Non-syndromic Cleft Lip With Or Without Palate Susceptible SNPs Are Associated With Supernumerary Teeth

Background: Supernumerary teeth(ST),or hyperdontia,is one of the more common oral hereditary diseases,always accompanied by complications such as impacted teeth,malocclusion and crowded dentition etc.,which bring great influence on oral health.According to if they are related to the syndromes,they can be divided into syndrome supernumerary teeth(SST)and non-syndrome supernumerary teeth(NSST).Nonsyndromic cleft lip with or without cleft palate(NSCL/P)is a kind of congenital developmental defect in craniomaxillofacial region,which is easily suffered by Asian people.In the previous GWAS study carried out by our research group,5 SNPs(rs2235371,rs7078160,rs8049367,rs4791774 and rs13041247)were confirmed to be associated with NSCL/P in Chinese population.ST is closely related to heredity and NSST may share common genetic determinants with NSCL/P.Materials and methods: In this study,five NSCL/P susceptible single nucleotide polymorphisms(SNPs)(rs2235371,rs7078160,rs8049367,rs4791774 and rs13041247)from previous studies in our research group were selected to investigate the relationship between these SNPs and the risk of NSST.And we recruited 163 NSST cases and 326 controls for their genomic DNA from blood samples.Additive,dominant,heterozygote,homozygote genetic models and allele comparison were applied in the following stratification analyses.Five NSCL/P susceptible SNPs were genotyped by Taq Man method.Odds ratio(OR)and 95% confidence interval(CI)were used to estimate the associations between the SNPs and the risk of NSST by PLINK software.Results: The results showed that rs4791774(A>G)and rs13041247(T>C)were associated with the risk of NSST(P<0.05).Stratified analysis of clinical subtypes showed that rs13041247 and rs13041247 were associated with the risk of one supernumerary tooth(OST).The G allele of rs4791774 had a protective effect on the risk of NSST(Additive model: P=0.010,OR=0.60,95% CI: 0.41-0.88;Dominant model: P=0.009,OR=0.56,95% CI: 0.36-0.87;Heterozygote model: P=0.015,OR=0.57,95% CI: 0.37-0.90).Compared with allele A,G allele reduced the incidence of OST by 39% in Chinese population(P=0.010,OR=0.61,95% CI: 0.42-0.89).Rs13041247 increased the risk of OST(P=0.040,OR=1.33,95%CI=1.01-1.76).Compared with TT genotype,rs13041247 CC genotype increased the risk of OST by 1.82 times(P=0.034,OR=1.82 95% CI: 1.05-3.15).The C allele significantly increased the OST risk in the Chinese population by 35%(P=0.035,OR=1.35,95% CI: 1.02-1.79).Rs4791774 was also showed association with risk of upper arch supernumerary teeth only(USTO)(P=0.010).The analysis results of additive model,dominant model and heterozygote model showed that the G allele of rs4791774 played a protective role in NSST(Additive model: P=0.010,OR=0.60,95%CI=0.41-0.89;Dominant model:P=0.016,OR=0.59,95% CI=0.39-0.91;Heterozygote model: P=0.035,OR=0.62,95%CI=0.40-0.97),that means,patients with rs4791774 AG genotype had a 38% lower risk of NSST than those with AA genotype,while those with GG genotype had a greater risk reduction,which was 76% lower than those with AA genotype.Stratified analysis of clinical subtypes of the dentition showed that the G allele of rs4791774 played a protective role in the risks of permanent dentition supernumerary teeth(Dominant model: P=0.005,OR=0.53,95% CI: 0.34-0.83;Comparison of alleles:P=0.004,OR=0.57,95% CI: 0.99-0.83)In 110 patients with CBCT,the C allele of rs13041247 was also showed association with increased risk of palate-side supernumerary teeth(Comparison of alleles: P=0.0001,OR=3.32,95% CI: 2.45-4.49).Further bioinformatics analysis showed that the G allele of rs4791774 could change the affinity between Myc＿disc7 and participate in tooth development.The C allele of rs13041247 may regulate cellular processes such as apoptosis and proliferation by influencing the affinity between NF-E2 and Nrf-2.The results of functional pathway analysis of MAFB related genes of rs13041247 also suggested that MAFB plays an important role in the differentiation and development of HOX gene,and may be involved in pharyngeal arch and maxillary development.In a word,NSCL/P susceptible loci rs4791774(A>G)and rs13041247(T>C)had associations with the risk of supernumerary teeth.