Genetic Polymorphisms in the DR2D, ANKK1, COMT, 5HTT Genes and Dental Fluorosis: Is There Any Interplay?

Luíse Gomes de Souza; Paula Cruz Porto Spada; Juliana Feltrin de Souza; Daniela Silva Barroso de Oliveira; Letícia Maira Wambier; Erika Calvano Küchler; João Armando Brancher

Authors

Luíse Gomes de Souza
Paula Cruz Porto Spada
Juliana Feltrin de Souza
Daniela Silva Barroso de Oliveira
Letícia Maira Wambier
Erika Calvano Küchler
João Armando Brancher

Keywords:

Fluorosis, Dental, Polymorphism, Genetic, Genetics

Abstract

Objective: To investigate the association between genetic polymorphisms in DRD2, ANKK1, COMT, and 5HTT genes and dental fluorosis (DF). Material and Methods: 256 adolescents were examined, and dental fluorosis was diagnosed using the modified Dean index. Genomic DNA was collected, and seven single nucleotide polymorphisms (SNPs), two in the DRD2 (rs6275 and rs6276), one in the ANKK1 (rs1800497), two in the COMT (rs6269 and rs4818), and two in the 5HTT (rs3813034 and rs1042173) were selected. Allele, haplotype, and diplotype frequency comparisons were performed. Multifactorial Dimensionality Reduction investigated SNP-SNP interactions. Allele and haplotype frequency comparisons were performed by PLINK version 1.06. The Fisher exact test performed genotypic analysis, and Poisson Regression was adjusted by gender. Results: In the allelic frequency analysis, rs6275 was associated with DF (p=0.040), and rs6276 was borderline (p=0.07), being confirmed in the haplotype (p<0.05) and diplotype (p=0.007) analysis. Conclusion: The data suggest that DRD2, ANKK1, COMT, and 5HTT genes synergistically interact to increase the dental fluorosis risk.

References

Fejerskov O, Manji F, Baelum V. The nature and mechanisms of dental fluorosis in man. J Dent Res 1990; 69(Spec No):692-721. https://doi.org/10.1177/00220345900690S135

McKay FS. Mass control of dental caries through the use of domestic water supplies containing fluorine. Am J Public Health Nations Health 1948; 38(6):828-832. https://doi.org/10.2105/ajph.38.6.828

Pramanik S, Saha D. The genetic influence in fluorosis. Environ Toxicol Pharmacol 2017; 56:157-162. https://doi.org/10.1016/j.etap.2017.09.008

Everett ET. Fluoride's effects on the formation of teeth and bones, and the influence of genetics. J Dent Res 2011; 90(5):552-560. https://doi.org/10.1177/0022034510384626

Majumdar KK. Health impact of supplying safe drinking water containing fluoride below permissible level on flourosis patients in a fluoride-endemic rural area of West Bengal. Indian J Public Health 2011; 55(4):303-308. https://doi.org/10.4103/0019-557X.92411

Santos EUD, Sampaio TF, Tenório Dos Santos AD, Bezerra Leite FC, da Silva RC, Crovella S, et al. The influence of SLC6A3 and DRD2 polymorphisms on levodopa-therapy in patients with sporadic Parkinson's disease. J Pharm Pharmacol 2019; 71(2):206-212. https://doi.org/10.1111/jphp.13031

Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, et al. Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 2002; 15(2):246-256. https://doi.org/10.1046/j.0953-816x.2001.01856.x

Mehta A. Biomarkers of fluoride exposure in human body. Indian J Dent 2013; 4(4):207-210. https://doi.org/10.1016/j.ijd.2013.05.002

Peckham S, Awofeso N. Water fluoridation: A critical review of the physiological effects of ingested fluoride as a public health intervention. Sci World J 2014; 2014:293019. https://doi.org/10.1155/2014/2930199

Aoba T, Fejerskov O. Dental fluorosis: Chemistry and biology. Crit Rev Oral Biol Med 2002; 13(2):155-170. https://doi.org/10.1177/154411130201300206

Saha D, Goswami R, Majumdar KK, Sikdar N, Pramanik S. Evaluating the association between dental fluorosis and polymorphisms in bone development and mineralization genes among population from a fluoride endemic region of Eastern India. Biol Trace Elem Res 2021; 199(1):1-8. https://doi.org/10.1007/s12011-020-02116-9

Küchler EC, Dea Bruzamolin C, Ayumi Omori M, Costa MC, Antunes LS, Pecharki GD, et al. Polymorphisms in nonamelogenin enamel matrix genes are associated with dental fluorosis. Caries Res 2018; 52(1-2):1-6. https://doi.org/10.1159/000479826

Romualdo PC, Pucinelli CM, Tannure PN, Nelson-Filho P, Segato RAB, Brancher JA, et al. Evaluation of genetic polymorphisms in MMP2, MMP9 and MMP20 in Brazilian children with dental fluorosis. Environ Toxicol Pharmacol 2019; 66:104-108. https://doi.org/10.1016/j.etap.2018.12.016

Abbasoglu Z, Dalledone M, Wambier LM, Pecharki G, Baratto-Filho F, Andrades KMR, et al. Single nucleotide polymorphism rs4284505 in microRNA17 and risk of dental fluorosis. Acta Odontol Scand 2020; 78(6):463-466. https://doi.org/10.1080/00016357.2020.1786600

Zhao L, Yu C, Lv J, Cui Y, Wang Y, Hou C, et al. Fluoride exposure, dopamine relative gene polymorphism and intelligence: A cross-sectional study in China. Ecotoxicol Environ Saf 2021; 209:111826. https://doi.org/10.1016/j.ecoenv.2020.111826

Galli C, Macaluso G, Passeri G. Serotonin: A novel bone mass controller may have implications for alveolar bone. J Negat Results Biomed 2013; 12:12. https://doi.org/10.1186/1477-5751-12-12

Feuer AJ, Demmer RT, Thai A, Vogiatzi MG. Use of selective serotonin reuptake inhibitors and bone mass in adolescents: An NHANES study. Bone 2015; 78:28-33. https://doi.org/10.1016/j.bone.2015.04.042

Baudry A, Schneider B, Launay JM, Kellermann O. Serotonin in stem cell based-dental repair and bone formation: A review. Biochimie 2019; 161:65-72. https://doi.org/10.1016/j.biochi.2018.07.030

Bertoli FMP, Bruzamolin CD, Pizzatto E, Losso EM, Brancher JA, de Souza JF. Prevalence of diagnosed temporomandibular disorders: A cross-sectional study in Brazilian adolescents. PLoS One 2018; 13(2):e0192254. https://doi.org/10.1371/journal.pone.0192254

Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Secretaria de Vigilância em Saúde. SB Brasil 2010: Pesquisa Nacional de Saúde Bucal: resultados principais / Ministério da Saúde. Secretaria de Atenção à Saúde. Secretaria de Vigilância em Saúde. – Brasília: Ministério da Saúde, 2012.116 p: il. [In Portuguese].

Hudson TJ, Cooper DN. STREGA: a 'How-To' guide for reporting genetic associations. Hum Genet 2009; 125(2):117-118. https://doi.org/10.1007/s00439-009-0624-y

Rozier RG. Epidemiologic indices for measuring the clinical manifestations of dental fluorosis: overview and critique. Adv Dent Res 1994; 8(1):39-55. https://doi.org/10.1177/08959374940080010901

Küchler EC, Tannure PN, Falagan-Lotsch P, Lopes TS, Granjeiro JM, Amorim LM. Buccal cells DNA extraction to obtain high quality human genomic DNA suitable for polymorphism genotyping by PCR-RFLP and Real-Time PCR. J Appl Oral Sci 2012; 20(4):467-471. https://doi.org/10.1590/s1678-77572012000400013

Trevilatto PC, Line SR. Use of buccal epithelial cells for PCR amplification of large DNA fragments. J Forensic Odontostomatol 2000; 18(1):6-9.

Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci 2007; 30(5):194-202. https://doi.org/10.1016/j.tins.2007.03.006

Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, et al. Distinct functions of the two isoforms of dopamine D2 receptors. Nature 2000; 408(6809):199-203. https://doi.org/10.1038/35041572

Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: A novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 2004; 23(6):540-545. https://doi.org/10.1002/humu.20039

Masiak J, Chmielowiec J, Chmielowiec K, Grzywacz A. DRD4, DRD2, DAT1, and ANKK1 genes polymorphisms in patients with dual diagnosis of polysubstance addictions. J Clin Med 2020; 9(11):3593. https://doi.org/10.3390/jcm9113593

Munafò MR, Matheson IJ, Flint J. Association of the DRD2 gene Taq1A polymorphism and alcoholism: A meta-analysis of case-control studies and evidence of publication bias. Mol Psychiatry 2007; 12(5):454-461. https://doi.org/10.1038/sj.mp.4001938

Chiang TI, Lane HY, Lin CH. D2 dopamine receptor gene (DRD2) Taq1A (rs1800497) affects bone density. Sci Rep 2020; 10(1):13236. https://doi.org/10.1038/s41598-020-70262-0

Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Gen 2004; 75(5):807-821.

Tunbridge EM, Huber A, Farrell SM, Stumpenhorst K, Harrison PJ, Walton ME. The role of catechol-O-methyltransferase in reward processing and addiction. CNS Neurol Disord Drug Targets 2012; 11(3):306-323. https://doi.org/10.2174/187152712800672409

Ermakov PN, Vorobyeva EV, Denisova EG, Yavna DV, Babenko VV, Kovsh EM, et al. Recognition of emotional and neutral visual scenes in carriers of the MAOA, COMT, DRD4, and 5HT2A gene polymorphisms. Psychol Russ 2022; 15(4):159-169. https://doi.org/10.11621/pir.2022.0410

David DJ, Gardier AM. Les bases de pharmacologie fondamentale du système sérotoninergique: application à la réponse antidépressive. Encephale 2016; 42(3):255-263. https://doi.org/10.1016/j.encep.2016.03.012 [In French].

Zhang S, Zhang X, Liu H, Qu W, Guan Z, Zeng Q, et al. Modifying effect of COMT gene polymorphism and a predictive role for proteomics analysis in children's intelligence in endemic fluorosis area in Tianjin, China. Toxicol Sci 2015; 144(2):238-245. https://doi.org/10.1093/toxsci/kfu311

Yu X, Chen J, Li Y, Liu H, Hou C, Zeng Q, et al. Threshold effects of moderately excessive fluoride exposure on children's health: A potential association between dental fluorosis and loss of excellent intelligence. Environ Int 2018; 118:116-124. https://doi.org/10.1016/j.envint.2018.05.042

Moiseiwitsch JR. The role of serotonin and neurotransmitters during craniofacial development. Crit Rev Oral Biol Med 2000; 11(2):230-239. https://doi.org/10.1177/10454411000110020601

Moiseiwitsch JR, Raymond JR, Tamir H, Lauder JM. Regulation by serotonin of tooth-germ morphogenesis and gene expression in mouse mandibular explant cultures. Arch Oral Biol 1998; 43(10):789-800. https://doi.org/10.1016/s0003-9969(98)0067-3

Cunha LF, Tomita NE. Dental fluorosis in Brazil: A systematic review from 1993 to 2004. Cad Saúde Pública 2006; 22(9):1809-1816. https://doi.org/10.1590/S0102-311X2006000900011

Lima IFP, Nóbrega DF, Cericato GO, Ziegelmann PK, Paranhos LR. Prevalence of dental fluorosis in regions supplied with non-fluoridated water in the Brazilian territory: A systematic review and meta-analysis. Cien Saude Colet 2019; 24(8):2909-2922. https://doi.org/10.1590/1413-81232018248.19172017

Zhao H, Pfeiffer R, Gail MH. Haplotype analysis in population genetics and association studies. Pharmacogenomics 2003; 4(2):171-178. https://doi.org/10.1517/phgs.4.2.171.22636

Baudry A, Alleaume-Butaux A, Dimitrova-Nakov S, Goldberg M, Schneider B, Launay JM, et al. Essential roles of dopamine and serotonin in tooth repair: functional interplay between odontogenic stem cells and platelets. Stem Cells 2015; 33(8):2586-2595. https://doi.org/10.1002/stem.2037

Balic A, Thesleff I. Tissue interactions regulating tooth development and renewal. Curr Top Dev Biol 2015; 115:157-186. https://doi.org/10.1016/bs.ctdb.2015.07.006

Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001; 69(1):138-147. https://doi.org/10.1086/321276