Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study.
Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study.
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DOI：
10.1002/gepi.20376
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发表时间：
2009-04
影响因子：
2.1
通讯作者：
Lie, Rolv T.
中科院分区：
文献类型：
--
作者：
Boyles, Abee L.;Wilcox, Allen J.;Taylor, Jack A.;Shi, Min;Weinberg, Clarice R.;Meye, Klaus;Fredriksen, Ase;Ueland, Per Magne;Johansen, Anne Marte W.;Drevon, Christian A.;Jugessur, Astanand;Trung, Truc Nguyen;Gjessing, Hakon K.;Vollset, Stein Emil;Murray, Jeffrey C.;Christensens, Kaare;Lie, Rolv T.
在怀孕期间，叶酸或维生素A摄入量较低的母亲患面部裂缝的风险增加。我们推测，与代谢叶酸或维生素A有关的基因可能会进一步降低唇腭裂的风险。我们纳入了425例病例父母三联体，其中儿童有唇腭裂或无腭裂（CL/P）或腭裂（CPO），没有其他重大缺陷。我们分析了29个叶酸/一碳代谢相关基因中的108个SNP和一个插入，以及16个维生素A代谢相关基因中的68个SNP。我们使用Triad Multi Marker（TRIMM）方法对CL/P和CPO的儿童或母体遗传效应进行SNP、基因、染色体区域和全路径关联检验。我们对围受孕期母亲摄入叶酸或维生素A的分析进行分层。正如预期的那样，在大量的统计检验中，有许多p值< 0.05的相关性;尽管比单独预测的要少。我们的数据中最强的相关性（胎儿FOLH 1和CPO之间，p=0.0008）与流行病学证据不一致，即叶酸降低了这些数据中CL/P的风险，而不是CPO。尽管有强有力的证据表明口面裂的遗传原因和母体维生素的保护作用，但我们没有发现令人信服的迹象表明这些维生素代谢基因的多态性在病因学中起作用。
An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period. As expected with this high number of statistical tests, there were many associations with p-values < 0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, p=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role.
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