Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate

Tao Wu, Kung Yee Liang, Jacqueline B. Hetmanski, Ingo Ruczinski, Margaret Daniele Fallin, Roxann G. Ingersoll, Hong Wang, Shangzhi Huang, Xiaoqian Ye, Yah Huei Wu-Chou, Philip K. Chen, Ethylin W. Jabs, Bing Shi, Richard Redett, Alan F. Scott, Terri H. Beaty

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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.

Original languageEnglish
Pages (from-to)401-410
Number of pages10
JournalHuman Genetics
Volume128
Issue number4
DOIs
Publication statusPublished - Oct 1 2010
Externally publishedYes

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Interferon Regulatory Factors
Gene-Environment Interaction
Cleft Lip
Cleft Palate
Single Nucleotide Polymorphism
Mothers
Smoke
Tobacco
Genes
Logistic Models
Maternal Exposure
Haplotypes
Taiwan
China

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate. / Wu, Tao; Liang, Kung Yee; Hetmanski, Jacqueline B.; Ruczinski, Ingo; Fallin, Margaret Daniele; Ingersoll, Roxann G.; Wang, Hong; Huang, Shangzhi; Ye, Xiaoqian; Wu-Chou, Yah Huei; Chen, Philip K.; Jabs, Ethylin W.; Shi, Bing; Redett, Richard; Scott, Alan F.; Beaty, Terri H.

In: Human Genetics, Vol. 128, No. 4, 01.10.2010, p. 401-410.

Research output: Contribution to journalArticle

Wu, T, Liang, KY, Hetmanski, JB, Ruczinski, I, Fallin, MD, Ingersoll, RG, Wang, H, Huang, S, Ye, X, Wu-Chou, YH, Chen, PK, Jabs, EW, Shi, B, Redett, R, Scott, AF & Beaty, TH 2010, 'Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate', Human Genetics, vol. 128, no. 4, pp. 401-410. https://doi.org/10.1007/s00439-010-0863-y
Wu, Tao ; Liang, Kung Yee ; Hetmanski, Jacqueline B. ; Ruczinski, Ingo ; Fallin, Margaret Daniele ; Ingersoll, Roxann G. ; Wang, Hong ; Huang, Shangzhi ; Ye, Xiaoqian ; Wu-Chou, Yah Huei ; Chen, Philip K. ; Jabs, Ethylin W. ; Shi, Bing ; Redett, Richard ; Scott, Alan F. ; Beaty, Terri H. / Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate. In: Human Genetics. 2010 ; Vol. 128, No. 4. pp. 401-410.
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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.",
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AU - Wu, Tao

AU - Liang, Kung Yee

AU - Hetmanski, Jacqueline B.

AU - Ruczinski, Ingo

AU - Fallin, Margaret Daniele

AU - Ingersoll, Roxann G.

AU - Wang, Hong

AU - Huang, Shangzhi

AU - Ye, Xiaoqian

AU - Wu-Chou, Yah Huei

AU - Chen, Philip K.

AU - Jabs, Ethylin W.

AU - Shi, Bing

AU - Redett, Richard

AU - Scott, Alan F.

AU - Beaty, Terri H.

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N2 - 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.

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