与健康绝经前女性同型半胱氨酸浓度及叶酸衍生物分布相关的遗传和生活方式变量。
Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women.
作者信息
Summers Carolyn M, Mitchell Laura E, Stanislawska-Sachadyn Anna, Baido Shirley F, Blair Ian A, Von Feldt Joan M, Whitehead Alexander S
机构信息
Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
出版信息
Birth Defects Res A Clin Mol Teratol. 2010 Aug;88(8):679-88. doi: 10.1002/bdra.20683.
BACKGROUND
Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype.
METHODS
The study comprised 26 Caucasian and 23 African-American premenopausal women. Subjects gave fasting blood samples for biochemical phenotyping and genotyping. Total Hcy (tHcy) and both plasma and red blood cell (RBC) folate derivatives (i.e. tetrahydrofolate [THF], 5-methylTHF [5-MTHF], and 5,10-methenylTHF [5,10-MTHF]) were measured using stable isotope dilution liquid chromatography, multiple reaction monitoring, and mass spectrometry. Eleven polymorphisms from nine folate/Hcy pathway genes were genotyped. Tests of association between genetic, lifestyle, and biochemical variables were applied.
RESULTS
In African American women, tHcy concentrations were associated (p < 0.05) with total RBC folate, RBC 5-MTHF, B(12), and polymorphisms in methionine synthase (MTR) and thymidylate synthase (TYMS). In Caucasian women, tHcy concentrations were not associated with total folate levels, but were associated (p < 0.05) with RBC THF, ratios of RBC 5-MTHF:THF, and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and MTR. In African Americans, folate derivative levels were associated with smoking, B(12), and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B(12), and polymorphisms in MTHFR, TYMS, and RFC1.
CONCLUSIONS
Polymorphisms in the folate/Hcy pathway are associated with tHcy and folate derivative levels. In African American and Caucasian women, different factors are associated with folate/Hcy phenotypes and may contribute to race-specific differences in the risks of a range of pregnancy-related pathologies.
背景
低叶酸和高同型半胱氨酸（Hcy）浓度与诸如脊柱裂等妊娠相关疾病有关。叶酸/Hcy代谢酶的多态性可能导致这种潜在的致病生化表型。
方法
该研究纳入了26名白种人和23名非裔美国绝经前女性。受试者提供空腹血样用于生化表型分析和基因分型。使用稳定同位素稀释液相色谱、多反应监测和质谱法测量总Hcy（tHcy）以及血浆和红细胞（RBC）叶酸衍生物（即四氢叶酸[THF]、5-甲基四氢叶酸[5-MTHF]和5,10-亚甲基四氢叶酸[5,10-MTHF]）。对来自9个叶酸/Hcy途径基因的11种多态性进行基因分型。应用了基因、生活方式和生化变量之间的关联测试。
结果
在非裔美国女性中，tHcy浓度与总RBC叶酸、RBC 5-MTHF、维生素B12以及甲硫氨酸合成酶（MTR）和胸苷酸合成酶（TYMS）的多态性相关（p < 0.05）。在白种女性中，tHcy浓度与总叶酸水平无关，但与RBC THF、RBC 5-MTHF:THF比值以及5,10-亚甲基四氢叶酸还原酶（MTHFR）和MTR的多态性相关（p < 0.05）。在非裔美国人中，叶酸衍生物水平与吸烟、维生素B12以及MTR、TYMS、甲硫氨酸合成酶还原酶（MTRR）和还原型叶酸载体1（RFC1）的多态性相关。在白种人中，叶酸衍生物水平与维生素使用、维生素B12以及MTHFR、TYMS和RFC1的多态性相关。
结论
叶酸/Hcy途径的多态性与tHcy和叶酸衍生物水平相关。在非裔美国女性和白种女性中，不同因素与叶酸/Hcy表型相关，可能导致一系列妊娠相关疾病风险的种族特异性差异。
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