Human Genetics

, Volume 126, Issue 3, pp 385–394

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

  • Jae Woong Sull
  • Kung-Yee Liang
  • Jacqueline B. Hetmanski
  • Tao Wu
  • Margaret Daniele Fallin
  • Roxann G. Ingersoll
  • Ji Wan Park
  • Yah-Huei Wu-Chou
  • Philip K. Chen
  • Samuel S. Chong
  • Felicia Cheah
  • Vincent Yeow
  • Beyoung Yun Park
  • Sun Ha Jee
  • Ethylin Wang Jabs
  • Richard Redett
  • Alan F. Scott
  • Terri H. Beaty
Original Investigation

DOI: 10.1007/s00439-009-0680-3

Cite this article as:
Sull, J.W., Liang, KY., Hetmanski, J.B. et al. Hum Genet (2009) 126: 385. doi:10.1007/s00439-009-0680-3

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.

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Jae Woong Sull
    • 1
    • 2
  • Kung-Yee Liang
    • 2
  • Jacqueline B. Hetmanski
    • 2
  • Tao Wu
    • 2
  • Margaret Daniele Fallin
    • 2
  • Roxann G. Ingersoll
    • 2
    • 3
  • Ji Wan Park
    • 4
  • Yah-Huei Wu-Chou
    • 5
  • Philip K. Chen
    • 5
  • Samuel S. Chong
    • 6
  • Felicia Cheah
    • 6
  • Vincent Yeow
    • 7
  • Beyoung Yun Park
    • 8
  • Sun Ha Jee
    • 1
    • 2
  • Ethylin Wang Jabs
    • 3
    • 9
  • Richard Redett
    • 3
  • Alan F. Scott
    • 3
  • Terri H. Beaty
    • 2
    • 10
  1. 1.Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public HealthYonsei UniversitySeoulKorea
  2. 2.Johns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.Johns Hopkins School of MedicineBaltimoreUSA
  4. 4.Sungkyunkwan University School of MedicineSeoulKorea
  5. 5.Chang Gung Memorial HospitalTaoyuanTaiwan
  6. 6.Department of PediatricsNational University of SingaporeSingaporeSingapore
  7. 7.KK Women’s and Children’s HospitalSingaporeSingapore
  8. 8.Department of Plastic Surgery, College of MedicineYonsei UniversitySeoulKorea
  9. 9.Mount Sinai School of MedicineNew YorkUSA
  10. 10.Department of Epidemiology, School of Public HealthJohns Hopkins UniversityBaltimoreUSA