title: Evidence that TGFA influences risk to cleft lip with/without cleft palate through unconventional genetic mechanisms.
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 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.
authors.affiliation: Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea. sulljw@yuhs.ac
authors.forename: Jae Woong
authors.initials: JW
authors.lastname: Sull
authors.forename: Kung-Yee
authors.initials: KY
authors.lastname: Liang
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Hetmanski
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Margaret Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Roxann G
authors.initials: RG
authors.lastname: Ingersoll
authors.forename: Ji Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Yah-Huei
authors.initials: YH
authors.lastname: Wu-Chou
authors.forename: Philip K
authors.initials: PK
authors.lastname: Chen
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Chong
authors.forename: Felicia
authors.initials: F
authors.lastname: Cheah
authors.forename: Vincent
authors.initials: V
authors.lastname: Yeow
authors.forename: Beyoung Yun
authors.initials: BY
authors.lastname: Park
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Jee
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.forename: Richard
authors.initials: R
authors.lastname: Redett
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
mesh_terms: D002971:Cleft Lip / Q000150:complications* / Q000235:genetics*; D002972:Cleft Palate / Q000150:complications* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D018811:Maternal Exposure; D008957:Models, Genetic; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping; D012846:Singapore; D016211:Transforming Growth Factor alpha / Q000235:genetics*
chemical_list: C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D016211:Transforming Growth Factor alpha