1. ¹Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea
2. ²Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
3. ³Johns Hopkins School of Medicine, Baltimore, MD, USA
4. ⁴Department of Molecular and Cellular Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
5. ⁵Chang Gung Memorial Hospital, Taoyuan, Taiwan
6. ⁶Department of Pediatrics, National University of Singapore, Singapore, Singapore
7. ⁷KK Women's & Children's Hospital, Singapore, Singapore
8. ⁸Yonsei University College of Medicine, Seoul, Korea

Correspondence: Terri H Beaty, Department of Epidemiology, School of Public Health, Johns Hopkins University, 615 N Wolfe Street, Baltimore, MD 21205, USA. Tel: +1 410 955 6960 ; Fax: +1 410 955 0863; E-mail: tbeaty@jhsph.edu

Received 20 February 2008; Revised 13 November 2008; Accepted 20 November 2008; Published online 14 January 2009.

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.