Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia.
Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia.
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DOI：
10.1371/journal.pone.0016681
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发表时间：
2011-01-31
期刊：
影响因子：
3.7
通讯作者：
Strauss JF 3rd
中科院分区：
文献类型：
--
作者：
Hill LD;York TP;Kusanovic JP;Gomez R;Eaves LJ;Romero R;Strauss JF 3rd
先兆子痫是围产期发病率和死亡率的主要原因。这种疾病被认为是多因素的起源，多个基因，环境和社会因素，有助于疾病。一种提出的机制是胎盘缺氧驱动的血管生成和抗血管生成因子的失衡，导致内皮细胞功能障碍。儿茶酚-O-甲基转移酶（Comt）缺陷的妊娠小鼠具有先兆子痫表型，该表型可被外源性2-甲氧基雌二醇（2-ME）逆转，2-ME是COMT产生的雌激素代谢产物。2-ME抑制缺氧诱导因子1α，一种介导缺氧反应的转录因子。COMT已被证明与亚甲基四氢叶酸还原酶（MTHFR）相互作用，后者调节COMT辅因子S-腺苷甲硫氨酸（SAM）的可用性。MTHFR的变化与先兆子痫有关。通过解释这两个基因中的等位基因变异，COMT的作用已被阐明。COMT等位基因变异与酶活性相关，四种单核苷酸多态性（SNP）（rs6269、rs 4633、rs 4680和rs 4818）形成表征COMT活性的单倍型。我们检测了1103例智利母胎二联体中COMT单倍型和MTHFR 677 C→T多态性与先兆子痫风险之间的关联。母体ACCG COMT单倍型与先兆子痫风险降低相关（P = 0.004），并且风险从低活性单倍型到高活性单倍型线性增加（P = 0.003）。 在胎儿样本中，我们发现胎儿ATCA COMT单倍型和胎儿MTHFR次要“T”等位基因相互作用增加先兆子痫风险（p = 0.022）。 我们发现，单独携带胎儿风险等位基因（P = 0.052）和胎儿风险等位基因与母体平衡等位基因（P<0.001）的先兆子痫患者数量高于预期。 在对照组中未观察到这种非随机分布（分别为P= 0.341和P =0.219）。 我们的研究结果证明了母体和胎儿COMT在先兆子痫中的作用，并强调了在MTHFR中纳入等位基因变异的重要性。
Preeclampsia is a leading cause of perinatal morbidity and mortality. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease. One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction. Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2-ME inhibits Hypoxia Inducible Factor 1α, a transcription factor mediating hypoxic responses. COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor. Variations in MTHFR have been associated with preeclampsia. By accounting for allelic variation in both genes, the role of COMT has been clarified. COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity. We tested for association between COMT haplotypes and the MTHFR 677 C→T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0.004), and that risk increased linearly from low to high activity haplotypes (P = 0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor “T” allele interact to increase preeclampsia risk (p = 0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0.052) and the fetal risk alleles in combination with a maternal balancing allele (P<0.001). This non-random distribution was not observed in controls (P = 0.341 and P = 0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR.
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影响因子：
3.5
作者：
Diatchenko, L;Slade, GD;Maixner, W
通讯作者：
Maixner, W
DOI：
10.1073/pnas.111134598
发表时间：
2001-06-05
影响因子：
11.1
作者：
Egan, MF;Goldberg, TE;Weinberger, DR
通讯作者：
Weinberger, DR
DOI：
10.1002/ajmg.b.30831
发表时间：
2009-04-05
影响因子：
2.8
作者：
Halleland, H.;Lundervold, A. J.;Johansson, S.
通讯作者：
Johansson, S.
影响因子：
9.8
作者：
Chaiworapongsa, T;Romero, R;Edwin, S
通讯作者：
Edwin, S
影响因子：
2.6
作者：
Bialecka, Monika;Kurzawski, Mateusz;Drozdzik, Marek
通讯作者：
Drozdzik, Marek