title: Maternal transmission effects of the PAX genes among cleft case-parent trios from four populations.
abstract: Isolated cleft lip with or without cleft palate (CL/P) is among the most common human birth defects, with a prevalence of 1 in 700 live births. The paired box (PAX) genes have been suggested as candidate genes for CL/P based largely on mouse models; however, few human studies have focused on this gene family. This study tests for association between markers in four PAX genes and CL/P using a case-parent trio design considering parent-of-origin effects. Trios from four populations (76 from Maryland, 146 from Taiwan, 35 from Singapore, and 40 from Korea) were genotyped for 34 single nucleotide polymorphisms (SNPs) in the PAX3, PAX6, PAX7, and PAX9 genes. We performed the transmission disequilibrium test (TDT) on individual SNPs. Parent-of-origin effects were assessed using the transmission asymmetry test (TAT) and the parent-of-origin likelihood ratio test (PO-LRT). TDT analysis showed one SNP (rs766325) in PAX7 yielding evidence of linkage and association when parent-of-origin was not considered, with an OR(transmission)=1.62 (P=0.003), and five SNPs in PAX6 (including two pairs in near perfect linkage disequilibrium). TAT analysis of all trios revealed two SNPs in PAX7 and four SNPs in PAX3 showing significant excess maternal transmission. For these six SNPs, the maternal OR(transmission) ranged between 1.74 and 2.40, and PO-LRT was also significant (P-values=0.035-0.012). When this analysis was limited to trios with male cases, SNPs in PAX7 showed higher maternal OR(transmission) and greater significance. PAX genes may influence the risk of CL/P through maternal effects, possibly imprinting, which seems to be stronger among male cases.
authors.affiliation: Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
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: Margaret Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Roxanne G
authors.initials: RG
authors.lastname: Ingersoll
authors.forename: Jiwan
authors.initials: J
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 W
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: D016022:Case-Control Studies; D002971:Cleft Lip / Q000453:epidemiology / Q000235:genetics*; D002972:Cleft Palate / Q000453:epidemiology / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D000072041:PAX3 Transcription Factor; D000071841:PAX6 Transcription Factor; D051763:PAX7 Transcription Factor / Q000235:genetics; D051764:PAX9 Transcription Factor / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins