Association Analysis of Class-II Division-2 (CII/D2) with RUNX2 and RUNX3

Objectives: Genetics factors influence the development of CII/D2 malocclusion. Interestingly, multiple tooth anomalies (including hypodontia of maxillary-incisors ans/or third-molars) coincide with CII/D2 at a higher frequency than observed with other malocclusions. Runt-homology-domain-transcription-factor-2 (RUNX2) and RUNX3 play important roles in osteoblast differentiation, tooth development and chondrocyte maturation. Gene-knock-out studies in mice show that RUNX2/3 are involved in both incisor and molar development. This study investigated whether the RUNX2/3 genes play a role in CII/D2 development (with-or-without-hypodontia), with a null-hypothesis stating no association of single-nucleotide-polymorphisms (SNPs) within or near the RUNX2/3 genes and CII/D2 (or with-hypodontia). Methods: Ninety-four CII/D2 Caucasian subjects (31-with-hypodontia) were compared to eighty-nine non-CII/D2 Caucasian subjects-without-hypodontia. Clinical exam, photographs, models, radiographs and saliva were collected and analyzed. SNPs within the RUNX2 (rs1406846 and rs6930053) and RUNX3 (rs6672420) genes were genotyped using Taqman Genotyping. Chi-square-tests were used to evaluate the association of CII/D2 (with-or-without-hypodontia) and each SNP. Results: All SNPs were in Hardy-Weinberg-Equilibrium. A marginally-significant-association (p=0.0911) was identified between CII/D2-with-or-without-hypodontia and RUNX2 (rs6930053) assuming a co-dominant mode-of-inheritance. No association of CII/D2 and RUNX2 (rs1406846) was identified under the same genetic model (p=0.6336). Genotyping and association analysis for CII/D2 subjects and RUNX3 are currently underway. No association of rs6930053 was identified for CII/D2-subjects-with-hypodontia of any permanent tooth, when compared to CII/D2-subjects-without-hypodontia (p=0.6867). Similarly, no association of rs6930053 was identified for CII/D2-subjects-with-hypodontia of 1 or more non-third-molar-teeth, compared to CII/D2-without-hypodontia or with-hypodonta of only the third-molar(s). Conclusions: The null-hypothesis was rejected for CII/D2 association with RUNX2 (rs6930053) but could not be rejected for CII/D2 association with RUNX2 (rs1406846). The data suggest that RUNX2 (or genetic loci in linkage-disequilibrium with RUNX2) plays a role in CII/D2 development but not in the occasionally-associated hypodontia. Supported by: Indiana University Bixler Fund for Research in Genetics, and the University of Kentucky E. Preston Hicks Endowed Chair.