189-3194