Department of Paediatrics, Institute of Mother and Child, Warsaw, Poland.
Arch Oral Biol. 2010 Nov;55(11):861-6. doi: 10.1016/j.archoralbio.2010.07.012. Epub 2010 Aug 23.
Maternal mid-pregnancy low levels of symmetric dimethylarginine and newborn low levels of citrulline are suspected to be risk factors for orofacial clefts. This study was undertaken to investigate the involvement of polymorphic variants of genes related to arginine metabolism in the susceptibility of clefting.
PCR-RFLP and HRM analyses were used to analyze single nucleotide polymorphisms (SNPs) of ASS1, ASL, and SLC25A13 in 172 children with non-syndromic cleft lip with or without cleft palate (CL/P) and 188 controls without congenital anomalies. The differences in allele and genotype frequencies between cases and controls were determined using standard Chi-square and Fisher exact tests. The odds ratio (OR) and associated 95% confidence intervals (95% CI) for individuals with CL/P versus controls were also calculated. Associations between the investigated polymorphisms and the risk of being born with an orofacial cleft were tested using the nonparametric and genetic model-free Multifactor Dimensionality Reduction (MDR) approach.
Analysis of five SNPs of the ASS1 gene revealed that the G allele of rs7860909 is associated with increased CL/P risk. Compared to individuals with the AA genotype, the G allele carriers had an OR of 1.768 (95% CI: 1.133-2.759; p=0.012). For the remaining SNPs of all analysed genes, there was no overall evidence for cleft association considering the allele and genotype distribution. However, gene-by-gene interaction analysis conducted using the MDR approach revealed a significant interactive genetic effect of ASS1 (rs666174) and SLC25A13 (rs10252573) on the occurrence of clefting (p=0.002).
Our results demonstrate moderate evidence for the association of polymorphic variants of genes related to arginine metabolism with abnormal palatogenesis.
孕妇妊娠中期低水平的对称二甲基精氨酸和新生儿低水平的瓜氨酸被怀疑是口腔裂的危险因素。本研究旨在探讨与精氨酸代谢相关基因的多态性变异在唇腭裂易感性中的作用。
采用 PCR-RFLP 和 HRM 分析方法，对 172 例非综合征性唇裂伴或不伴腭裂（CL/P）患儿和 188 例无先天畸形对照者的 ASS1、ASL 和 SLC25A13 基因的单核苷酸多态性（SNP）进行分析。采用标准卡方检验和 Fisher 确切概率法比较病例组和对照组的等位基因和基因型频率差异。还计算了 CL/P 个体与对照组个体的比值比（OR）及其 95%置信区间（95%CI）。采用非参数和遗传模型自由多因子维度缩减（MDR）方法，对所研究的多态性与出生时口腔裂风险之间的关系进行了检验。
分析 ASS1 基因的 5 个 SNP 发现，rs7860909 的 G 等位基因与 CL/P 风险增加相关。与 AA 基因型个体相比，G 等位基因携带者的 OR 为 1.768（95%CI：1.133-2.759；p=0.012）。对于所有分析基因的其余 SNP，考虑等位基因和基因型分布，没有总体上与唇腭裂相关的证据。然而，采用 MDR 方法进行的基因-基因相互作用分析显示，ASS1（rs666174）和 SLC25A13（rs10252573）之间存在显著的交互遗传效应，与唇腭裂的发生有关（p=0.002）。
我们的结果表明，与精氨酸代谢相关的基因的多态性变异与腭畸形异常有关，具有中等程度的证据。
