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

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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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Acknowledgments

This research was supported by R21-DE-013707 and R01-DE-014581 from the National Institute of Dental and Craniofacial Research. TW is supported by the International Collaborative Genetics Research Training Program (ICGRTP), NIH D43 TW06176. We thank all participants who donated samples for this multi-center study of oral clefts, as well as the staff at each participating site and institution. We also thank the Smile Train Foundation for supporting cleft researches in China.

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Authors and Affiliations

  1. Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Tao Wu, Kung Yee Liang, Jacqueline B. Hetmanski, Ingo Ruczinski, Margaret Daniele Fallin, Roxann G. Ingersoll & Terri H. Beaty

  2. Beijing University School of Public Health, Beijing, China

    Tao Wu & Hong Wang

  3. Johns Hopkins School of Medicine, Baltimore, MD, USA

    Roxann G. Ingersoll, Ethylin W. Jabs, Richard Redett & Alan F. Scott

  4. Peking Union Medical College, Beijing, China

    Shangzhi Huang

  5. Mount Sinai School of Medicine, New York, NY, USA

    Xiaoqian Ye & Ethylin W. Jabs

  6. Key Laboratory for Oral Biomedical Engineering of Ministry of Education, Hospital and School of Stomatology, Wuhan University, Wuhan, China

    Xiaoqian Ye

  7. Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Yah-Huei Wu-Chou & Philip K. Chen

  8. West China College of Stomatology, Sichuan University, Sichuan, China

    Bing Shi

  9. Department of Epidemiology, School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD, 21205, USA

    Terri H. Beaty

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  1. Tao Wu
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Correspondence to Terri H. Beaty.

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Wu, T., Liang, K.Y., Hetmanski, J.B. et al. Evidence of gene–environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate. Hum Genet 128, 401–410 (2010). https://doi.org/10.1007/s00439-010-0863-y

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