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Association Between PAX9 Single-Nucleotide Polymorphisms and Nonsyndromic Cleft Lip With or Without Cleft Palate

Lee, Jin Kyung DDS, MSD*; Park, Ji Wan PhD; Kim, Young Ho DDS, PhD; Baek, Seung-Hak DDS, PhD§

doi: 10.1097/SCS.0b013e31824e27c7
Original Articles

The purpose of this study was to investigate the contribution of PAX9 gene to the risk of nonsyndromic cleft lip with or without cleft palate (NS-CL/P). The samples consisted of 142 Korean NS-CL/P families (90 males and 52 females; 9 cleft lip, 26 cleft lip and alveolus, and 107 cleft lip and palate; 76 trios and 66 dyads). A total of 10 single-nucleotide polymorphisms (SNPs) were tested for association with Korean CL/P case-parent trios using transmission disequilibrium test (TDT) and conditional logistic regression models. The minor allele frequency, heterozygosity, and a χ2 test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as both D′ and r 2 for all SNPs. Both allelic and genotypic TDTs were performed for individual SNPs using family-based association test program. Sliding windows of haplotypes consisting of 2 to 8 SNPs were tested using haplotype-based association test program. Genotypic odd ratios were obtained from conditional logistic regression models using STATA software. The family-based TDT using individual SNPs and 2- to 8-SNP haplotypes of the gene indicated a significant association at rs17104928 (P = 0.014). The haplotype analysis revealed that the association was most significant for the haplotype consisting of 3 SNPs (rs2073247, rs17104928, and rs17176643; P = 0.007). G/A heterozygote at rs17104928 had a significantly increased association with NS-CL/P (genotypic odd ratio, 2.88; 95% confidence interval, 1.42–5.84; P = 0.0014, dominant model). The high-risk SNP and genotype may provide a better understanding of the etiologic role of PAX9 gene in NS-CL/P and potential options for genetic counseling.

From the *Department of Orthodontics, School of Dentistry, Seoul National University, Seoul; †Department of Medical Genetics, College of Medicine, Hallym University, Chuncheon, Gangwon Province; ‡Department of Orthodontics, The Institute of Oral Health Science, Samsung Medical Center, Sungkyunkwan University School of Medicine; and §Department of Orthodontics, School of Dentistry, Dental Research Institute, Seoul National University, Seoul, South Korea.

Received October 22, 2011.

Accepted for publication January 17, 2012.

Address correspondence and reprint requests to Seung-Hak Baek, DDS, PhD, Department of Orthodontics, School of Dentistry, Dental Research Institute, Seoul National University, Yeonkun-dong #28, Jongro-ku, Seoul, 110-768, South Korea; E-mail:

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF 2009-0069859), Gene-Gene Interaction Underlying Genetic Susceptibility to Nonsyndromic Oral Clefts in Korea Case-Parent Trios funded by the Ministry of Education, Science, and Technology.

The authors report no conflicts of interest.

© 2012 Mutaz B. Habal, MD