Sabbagh Heba Jafar, Innes Nicola P T, Edris Ahmed Sherif, Butali Azeez, Alnamnakani Eman Abdulbaset, Rabah Sari M, Hamdan Mustafa A, Alhamlan Nasir H, Abdulhameed Fatma Dawood, Hassan Mona Hassan Ahmed, Al Mahdi Hadiah Bassam, Alamoudi Najlaa M, Al-Aama Jumana Y, Alaki Sumer M, Mossey Peter A
1 Department of Pediatric Dentistry, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
2 School of Dentistry, University of Dundee Dental School, Dundee, Scotland, United Kingdom.
Genet Test Mol Biomarkers. 2019 Jan;23(1):45-50. doi: 10.1089/gtmb.2018.0207.
Nonsyndromic orofacial cleft (NSOFC) including cleft lip with or without cleft palate (CL±P) and cleft palate (CP) are multifactorial developmental disorders with both genetic and environmental etiological factors. In this study we investigated the association between CL±P and CP, and two polymorphisms previously determined using genome-wide association studies, as well as the association between consanguinity and CL±P and CP.
DNA was extracted from saliva specimens from 171 triads consisting of affected individuals and their parents, as well as 189 control triads (matched for age, gender, and location) that were recruited from 11 referral hospitals in Saudi Arabia. Two polymorphisms, rs4752028 and rs7078160, located in the VAX1 gene were genotyped using real-time polymerase chain reaction. A transmission disequilibrium test was carried out using the Family-Based Association Test and PLINK (genetic tool-set) to measure the parent-of-origin effect.
Significant differences were found between affected individuals and the control group. In the case of the rs4752028 risk allele in cleft, the phenotypes were: CL±P (fathers: odds ratio [OR] 2.16 [95% CI 1.38-3.4]; mothers: OR 2.39 [95% CI 1.53-3.71]; and infants: OR 2.77 [95% CI 1.77-4.34]) and CP (fathers: OR 2.24 [95% CI 1.15-4.36] and infants: OR 2.43 [95% CI 1.25-4.7]). For CL±P and the rs7078160 risk allele, the phenotypes were: (fathers: OR 1.7 [95% CI 1.05-2.86]; mothers: OR 2.43 [95% CI 1.49-3.97]; and infants: OR 2.34 [95% CI 1.44-3.81]). In terms of consanguinity, we found significant association between consanguinity and the rs4752028 polymorphism minor allele among CL±P compared with controls (p = 0.001).
This is the first study to find a relationship between these two loci on 10q25 (rs4752028 and rs7078160) and NSOFC in a population with high levels of consanguinity.
非综合征性口面部裂隙（NSOFC），包括唇裂伴或不伴腭裂（CL±P）和腭裂（CP），是具有遗传和环境病因的多因素发育障碍。在本研究中，我们调查了CL±P和CP之间的关联，以及先前通过全基因组关联研究确定的两种多态性，还有近亲结婚与CL±P和CP之间的关联。
从沙特阿拉伯11家转诊医院招募的171个三联体（由患病个体及其父母组成）以及189个对照三联体（在年龄、性别和地点上匹配）的唾液样本中提取DNA。使用实时聚合酶链反应对位于VAX1基因中的两种多态性rs4752028和rs7078160进行基因分型。使用基于家系的关联检验和PLINK（遗传工具集）进行传递不平衡检验，以测量亲本来源效应。
在患病个体和对照组之间发现了显著差异。对于rs4752028风险等位基因在腭裂中的情况，各表型的比值比（OR）为：CL±P（父亲：OR 2.16 [95%置信区间1.38 - 3.4]；母亲：OR 2.39 [95%置信区间1.53 - 3.71]；婴儿：OR 2.77 [95%置信区间1.77 - 4.34]）和CP（父亲：OR 2.24 [95%置信区间1.15 - 4.36]；婴儿：OR 2.43 [95%置信区间1.25 - 4.7]）。对于CL±P和rs7078160风险等位基因，各表型的OR为：（父亲：OR 1.7 [95%置信区间1.05 - 2.86]；母亲：OR 2.43 [95%置信区间1.49 - 3.97]；婴儿：OR 2.34 [95%置信区间1.44 - 3.81]）。在近亲结婚方面，我们发现与对照组相比，CL±P中近亲结婚与rs4752028多态性次要等位基因之间存在显著关联（p = 0.001）。
这是第一项在近亲结婚率高的人群中发现10q25上的这两个位点（rs4752028和rs7078160）与NSOFC之间存在关联的研究。
