TY - JOUR
T1 - Maternal transmission effects of the PAX genes among cleft case-parent trios from four populations
AU - Sull, Jae Woong
AU - Liang, Kung Yee
AU - Hetmanski, Jacqueline B.
AU - Fallin, Margaret Daniele
AU - Ingersoll, Roxanne G.
AU - Park, Jiwan
AU - Wu-Chou, Yah Huei
AU - Chen, Philip K.
AU - Chong, Samuel S.
AU - Cheah, Felicia
AU - Yeow, Vincent
AU - Park, Beyoung Yun
AU - Jee, Sun Ha
AU - Jabs, Ethylin W.
AU - Redett, Richard
AU - Scott, Alan F.
AU - Beaty, Terri H.
N1 - Funding Information:
This research was supported by R21-DE-013707 and R01-DE-014581 from the National Institute of Dental & Craniofacial Research and Korean Research Foundation (2004-041-E00104), 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 CL/P patients at Hopkins.
PY - 2009/1/15
Y1 - 2009/1/15
N2 - 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.
AB - 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.
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U2 - 10.1038/ejhg.2008.250
DO - 10.1038/ejhg.2008.250
M3 - Article
C2 - 19142206
AN - SCOPUS:67349272731
SN - 1018-4813
VL - 17
SP - 831
EP - 839
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 6
ER -