title: Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate.
abstract: Although multiple genes have been identified as genetic risk factors for isolated, non-syndromic cleft lip with/without cleft palate (CL/P), a complex and heterogeneous birth defect, interferon regulatory factor 6 gene (IRF6) is one of the best documented genetic risk factors. In this study, we tested for association between markers in IRF6 and CL/P in 326 Chinese case-parent trios, considering gene-environment interaction for two common maternal exposures, and parent-of-origin effects. CL/P case-parent trios from three sites in mainland China and Taiwan were genotyped for 22 single nucleotide polymorphisms (SNPs) in IRF6. The transmission disequilibrium test was used to test for marginal effects of individual SNPs. We used PBAT to screen the SNPs and haplotypes for gene-environment (G×E) interaction and conditional logistic regression models to quantify effect sizes for SNP-environment interaction. After Bonferroni correction, 14 SNPs showed statistically significant association with CL/P. Evidence of G×E interaction was found for both maternal exposures, multivitamin supplementation and environmental tobacco smoke (ETS). Two SNPs showed evidence of interaction with multivitamin supplementation in conditional logistic regression models (rs2076153 nominal P=0.019, rs17015218 nominal P=0.012). In addition, rs1044516 yielded evidence for interaction with maternal ETS (nominal P=0.041). Haplotype analysis using PBAT also suggested interaction between SNPs in IRF6 and both multivitamin supplementation and ETS. However, no evidence for maternal genotypic effects or significant parent-of-origin effects was seen in these data. These results suggest IRF6 gene may influence risk of CL/P through interaction with multivitamin supplementation and ETS in the Chinese population.
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. twu@jhsph.edu
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Kung Yee
authors.initials: KY
authors.lastname: Liang
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Hetmanski
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Margaret Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Roxann G
authors.initials: RG
authors.lastname: Ingersoll
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Shangzhi
authors.initials: S
authors.lastname: Huang
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Ye
authors.forename: Yah-Huei
authors.initials: YH
authors.lastname: Wu-Chou
authors.forename: Philip K
authors.initials: PK
authors.lastname: Chen
authors.forename: Ethylin W
authors.initials: EW
authors.lastname: Jabs
authors.forename: Bing
authors.initials: B
authors.lastname: Shi
authors.forename: Richard
authors.initials: R
authors.lastname: Redett
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D002681:China; D002971:Cleft Lip / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D002972:Cleft Palate / Q000208:ethnology / Q000209:etiology / Q000235:genetics; D019587:Dietary Supplements; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D009679:Nuclear Family; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics; D012307:Risk Factors; D013624:Taiwan; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014815:Vitamins / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D014028:Tobacco Smoke Pollution; D014815:Vitamins