Genetic Analysis of Cleft lip With or Without Cleft Palate

本研究共招募了200名日本非综合征型唇腭裂先证者及其父母。十个先证者中的每一个都有一位受影响的父母。获得所有受试者的书面和口头知情同意书。本研究得到了东北大学医学部伦理委员会的批准。首先，分析了非综合征性唇腭裂（唇裂、腭裂、唇腭裂）与候选基因（MSX 1、TGFA、TGFB 2、TGFB 3、RARA、GAD 67和MTHFR）之间的关联，这些候选基因被认为在高加索人中具有显著的关联性。接下来，为了评估环境因素如2，3，7，8-四氯二苯并-对-二恶英（TCDD）是否在非综合征性口裂的病因学中发挥重要作用，我们评估了日本人群中非综合征性口裂与AHR、ARNT、采用传递不平衡检验（TDT）和病例对照研究方法，对参与TCDD代谢的CYP 1A 1和CYP 1A 1进行了研究。我们确定并研究了ARNT中的三个SNP。还研究了AHR和CYP 1A 1中的两个氨基酸取代。我们的研究结果表明，ARNT是参与发展的非综合征性口裂在日本人口。

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.