Genetic Analysis of Cleft lip With or Without Cleft Palate

本研究共招募了200名日本非综合征型先证者及其父母。每十个先证者都有一个患病的父母。获得所有受试者的书面和口头知情同意。本研究已获东北大学医学院伦理委员会批准。首先，我们分析了非综合征性唇裂（唇裂、腭裂、唇裂和腭裂）与候选基因（MSX1、TGFA、TGFB2、TGFB3、RARA、GAD67和MTHFR）的相关性，这些基因被认为在白种人中存在显著相关性。结果表明，只有GAD67在日本人群中具有显著相关性。其次，为了评估环境因素如2,3,7,8-四氯二苯并-对二英（TCDD）是否在非综合征性口腔裂的病因学中发挥重要作用，我们使用传播不平衡试验（TDT）和病例对照研究评估了日本人群中非综合征性口腔裂与AHR、ARNT和CYP1A1中涉及TCDD代谢的单核苷酸多态性（snp）是否存在关联。我们鉴定并研究了ARNT中的三个snp。还研究了AHR和CYP1A1中两个氨基酸的取代。我们的研究结果表明，在日本人群中，ARNT参与了非综合征性唇裂的发展。

A total of 200 Japanese nonsyndromic oral clefts probands and their parents were recruited for this study. Each of ten probands had an affected parent. Written and oral informed consent was obtained from all subjects. This study was approved by the Ethics Committee of Tohoku University School of Medicine.The first, we analyzed the association between nonsyndromic oral clefts (cleft lip, cleft palate, and cleft lip and palate) and candidate genes (MSX1,TGFA, TGFB2,TGFB3,RARA, GAD67 and MTHFR), which were suggested to save significant association in Caucasian. The result indicated that only GAD67 have significant associations in Japanese populations.The next, in order to assess whether environmental factors such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) play a significant roll for the etiology of nonsyndromic oral clefts, we assessed whether there is any association in the Japanese population of nonsyndromic oral clefts and single nucleotide polymorphisms (SNPs) in AHR, ARNT, and CYP1A1 which are involved in TCDD metabolism using transmission disequilibrium test (TDT) and case-control study. We identified and investigated three SNPs in ARNT. Two amino acid substitutions in AHR and CYP1A1 were also investigated. Our results suggest that ARNT is involved in the development of nonsyndromic oral clefts in the Japanese population.