title: 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: Peking University Health Science Center, Beijing, China ; Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: Tao
authors: T
authors: Wu
authors: Mathematical Institute, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
authors: Holger
authors: H
authors: Schwender
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: Ingo
authors: I
authors: Ruczinski
authors: University of Iowa, Children's Hospital, Iowa City, Iowa, United States of America.
authors: Jeffrey C
authors: JC
authors: Murray
authors: Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Mary L
authors: ML
authors: Marazita
authors: Utah State University, Logan, Utah, United States of America.
authors: Ronald G
authors: RG
authors: Munger
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: Jacqueline B
authors: JB
authors: Hetmanski
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: Margaret M
authors: MM
authors: Parker
authors: Peking University Health Science Center, Beijing, China.
authors: Ping
authors: P
authors: Wang
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: Tanda
authors: T
authors: Murray
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: Margaret
authors: M
authors: Taub
authors: Peking University Health Science Center, Beijing, China.
authors: Shuai
authors: S
authors: Li
authors: Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors: Richard J
authors: RJ
authors: Redett
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: M Daniele
authors: MD
authors: Fallin
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America ; National Yang-Ming University, Taipei, Taiwan.
authors: Kung Yee
authors: KY
authors: Liang
authors: Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Yah Huei
authors: YH
authors: Wu-Chou
authors: National University of Singapore, Singapore, Singapore.
authors: Samuel S
authors: SS
authors: Chong
authors: KK Women's & Children's Hospital, Singapore, Singapore.
authors: Vincent
authors: V
authors: Yeow
authors: Wuhan University, School of Stomatology, Wuhan, China ; Mount Sinai Medical Center, New York, New York, United States of America.
authors: Xiaoqian
authors: X
authors: Ye
authors: Peking University Health Science Center, Beijing, China.
authors: Hong
authors: H
authors: Wang
authors: Peking Union Medical College, Beijing, China.
authors: Shangzhi
authors: S
authors: Huang
authors: Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America ; Mount Sinai Medical Center, New York, New York, United States of America.
authors: Ethylin W
authors: EW
authors: Jabs
authors: State Key Laboratory of Oral Disease, West China College of Stomatology, Sichuan University, Chengdu, China.
authors: Bing
authors: B
authors: Shi
authors: NIEHS/NIH, Epidemiology Branch, Durham, North Carolina, United States of America.
authors: Allen J
authors: AJ
authors: Wilcox
authors: Yonsei University, School of Public Health, Seoul, Korea.
authors: Sun Ha
authors: SH
authors: Jee
authors: Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors: Alan F
authors: AF
authors: Scott
authors: Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America.
authors: Terri H
authors: TH
authors: Beaty
mesh_terms: D044466:Asian People / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D008840:Microfilament Proteins; C411811:SLC2A9 protein, human; D014028:Tobacco Smoke Pollution; C118067:WDR1 protein, human