Abstract
Substantial evidence suggests that a low folate/high homocysteine phenotype is pathogenic. We analyzed the impact of the thymidylate synthase (TYMS) 3′UTR ins/del polymorphism on folate and homocysteine levels and assessed the relationship between the TYMS 3′UTR ins/del polymorphism and key genetic and lifestyle variables. Among non-smokers only, the TYMS 3′UTR ins/del polymorphism was significantly associated with red blood cell folate (RBC folate; P=0.002) and homocysteine (P=0.03) concentrations. Median RBC folate concentration was much higher for TYMS 3′UTR del/del subjects (434 μg/l) compared with either ins/ins (282 μg/l) or ins/del (298 μg/l) subjects. The median homocysteine concentration for del/del homozygotes was considerably lower compared with either ins/ins homozygotes or ins/del heterozygotes. A possible additive effect for the impact of the TYMS 3′UTR del/del and MTHFR 677CC genotypes on RBC folate concentration was also observed. Our findings suggest that the TYMS 3′UTR del/del genotype is a significant determinant of elevated RBC folate concentration in a non-smoking population of northwestern European adults and that this genotype confers protection against diseases for which a low folate/high homocysteine phenotype appears to be an etiologic component.
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References
Boreham CA, Twisk J, Savage MJ, Cran GW, Strain JJ (1997) Physical activity, sports participation, and risk factors in adolescents. Med Sci Sports Exerc 29:788–793
Boreham C, Twisk J, Mechelen W van, Savage M, Strain J, Cran G (1999) Relationships between the development of biological risk factors for coronary heart disease and lifestyle parameters during adolescence: the Northern Ireland Young Hearts Project. Public Health 113:7–12
Brown KS, Kluijtmans LA, Young IS, McNulty H, Mitchell LE, Yarnell JW, Woodside JV, Boreham CA, McMaster D, Murray L, Strain JJ, Whitehead AS (2004a) The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects. Hum Genet 114:182–185
Brown KS, Kluijtmans LA, Young IS, Murray L, McMaster D, Woodside J, Yarnell JW, Boreham CA, McNulty H, Strain JJ, McPartlin J, Scott JM, Michell LE, Whitehead AS (2004b) The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine. Atherosclerosis 174:315–322
Chu J, Dolnick BJ (2002) Natural antisense (rTSalpha) RNA induces site-specific cleavage of thymidylate synthase mRNA. Biochim Biophys Acta 1587:183–193
Czeizel A, Dudas I (1992) Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Eng J Med 327:1832–1835
De Bree A, Verschuren WM, Kromhout D, Kluijtmans LA, Blom HJ (2002) Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacol Rev 54:599–618
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, Heijer M den, Kluijtmans LA, van den Heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113
Hardin J, Hilbe J (2001) Generalized linear models and extensions. Stata, Texas, USA
Harmon DL, Woodside JV, Yarnell JW, McMaster D, Young IS, McCrum EE, Gey KF, Whitehead AS, Evans AE (1996) The common ‘thermolabile’ variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM 89:571–577
Horie N, Aiba H, Oguro K, Hojo H, 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
Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93:7–9
Kawakami K, Omura K, Kanehira E, 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
Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J, Omura K, Watanabe G, Danenberg PV (2001) Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 7:4096–4101
Kluijtmans LA, Young IS, Boreham CA, Murray L, McMaster D, McNulty H, Strain JJ, McPartlin J, Scott JM, Whitehead AS (2003) Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood 101:2483–2488
Liu J, Schmitz JC, Lin X, Tai N, Yan W, Farrell M, Baillly M, Chen T, Chu E (2002) Thymidylate synthase as a translational regulator of cellular gene expression. Biochim Biophys Acta 1587:174–182
Lucock M (2000) Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab 71:121–138
Mansoor MA, Kristensen O, Hervig T, Drablos PA, Stakkestad JA, Woie L, Hetland O, Osland A (1997) Low concentrations of folate in serum and erythrocytes of smokers: methionine loading decreases folate concentrations in serum of smokers and nonsmokers. Clin Chem 43:2192–2194
Mills JL, McPartlin JM, Kirke PM, Lee YJ, Conley MR, Weir DG, Scott JM (1995) Homocysteine metabolism in pregnancies complicated by neural tube defects. Lancet 345:149–151
Molloy AM, Scott JM (1997) Microbiological assay for serum, plasma, and red cell folate using cryopreserved, microtiter plate method. Methods Enzymol 281:43–53
Molloy AM, Dalys S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG, Scott JM (1997) Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349:1591–1593
MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338:131–137
Refsum H, Ueland PM, Nygard O, Vollset SE (1998) Homocysteine and cardiovascular disease. Annu Rev Med 49:31–62
Trinh BN, Ong CN, Coetzee GA, Yu MC, Laird PW (2002) Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels. Hum Genet 111:299–302
Ubbink JB, Hayward Vermaak WJ, Bissbort S (1991) Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 565:441–446
Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD (2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 9:1381–1385
Ulrich CM, Bigler J, Bostick R, Fosdick L, Potter JD (2002) Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Res 62:3361–3364
Volcik KA, Shaw GM, Zhu H, Lammer EJ, Laurent C, Finnell RH (2003) Associations between polymorphisms within the thymidylate synthase gene and spina bifida. Birth Defects Res Part A Clin Mol Teratol 67:924–928
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This work was supported by NIH grant AR47663 and in part by NIH grants HD39195 and HD39081. Support for the Young Hearts Project was provided by the British Heart Foundation and the Wellcome Trust.
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Kealey, C., Brown, K.S., Woodside, J.V. et al. A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations. Hum Genet 116, 347–353 (2005). https://doi.org/10.1007/s00439-004-1243-2
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DOI: https://doi.org/10.1007/s00439-004-1243-2