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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 
 HUMAN GENETICS, Vol.126(3) : 385-394, 2009 
Journal Title
Issue Date
Cleft Lip/complications* ; Cleft Lip/genetics* ; Cleft Palate/complications* ; Cleft Palate/genetics* ; Female ; Genotype ; Humans ; Interferon Regulatory Factors/genetics ; Linkage Disequilibrium ; Male ; Maternal Exposure ; Models, Genetic ; Parents ; Polymorphism, Single Nucleotide ; Protein Interaction Mapping ; Singapore ; Transforming Growth Factor alpha/genetics*
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 x 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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1. College of Medicine (의과대학) > Dept. of Plastic and Reconstructive Surgery (성형외과학교실) > 1. Journal Papers
4. Graduate School of Public Health (보건대학원) > Graduate School of Public Health (보건대학원) > 1. Journal Papers
Yonsei Authors
Park, Beyoung Yun(박병윤)
Sull, Jae Woong(설재웅)
Jee, Sun Ha(지선하) ORCID logo https://orcid.org/0000-0001-9519-3068
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