Dataset Information

Targeted sequencing of NOTCH signaling pathway genes and association analysis of variants correlated with mandibular prognathism.

ABSTRACT:

Introduction

The purpose of this study was to systematically identify variants in NOTCH signaling pathway genes that correlate with mandibular prognathism (MP) in the general Chinese population.

Methods

Targeted sequencing of NOTCH signaling pathway genes was conducted in 199 MP individuals and 197 class I malocclusion control individuals. The associations of common and rare variants with MP, cephalometric parameters, and continuous cephalometric phenotypes were analyzed by principal component (PC) analysis. The associations between rare variants and MP were tested for each gene.

Results

Six SNPs, including rs415929, rs520688, and rs423023 in an exonic region of NOTCH4; rs1044006 in an exonic region of NOTCH3; rs1051415 in an exonic region of JAG1; and rs75236173 in the 3'-untranslated region (3'-UTR) of NUMB were associated with MP (P < 0.05). One common variant, rs1051415, in an exonic region of JAG1 was significantly related to PC1 (P = 3.608 × 10^- 4), which explained 24.3% of the overall phenotypic variation observed and corresponded to the sagittal mandibular position towards the maxilla, ranging from a posterior positioned mandible to an anterior positioned mandible. Additionally, 41 other variants were associated with PC1-5 (P < 0.05). With respect to rare variant analysis, variants within the EP300, NCOR2, and PSEN2 gene showed an association with MP (t < 0 .05).

Conclusions

An association between NOTCH signaling pathway genes and MP has been identified.

SUBMITTER: Han X

PROVIDER: S-EPMC8152080 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionSeveral candidate loci have been suggested as influencing mandibular prognathism (1p22.1, 1p22.2, 1p36, 3q26.2, 5p13-p12, 6q25, 11q22.2-q22.3, 12q23, 12q13.13, and 19p13.2). The goal of this study was to replicate these results in a well-characterized homogeneous sample set.MethodsThirty-three single nucleotide polymorphisms spanning all candidate regions were studied in 44 prognathic and 35 Class I subjects from the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository. The 44 subjects with mandibular prognathism had an average age of 18.4 years; 31 were female and 13 male; and 24 were white, 15 African American, 2 Hispanic, and 3 Asian. The 36 Class I subjects had an average age of 17.6 years; 27 were female and 9 male; and 27 were white, 6 African American, 1 Hispanic, and 2 Asian. Skeletal mandibular prognathism diagnosis included cephalometric values indicative of Class III such as an ANB smaller than 2°, a negative Wits appraisal, and a positive A-B plane. Additional mandibular prognathism criteria included negative overjet and visually prognathic (concave) profile as determined by the subject's clinical evaluation. Orthognathic subjects without jaw deformations were used as the comparison group. The mandibular prognathic and orthognathic subjects were matched by race, sex, and age. Genetic markers were tested by polymerase chain reaction with TaqMan chemistry. Chi-square and Fisher exact tests were used to determine overrepresentation of marker allele with an alpha of 0.05.ResultsAn association was unveiled between a marker in MYO1H (rs10850110) and the mandibular prognathism phenotype (P = 0.03). MYO1H is a Class I myosin that is in a different protein group than the myosin isoforms of muscle sarcomeres, which are the basis of skeletal muscle fiber typing. Class I myosins are necessary for cell motility, phagocytosis, and vesicle transport.ConclusionsMore strict clinical definitions might increase homogeneity and aid the studies of genetic susceptibility to malocclusions. We provide evidence that MYO1H can contribute to mandibular prognathism.