Wu Tao, Schwender Holger, Ruczinski Ingo, Murray Jeffrey C, Marazita Mary L, Munger Ronald G, Hetmanski Jacqueline B, Parker Margaret M, Wang Ping, Murray Tanda, Taub Margaret, Li Shuai, Redett Richard J, Fallin M Daniele, Liang Kung Yee, Wu-Chou Yah Huei, Chong Samuel S, Yeow Vincent, Ye Xiaoqian, Wang Hong, Huang Shangzhi, Jabs Ethylin W, Shi Bing, Wilcox Allen J, Jee Sun Ha, Scott Alan F, Beaty Terri H
Peking University Health Science Center, Beijing, China ; Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
Mathematical Institute, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
PLoS One. 2014 Feb 6;9(2):e88088. doi: 10.1371/journal.pone.0088088. eCollection 2014.
Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10(-6)<P<10(-4)) in a test for GxETS interaction. SNPs rs3733585 and rs12508991 in SLC2A9 yielded P = 2.26×10(-7) in a test for GxETS interaction. SNPs rs6820756 and rs7699512 in WDR1 also yielded P = 1.79×10(-7) and P = 1.98×10(-7) in a 1 df test for GxE interaction. Although further replication studies are critical to confirming these findings, these results illustrate how genetic associations for nonsyndromic CP can be missed if potential GxE interaction is not taken into account, and this study suggest SLC2A9 and WDR1 should be considered as candidate genes for CP.
非综合征性腭裂（CP）是最常见的人类出生缺陷之一，遗传和环境风险因素均对其病因有影响。我们利用在一个国际联盟中确定的550个CP病例-父母三联体进行了全基因组关联研究（GWAS）。使用条件逻辑回归模型对不同血统的三联体进行分层分析，以检验与常见母体暴露的基因-环境（GxE）相互作用。虽然单独考虑时没有单核苷酸多态性（SNP）达到全基因组显著性，但当模型纳入GxE相互作用项时，4号染色体p16.1上SLC2A9及其邻近的WDR1中的标记在259个亚洲三联体中给出了与环境烟草烟雾（ETS）存在基因-环境相互作用的提示性证据。如果母亲在围孕期（受孕前3个月至孕早期）暴露于ETS，这两个基因中的多个SNP与非综合征性CP风险增加相关。当考虑母体ETS时，映射到SLC2A9的135个SNP中的15个以及WDR1中59个SNP中的9个在GxETS相互作用测试中给出了接近全基因组显著性的P值（10^(-6) < P < 10^(-4)）。SLC2A9中的SNP rs3733585和rs12508991在GxETS相互作用测试中产生的P = 2.26×10^(-7)。WDR1中的SNP rs6820756和rs7699512在1自由度的GxE相互作用测试中也分别产生了P = 1.79×10^(-7)和P = 1.98×10^(-7)。尽管进一步的重复研究对于证实这些发现至关重要，但这些结果说明了如果不考虑潜在的GxE相互作用，可能会遗漏非综合征性CP的遗传关联，并且本研究表明SLC2A9和WDR1应被视为CP的候选基因。
