Carter Tonia C, Molloy Anne M, Pangilinan Faith, Troendle James F, Kirke Peadar N, Conley Mary R, Orr David J A, Earley Michael, McKiernan Eamon, Lynn Ena C, Doyle Anne, Scott John M, Brody Lawrence C, Mills James L
Division of Epidemiology, Statistics, and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Birth Defects Res A Clin Mol Teratol. 2010 Feb;88(2):84-93. doi: 10.1002/bdra.20639.
Suggestive, but not conclusive, studies implicate many genetic variants in oral cleft etiology. We used a large, ethnically homogenous study population to test whether reported associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) could be confirmed.
Thirty-one single nucleotide polymorphisms (SNPs) in exons, splice sites, and conserved non-coding regions were studied in 509 patients with cleft lip with or without cleft palate (CLP), 383 with cleft palate only (CP), 838 mothers and 719 fathers of patients with oral clefts, and 902 controls from Ireland. Case-control and family-based statistical tests were performed using isolated oral clefts for the main analyses.
In case-control comparisons, the minor allele of PTCH1 A562A (rs2066836) was associated with reduced odds of CLP (odds ratios [OR], 0.29; 95% confidence interval [CI], 0.13-0.64 for homozygotes), whereas the minor allele of PTCH1 L1315P (rs357564) was associated with increased odds of CLP (OR, 1.36; 95% CI, 1.07-1.74 for heterozygotes; and OR, 1.56; 95% CI, 1.09-2.24 for homozygotes). The minor allele of one SUMO1 SNP, rs3769817 located in intron 2, was associated with increased odds of CP (OR, 1.45; 95% CI, 1.06-1.99 for heterozygotes). Transmission disequilibrium was observed for the minor allele of TGFA V159V (rs2166975) which was over-transmitted to CP cases (p = 0.041).
For 10 of the 12 genes, this is the largest candidate gene study of nonsyndromic oral clefts to date. The findings provide further evidence that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts.
有提示性但非结论性的研究表明，许多基因变异与口腔裂隙病因有关。我们使用了一个种族同质化的大型研究群体，以检验非综合征性口腔裂隙与12个基因（CLPTM1、CRISPLD2、FGFR2、GABRB3、GLI2、IRF6、PTCH1、RARA、RYK、SATB2、SUMO1、TGFA）之间已报道的关联是否能够得到证实。
对509例唇裂伴或不伴腭裂（CLP）患者、383例单纯腭裂（CP）患者、838例口腔裂隙患者的母亲和719例父亲以及902名来自爱尔兰的对照者，研究了外显子区、剪接位点和保守非编码区的31个单核苷酸多态性（SNP）。主要分析采用孤立性口腔裂隙进行病例对照和基于家系的统计检验。
在病例对照比较中，PTCH1 A562A（rs2066836）的次要等位基因与CLP发生几率降低相关（纯合子的优势比[OR]为0.29；95%置信区间[CI]为0.1[13-0.64]），而PTCH1 L1315P（rs357564）的次要等位基因与CLP发生几率增加相关（杂合子的OR为1.36；95%CI为1.07-1.74；纯合子的OR为1.56；95%CI为1.09-2.24）。位于内含子2的SUMO1 SNP rs3769817的次要等位基因与CP发生几率增加相关（杂合子的OR为1.45；95%CI为1.06-1.99）。观察到TGFA V159V（rs2166975）的次要等位基因存在传递不平衡，该等位基因过度传递给CP病例（p = 0.041）。
对于这12个基因中的10个，这是迄今为止关于非综合征性口腔裂隙的最大规模候选基因研究。这些发现进一步证明PTCH1、SUMO1和TGFA与非综合征性口腔裂隙有关。
