Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate.

Abstract

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.

• Authors: Tao Wu, Holger Schwender, Ingo Ruczinski, Jeffrey C Murray, Mary L Marazita, Ronald G Munger, Jacqueline B Hetmanski, Margaret M Parker, Ping Wang, Tanda Murray, Margaret Taub, Shuai Li, Richard J Redett, M Daniele Fallin, Kung Yee Liang, Yah Huei Wu-Chou, Samuel S Chong, Vincent Yeow, Xiaoqian Ye, Hong Wang, Shangzhi Huang, Ethylin W Jabs, Bing Shi, Allen J Wilcox, Sun Ha Jee, Alan F Scott, Terri H Beaty
• Journal: PloS one (PLoS One) Vol. 9 Issue 2 Pg. e88088 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24516586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucose Transport Proteins, Facilitative
• Microfilament Proteins
• SLC2A9 protein, human
• Tobacco Smoke Pollution
• WDR1 protein, human

Topics

• Asian People (genetics)
• Chromosomes, Human, Pair 4 (genetics)
• Cleft Palate (genetics)
• Female
• Gene-Environment Interaction
• Genetic Predisposition to Disease
• Glucose Transport Proteins, Facilitative (genetics)
• Humans
• Logistic Models
• Male
• Microfilament Proteins (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Risk Factors
• Tobacco Smoke Pollution (adverse effects)