title: Genetic Variants of BMP2 and Their Association with the Risk of Non-Syndromic Tooth Agenesis.
abstract: Non-syndromic tooth agenesis (or non-syndromic congenitally missing tooth) is one of the most common congenital defects in humans affecting the craniofacial function and appearance. Single nucleotide polymorphisms (SNPs) have been associated with an individual's susceptibility to these anomalies. The aim of the present study was therefore to investigate the roles of the potentially functional SNPs of BMP2 in the occurrence of tooth agenesis. Overall, four potentially functional SNPs of BMP2 (rs15705, rs235768, rs235769 and rs3178250) were selected, and their associations with the susceptibility of tooth agenesis were evaluated in a case-control study of 335 non-syndromic tooth agenesis cases and 444 healthy controls. The SNPs rs15705 and rs3178250 were found to be associated with an individual's risk of tooth agenesis (P = 0.046 and P = 0.039, respectively). Both SNPs showed an increased risk of mandibular incisor agenesis (rs15705, AA/AC vs. CC = 1.58, 95% CI = [1.06-2.34], P = 0.024; rs3178250, TT/TC vs. CC = 1.60, 95% CI = [1.08-2.37], P = 0.020). Bioinformatics analysis indicated that these two SNPs located at the 3'-untranslated region (3'-UTR) of BMP2 might alter the binding ability of miR-1273d and miR-4639-5p, respectively, which was confirmed by luciferase activity assays in the 293A and COS7 cell lines (P < 0.001 in 293A and P < 0.01 in COS7 for miR-1273d; and P < 0.001 in both cells for miR-4639-5p). Furthermore, BMP2 mRNA expression decreased after transfecting either miR-1273d or miR-4639-5p into these two cell lines (P < 0.01 in 293A and P < 0.001 in COS7 for miR-1273d, and P < 0.01 in both cell lines for miR-4639-5p). Taken together, our findings indicate that rs15705 and rs317250 are associated with the susceptibility of non-syndromic tooth agenesis by possibly affecting miRNAs and mRNA interaction.
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, College of Stomatology, Dalian Medical University, Dalian, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Orofacial Pain and TMD Research Unit, Institute of Stomatology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Jinglu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Gong
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Yongchu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000848:Anodontia / Q000235:genetics*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C000618326:MIRN1273 microRNA, human; C000621371:MIRN4639 microRNA, human; D035683:MicroRNAs