Sull Jae Woong, Liang Kung-Yee, Hetmanski Jacqueline B, Wu Tao, Fallin Margaret Daniele, Ingersoll Roxann G, Park Ji Wan, Wu-Chou Yah-Huei, Chen Philip K, Chong Samuel S, Cheah Felicia, Yeow Vincent, Park Beyoung Yun, Jee Sun Ha, Jabs Ethylin Wang, Redett Richard, Scott Alan F, Beaty Terri H
Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
Hum Genet. 2009 Sep;126(3):385-94. doi: 10.1007/s00439-009-0680-3. Epub 2009 May 15.
This study examined the association between markers in transforming growth factor alpha (TGFA) and isolated, non-syndromic cleft lip with/without palate (CL/P) using a case-parent trio design, considering parent-of-origin effects. We also tested for gene-environmental interaction with common maternal exposures, and for gene-gene interaction using markers in TGFA and another recognized causal gene, IRF6. CL/P case-parent trios from four populations (76 from Maryland, 146 from Taiwan, 35 from Singapore, and 40 from Korea) were genotyped for 17 single nucleotide polymorphisms (SNPs) in TGFA. The transmission disequilibrium test was used to test individual SNPs, and the parent-of-origin likelihood ratio test (PO-LRT) was used to assess parent-of-origin effects. We also screened for possible gene-environment interaction using PBAT, and tested for gene-gene interaction using conditional logistic regression models. When all trios were combined, four SNPs showed significant excess maternal transmission, two of which gave significant PO-LRT values [rs3821261: P = 0.004 and OR(imprinting) = 4.17; and rs3771475: P = 0.027 and OR(imprinting) = 2.44]. Haplotype analysis of these two SNPS also supported excess maternal transmission. We saw intriguing but suggestive evidence of G x E interaction for several SNPs in TGFA when either individual SNPs or haplotypes of adjacent SNPs were considered. Thus, TGFA appears to influence risk of CL/P through unconventional means with an apparent parent-of-origin effect (excess maternal transmission) and possible interaction with maternal exposures.
本研究采用病例-父母三联体设计，考虑亲本来源效应，探讨转化生长因子α（TGFA）中的标记与孤立性、非综合征性唇裂伴或不伴腭裂（CL/P）之间的关联。我们还测试了与常见母亲暴露因素的基因-环境相互作用，以及使用TGFA和另一个公认的致病基因IRF6中的标记进行基因-基因相互作用分析。对来自四个群体（76个来自马里兰州、146个来自台湾、35个来自新加坡和40个来自韩国）的CL/P病例-父母三联体进行了TGFA中17个单核苷酸多态性（SNP）的基因分型。采用传递不平衡检验来检测单个SNP，并使用亲本来源似然比检验（PO-LRT）来评估亲本来源效应。我们还使用PBAT筛选可能的基因-环境相互作用，并使用条件逻辑回归模型测试基因-基因相互作用。当所有三联体合并时，四个SNP显示出显著的母系传递过量，其中两个给出了显著的PO-LRT值[rs3821261：P = 0.004，OR（印记）= 4.17；以及rs3771475：P = 0.027，OR（印记）= 2.44]。对这两个SNP的单倍型分析也支持母系传递过量。当考虑单个SNP或相邻SNP的单倍型时，我们发现了TGFA中几个SNP存在基因-环境相互作用的有趣但提示性的证据。因此，TGFA似乎通过非常规方式影响CL/P的风险，具有明显的亲本来源效应（母系传递过量）以及可能与母亲暴露因素的相互作用。
