Genes and Genomics

The Genetics Society of Korea (한국유전학회)
권호 표지

Polymorphisms of Thymidylate Synthase Enhancer Region (TSER) and Upstream Stimulatory Factor 1 (USF1 306G > A) Genes are Associated with Plasma Homocysteine Level and Susceptibility to Ischemic Stroke in a Korean Population

Lee, Jae-Ho;Kim, Ok-Joon;Kim, Hyun-Sook;Oh, Seung-Hun;Jeung, Min-Gull;Kwon, Young-Do;Kim, Nam-Keun

  • Published : 20081200
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Abstract

The thymidylate synthase enhancer region ( TSER) gene promoter has a variable tandem repeat polymorphism containing an upstream stimulatory factor (USF) family E-box binding site that affects expression of the enzyme. Also, the tandem repeat polymorphism of the TS promoter is known to affect plasma homocysteine (phcy) level. Upstream stimulatory factor 1 (USF1) is a transcription factor controlling expression of several genes involved in lipid and glucose homeostasis. We therefore investigated the influence of the TSER and the USF1 gene polymorphisms on susceptibility to ischemic stroke and phcy levels in a Korean population. The TSER and USF1 306G > A genotypes in 234 ischemic stroke patients and 203 age and sex-matched controls subjects were identified by PCR. Plasma hcy levels were measured by fluorescent polarizing immunoassay. Frequencies of USF1 306G > A genotypes and TSER variants were not significantly different between the controls and patients with ischemic stroke. The stroke patients, however, had significantly higher phcy levels with the TSER 2R3R+2R2R genotype than the control group. Also, phcy levels differed according to combined TSER and USF1 306G > A genotypes. The combined TSER 2R3R+2R2R and USF1 306GA+AA genotypes and the phcy concentration of the patient group were also higher than those of the control group ( p = 0.027). In addition, the phcy concentration of the combined TSER 2R3R+2R2R and USF1 306AA genotype was higher than that of the combined TSER 3R3R and USF1 306GG genotype ( p= 0.004) in the patient group. Our results suggest that TSER and USF1 306G > A polymorphisms may influence total homocysteine levels, leading to an increased risk of ischemic stroke.

Keywords

References

  1. Brown KS, Kluijtmans LA, Young IS, McNulty H, Mitchell LE and Yarnell JW (2004) The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects. Hum. Genet. 114: 182-185 https://doi.org/10.1007/s00439-003-1039-9
  2. Casado M, Vallet VS, Kahn A and Vaulont S (1999) Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J. Biol. Chem. 274: 2009-2013 https://doi.org/10.1074/jbc.274.4.2009
  3. Choi BO, Kim NK, Kim SH, Kang MS, Lee S, Ahn JY, Kim OJ, Kim S and Oh D (2003) Homozygous C677T mutation in the MTHFR gene as an independent risk factor for multiple small-artery occlusions. Thromb. Res. 111: 39-44 https://doi.org/10.1016/j.thromres.2003.08.022
  4. Choquette AC, Bouchard L, Houde A, Bouchard C, Perusse L and Vohl MC (2007) Associations between USF1 gene variants and cardiovascular risk factors in the Quebec Family Study. Clinical Genet. 71: 245-253 https://doi.org/10.1111/j.1399-0004.2007.00755.x
  5. Danenberg PV (1977) Thymidylate synthetase: A target enzyme in cancer chemotherapy. Biochim. Biophys. Acta. 473: 73-92
  6. Gibson F, Hercberg S and Froguel P (2005) Common polymorphisms in the USF1 gene are not associated with type 2 diabetes in French Caucasians. Diabetes 54: 3040-3042 https://doi.org/10.2337/diabetes.54.10.3040
  7. Gregor PD, Sawadogo M and Roeder RG (1990) The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 4: 1730-1740 https://doi.org/10.1101/gad.4.10.1730
  8. Horie N, Aiba H, Oguro K, Hojo H and Takeishi K (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct. Funct. 20: 191-197 https://doi.org/10.1247/csf.20.191
  9. Horie N, Chimoto M, Nozawa R and Takeishi K (1993) Characterization of regulatory sequences and nuclear factors that function in cooperation with the promoter of the human thymidylate synthase gene. Biochim. Biophys. Acta. 1216: 409-416 https://doi.org/10.1016/0167-4781(93)90008-2
  10. Iynedjian PB (1998) Identification of upstream stimulatory factor as transcriptional activator of the liver promoter of the glucokinase gene. Biochem. J. 333: 705-712 https://doi.org/10.1042/bj3330705
  11. Kawakami K, Omura K, Kanehira E and Watanabe Y (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 19: 3249-3252
  12. Lee SK, Kim HJ, Kim BJ, Jo YS, Park KS, Baik HW, Hyun SH, Lee JC and Kim SA (2008) Body mass index is associated with USF1 haplotype in Korean premenopausal women. J. Korean Med. Sci. 23: 83-88 https://doi.org/10.3346/jkms.2008.23.1.83
  13. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ and Ladner RD (2003) A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 63: 2898- 2904
  14. Moore ML, Park EA and McMillin JB (2003) Upstream stimulatory factor represses the induction of carnitine palmitoyltransferase-Ib expression by PGC-1. J. Biol. Chem. 278: 17263-17268 https://doi.org/10.1074/jbc.M210486200
  15. Ng MC, Miyake K, So WY, Poon EW, Lam VK, Li JK, Cox NJ, Bell GI and Chan JC (2005) The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population. Diabetologia 48: 2018-2024 https://doi.org/10.1007/s00125-005-1914-0
  16. Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M, Duan XJ, Soro-Paavonen A, Naukkarinen J, Saarela J, Laakso M, Ehnholm C, Taskinen M-R and Peltonen L (2004) Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat. Genet. 36: 371- 376 https://doi.org/10.1038/ng1320
  17. Putt W, Palmen J, Nicaud V, Tregouet DA, Tahri- Daizadeh N, Flavell DM, Humphries SE and Talmud PJ (2004) Variation in USF1 shows haplotype effects, gene: gene and gene: environment associations with glucose and lipid parameters in the European Atherosclerosis Research Study II. Hum. Mol. Genet. 13: 1587-1597 https://doi.org/10.1093/hmg/ddh168
  18. Qian J, Kay EN, Towle HC and Olson LK (1999) Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic B-cells. Biochem. J. 341: 315-322 https://doi.org/10.1042/0264-6021:3410315
  19. Ribeiro A, Pastier D, Kardassis D, Chambaz J and Cardot P (1999) Cooperative binding of upstream stimulatory factor and hepatic nuclear factor 4 drives the transcription of the human apolipoprotein A-II gene. J. Biol. Chem. 274: 1216-1225 https://doi.org/10.1074/jbc.274.3.1216
  20. Salero E, Gimenez C and Zafra F (2003) Identification of a non-canonical E-box motif as a regulatory element in the proximal promoter region of the apolipoprotein E gene. Biochem. J. 370: 979-986 https://doi.org/10.1042/BJ20021142
  21. Shoulders CC and Naoumova RP (2004) USF1 implicated in the aetiology of familial combined hyperlipidaemia and the metabolic syndrome Trends Mol. Med. 10: 362-365
  22. te Poele-Pothoff MT, van den Berg M, Franken DG, Boers GH, Jakobs C, de Kroon IF, Eskes TK, Trijbels JM and Blom HJ (1995) Three different methods for the determination of total homocysteine in plasma. Ann. Clin. Biochem. 32: 218-220 https://doi.org/10.1177/000456329503200218
  23. Trinh BN, Ong CN, Coetzee GA, Yu MC and Laird PW (2002) Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels. Hum. Genet. 111: 299-302 https://doi.org/10.1007/s00439-002-0779-2
  24. Worley K, Umayam L and Mullikin J (2003) Human Genome Sequencing Center, Baylor College of Medicine, NIH chr1.NT_004668.15_7465161, http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs= 2073653
  25. Yim DJ, Han JH, Ji SI, Hwang SG, Oh D and Kim NK (2005) 5' and 3' unreanslated region polymorphisms of thymidylate synthase gene in Korean population. Korean J. Genetics 27: 161-168