Association of type and severity of nonsyndromic OROFACIAL CLEFTS with combined genotypes of RFC1 80 GA, MTHFR 677 CT, IRF6 rs642961 and rs2235371 gene polymorphisms in an Indian population Abstract By Chantal Hakim University of the Pacific. Arthur Dugoni School of Dentistry 2020 Introduction. Genetic etiology of nonsyndromic orofacial clefts comprises many genes acting together. However, little is known about their interactions. The purpose of our study was to analyze associations of phenotypic subtypes of nonsyndromic orofacial clefts with combinations of four genotypes involving candidate gene polymorphisms. Materials and Methods. We analyzed a large dataset of cases and controls collected in one location (Karaikal in India) and genotyped for four gene polymorphisms: RFC1 G80A, MTHFR C677T, IRF6 GA rs642961 and IRF6 CT rs2235371 (IRB approval Nr. 17-118 for existing data). The samples were tested for Hardy-Weinberg genetic equilibrium. Combinations of genotypes in cleft subsamples were compared with controls using Odds Ratio and Confidence Interval (95% significance level) calculations. Results. The Hardy-Weinberg equilibrium test showed that all samples were in genetic equilibrium. Some combinations of RFC1 G80A, MTHFR C677T, IRF6 GA rs642961 and IRF6 CT rs2235371 yielded increased or decreased Odds Ratio (OR>1 or OR<1).This means that subtypes of orofacial clefts were differentially determined by genotype combinations of four gene polymorphisms. Conclusions. Our results suggest that combinations of gene polymorphisms may modulate genetic risk in subtypes of nonsyndromic orofacial clefts. Such studies seem to be important for development of a general procedure and how a prevention plan for a specific location needs to be prepared, which data needs to be collected and which analyses need to be performed.