STUDY OF CHROMOSOME 11q22.2q22.3 FOR LINKAGE TO CLASS III\ud MALOCCLUSION IN SOUTH AMERICANS

Class III malocclusion is one of the dentofacial deformities that represents a challenge for orthodontists in terms of treatment and prognosis. Due to its complexity and aesthetic involvement, a lot of research have been undertaken to understand the mechanisms underlying the development of this growth deformity. Several studies have suggested a strong genetic contribution in the formation of class III malocclusion. Previous studies have implicated a region on chromosome 11 (11q22.2-q22.3) that is linked with class III phenotype in a Hispanic cohort (Frazier-Bowers et al., 2009). To further investigate the region and find genes that might affect the incidence of class III malocclusion, Dr. Hartsfield and Dr. Lorri Ann Morford at the University of Kentucky have selected and genotyped 4 single nucleotide polymorphisms (SNPs; rs666723, rs578169, rs1386719 and rs12416856) within the 11q22.2-22.3 region on two multi-generational family-based cohorts from Brazil and Colombia for multipoint linkage analysis. The families in each cohort had a high prevalence of class III malocclusion; and varied greatly in the size, structure, and number of affected individuals. Class III affected and unaffected individuals were diagnosed based on cephalometric measurements, models, photographs and/or oral examination. Maximum maximized LOD score (MMLS) and multipoint heterogeneity LOD scores (HLODs) maximized over different levels of heterogeneity, and two genetic models (reduced penetrance dominant and recessive), were generated using SimWalk2. To estimate the empirical significance of these multipoint HLODs, 1000 replicates of unlinked genotype data based on real data pedigree structures, affection status and pattern of missing genotypes were simulated for the Brazilian and Colombian cohort using SLINK and SIMULATE respectively. These replicates were then analyzed using SimWalk2 with the original maximizing mode of inheritance. Power was estimated similarly for each cohort by generating 1000 replicates of pedigree data linked to the SNP with the highest HLOD. The corresponding cohort-specific mode of inheritance was used for the power simulation genetic parameters. For the Brazilian cohort, the MMLS was observed for rs12416856 at 191.6 cM (HLOD=1.84), under a recessive mode of inheritance. The empirical significance for this HLOD was a p-value