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Evidence that TGFA influences risk to cleft lip with/without cleft palate through unconventional genetic mechanisms

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Abstract

This study examined the association between markers in transforming growth factor alpha (TGFA) and isolated, non-syndromic cleft lip with/without palate (CL/P) using a case–parent trio design, considering parent-of-origin effects. We also tested for gene–environmental interaction with common maternal exposures, and for gene–gene interaction using markers in TGFA and another recognized causal gene, IRF6. CL/P case–parent trios from four populations (76 from Maryland, 146 from Taiwan, 35 from Singapore, and 40 from Korea) were genotyped for 17 single nucleotide polymorphisms (SNPs) in TGFA. The transmission disequilibrium test was used to test individual SNPs, and the parent-of-origin likelihood ratio test (PO-LRT) was used to assess parent-of-origin effects. We also screened for possible gene–environment interaction using PBAT, and tested for gene–gene interaction using conditional logistic regression models. When all trios were combined, four SNPs showed significant excess maternal transmission, two of which gave significant PO-LRT values [rs3821261: P = 0.004 and OR(imprinting) = 4.17; and rs3771475: P = 0.027 and OR(imprinting) = 2.44]. Haplotype analysis of these two SNPS also supported excess maternal transmission. We saw intriguing but suggestive evidence of G × E interaction for several SNPs in TGFA when either individual SNPs or haplotypes of adjacent SNPs were considered. Thus, TGFA appears to influence risk of CL/P through unconventional means with an apparent parent-of-origin effect (excess maternal transmission) and possible interaction with maternal exposures.

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Acknowledgments

This research was supported by R21-DE-013707 and R01-DE-014581 from the National Institute of Dental & Craniofacial Research, NIH R01 HL 090577, Korean Research Foundation (2005-214-E00042), and the Seoul City R&BD program (10526) in Korea. 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 Gerald Raymond for his assistance in screening patients at Hopkins.

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Authors and Affiliations

  1. Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea

    Jae Woong Sull & Sun Ha Jee

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

    Jae Woong Sull, Kung-Yee Liang, Jacqueline B. Hetmanski, Tao Wu, Margaret Daniele Fallin, Roxann G. Ingersoll, Sun Ha Jee & Terri H. Beaty

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

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

  4. Sungkyunkwan University School of Medicine, Seoul, Korea

    Ji Wan Park

  5. Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Yah-Huei Wu-Chou & Philip K. Chen

  6. Department of Pediatrics, National University of Singapore, Singapore, Singapore

    Samuel S. Chong & Felicia Cheah

  7. KK Women’s and Children’s Hospital, Singapore, Singapore

    Vincent Yeow

  8. Department of Plastic Surgery, College of Medicine, Yonsei University, Seoul, Korea

    Beyoung Yun Park

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

    Ethylin Wang Jabs

  10. 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. Jae Woong Sull
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  2. Kung-Yee Liang
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  3. Jacqueline B. Hetmanski
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  8. Yah-Huei Wu-Chou
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  9. Philip K. Chen
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  10. Samuel S. Chong
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  11. Felicia Cheah
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  12. Vincent Yeow
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  13. Beyoung Yun Park
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  14. Sun Ha Jee
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  15. Ethylin Wang Jabs
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  16. Richard Redett
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  17. Alan F. Scott
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  18. Terri H. Beaty
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Correspondence to Terri H. Beaty.

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Sull, J.W., Liang, KY., Hetmanski, J.B. et al. Evidence that TGFA influences risk to cleft lip with/without cleft palate through unconventional genetic mechanisms. Hum Genet 126, 385–394 (2009). https://doi.org/10.1007/s00439-009-0680-3

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  • DOI: https://doi.org/10.1007/s00439-009-0680-3

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