Lee Jin Kyung, Park Ji Wan, Kim Young Ho, Baek Seung-Hak
Department of Orthodontics, School of Dentistry, Seoul National University, Seoul, South Korea.
J Craniofac Surg. 2012 Sep;23(5):1262-6. doi: 10.1097/SCS.0b013e31824e27c7.
The purpose of this study was to investigate the contribution of PAX9 gene to the risk of nonsyndromic cleft lip with or without cleft palate (NS-CL/P). The samples consisted of 142 Korean NS-CL/P families (90 males and 52 females; 9 cleft lip, 26 cleft lip and alveolus, and 107 cleft lip and palate; 76 trios and 66 dyads). A total of 10 single-nucleotide polymorphisms (SNPs) were tested for association with Korean CL/P case-parent trios using transmission disequilibrium test (TDT) and conditional logistic regression models. The minor allele frequency, heterozygosity, and a χ test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as both D' and r2 for all SNPs. Both allelic and genotypic TDTs were performed for individual SNPs using family-based association test program. Sliding windows of haplotypes consisting of 2 to 8 SNPs were tested using haplotype-based association test program. Genotypic odd ratios were obtained from conditional logistic regression models using STATA software. The family-based TDT using individual SNPs and 2- to 8-SNP haplotypes of the gene indicated a significant association at rs17104928 (P = 0.014). The haplotype analysis revealed that the association was most significant for the haplotype consisting of 3 SNPs (rs2073247, rs17104928, and rs17176643; P = 0.007). G/A heterozygote at rs17104928 had a significantly increased association with NS-CL/P (genotypic odd ratio, 2.88; 95% confidence interval, 1.42-5.84; P = 0.0014, dominant model). The high-risk SNP and genotype may provide a better understanding of the etiologic role of PAX9 gene in NS-CL/P and potential options for genetic counseling.
本研究的目的是调查PAX9基因对非综合征性唇裂伴或不伴腭裂（NS-CL/P）风险的影响。样本包括142个韩国NS-CL/P家系（90名男性和52名女性；9例唇裂、26例唇裂合并牙槽突裂和107例唇腭裂；76个三联体和66个二元组）。使用传递不平衡检验（TDT）和条件逻辑回归模型，对10个单核苷酸多态性（SNP）与韩国CL/P病例-父母三联体进行关联测试。计算父母之间每个SNP的次要等位基因频率、杂合度以及哈迪-温伯格平衡的χ检验。计算所有SNP的D'和r2作为成对连锁不平衡。使用基于家系的关联测试程序对单个SNP进行等位基因和基因型TDT。使用基于单倍型的关联测试程序测试由2至8个SNP组成的单倍型滑动窗口。使用STATA软件从条件逻辑回归模型中获得基因型比值比。使用该基因的单个SNP和2至8个SNP单倍型进行的基于家系的TDT表明，rs17104928存在显著关联（P = 0.014）。单倍型分析显示，由3个SNP（rs2073247、rs17104928和rs17176643；P = 0.007）组成的单倍型关联最为显著。rs17104928处的G/A杂合子与NS-CL/P的关联显著增加（基因型比值比，2.88；95%置信区间，1.42 - 5.84；P = 0.0014，显性模型）。高危SNP和基因型可能有助于更好地理解PAX9基因在NS-CL/P中的病因作用以及遗传咨询的潜在选择。
