Investigation of Parental Transmission of RUNX2 Single Nucleotide Polymorphism and Its Association with Nonsyndromic Cleft Lip with or Without Palate

Abstract

Objective

To investigate the association and parental transmission of RUNX2 single nucleotide polymorphisms (SNPs) with risk of nonsyndromic cleft lip with or without cleft palate (NS-CL±P).

Design

Four RUNX2 SNPs in 142 Korean NS-CL±P families (nine cleft lip, 26 cleft lip and alveolus, and 107 cleft lip and palate; 76 trios and 66 dyads) were genotyped. The minor allele frequency, heterozygosity, and chi-square test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as D′ and r² for all SNPs. Both allelic and genotypic transmission disequilibrium tests (TDTs) were performed for individual SNPs using a family-based association test program. Sliding windows of haplotypes consisting of two to four SNPs were tested using a haplotype-based association test program. Genotypic odds ratios (GORs) were calculated from conditional logistic regression models. Parent-of-origin effects were assessed using transmission asymmetry test and parent-of-origin likelihood ratio test.

Results

The family-based TDT showed significant evidence of linkage and association at rs1934328 (P = .001). In the haplotype analysis, two, three, and four haplotypes containing rs1934328 revealed significant associations (P = .0017, P = .0022, and P = .0020, respectively). The genotypes A/T and T/T at rs1934328 were significantly associated with NS-CL±P compared with the genotype A/A (GOR = 2.75, 95% confidence interval [CI] = 1.39–5.45, P =0.0019 in the dominant model; GOR = 5.38, 95% CI = 1.34–21.68, P = .0046 in the additive model). However, no parent-of origin effect was observed.

Conclusion

These findings suggest possible involvement of RUNX2-rs 194328 in the etiology of NS-CL±P in Korean cleft-parent trios without excess parental transmission.