Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations.
Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations.
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DOI：
10.1093/ajcn/88.4.1149
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Crott JW
中科院分区：
文献类型：
--
作者：
DeVos L;Chanson A;Liu Z;Ciappio ED;Parnell LD;Mason JB;Tucker KL;Crott JW
叶酸是一种支持核苷酸合成和生物甲基化反应的基本营养物质。叶酸状态降低会导致染色体断裂，并与包括结直肠癌在内的几种疾病有关。叶酸状况也与血浆同型半胱氨酸浓度呈负相关--同型半胱氨酸是心血管疾病的危险因素。我们试图进一步了解血浆叶酸和同型半胱氨酸浓度的遗传决定因素。由于叶酸是从尿嘧啶合成胸腺嘧啶核苷所必需的，而尿嘧啶在叶酸耗尽过程中积累并错误结合到DNA中，因此也测量了DNA尿嘧啶的含量。对991名个体进行了叶酸水解酶、叶酸多谷氨酸合成酶、γ谷氨酰水解酶、亚甲基四氢叶酸还原酶、蛋氨酸合成酶、质子偶联叶酸转运体和还原型叶酸载体等13个单核苷酸多态性的研究。MTHFR 677TT基因型与血浆同型半胱氨酸升高、血浆叶酸降低相关。MTHFR 1298A>；C和Rfc1内含子5A>；G多态与血浆同型半胱氨酸浓度显著相关。FOLH1 1561C>；T SNP与血浆叶酸浓度变化相关。MTHFR677TT等位基因与≈尿嘧啶含量降低34%相关(P=0.045)，而GGH-124T>；G等位基因G等位基因与尿嘧啶含量逐渐升高相关(P=0.022)。由于尿嘧啶在DNA中的积聚会导致染色体断裂和突变，我们认为，对于MTHFR C677T，GGH-124T和GT；G SNP可能调节致癌风险，因此值得进一步关注。
Folate is an essential nutrient that supports nucleotide synthesis and biological methylation reactions. Diminished folate status results in chromosome breakage and is associated with several diseases, including colorectal cancer. Folate status is also inversely related to plasma homocysteine concentrations—a risk factor for cardiovascular disease. We sought to gain further understanding of the genetic determinants of plasma folate and homocysteine concentrations. Because folate is required for the synthesis of thymidine from uracil, the latter accumulating and being misincorporated into DNA during folate depletion, the DNA uracil content was also measured. Thirteen single nucleotide polymorphisms (SNPs) in genes involved in folate uptake and metabolism, including folate hydrolase (FOLH1), folate polyglutamate synthase (FPGS), γ-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC1), were studied in a cohort of 991 individuals. The MTHFR 677TT genotype was associated with increased plasma homocysteine and decreased plasma folate. MTHFR 1298A>C and RFC1 intron 5A>G polymorphisms were associated with significantly altered plasma homocysteine concentrations. The FOLH1 1561C>T SNP was associated with altered plasma folate concentrations. The MTHFR 677TT genotype was associated with a ≈34% lower DNA uracil content (P = 0.045), whereas the G allele of the GGH – 124T>G SNP was associated with a stepwise increase in DNA uracil content (P = 0.022). Because the accumulation of uracil in DNA induces chromosome breaks, mutagenic lesions, we suggest that, as for MTHFR C677T, the GGH – 124 T>G SNP may modulate the risk of carcinogenesis and therefore warrants further attention.
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影响因子：
4.8
作者：
Duthie, SJ;Hawdon, A
通讯作者：
Hawdon, A
DOI：
10.1097/00008571-200411000-00004
发表时间：
2004-11-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Dervieux, T;Kremer, J;Furst, DE
通讯作者：
Furst, DE
影响因子：
120.7
作者：
Cole, Bernard F.;Baron, John A.;Greenberg, E. Robert
通讯作者：
Greenberg, E. Robert
影响因子：
7.1
作者：
Devlin, AM;Clarke, R;Halsted, CH
通讯作者：
Halsted, CH
影响因子：
3.5
作者：
Chave, KJ;Ryan, TJ;Galivan, J
通讯作者：
Galivan, J