Genetic Analysis of Cleft lip With or Without Cleft Palate

本研究共招募了200名日本非综合征性口腔裂先证者及其父母。十名先证者中的每一位都有一位受影响的父母。所有受试者均获得书面和口头知情同意。这项研究得到了东北大学医学部伦理委员会的批准。首先，我们分析了非综合征性口腔裂(唇裂、腭裂和唇腭裂)与候选基因(Msx1、TGFA、TGFB2、TGFB3、RARA、GAD67和MTHFR)的关联，这些基因在高加索人中被建议保留显著的关联。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发病机制中起重要作用，我们采用传递不平衡检验(TDT)和病例对照研究，评估了日本人群中与TCDD代谢相关的AHR、ARNT和CYP1A1的单核苷酸多态(SNPs)与非综合征性口裂的相关性。我们鉴定并调查了ARNT的三个SNPs。对AHR和CYP1A1的两个氨基酸替换进行了研究。我们的结果表明，ARNT参与了日本人群中非综合征性口裂的发生。

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.