Influência e interações (epistáticas e gene-ambiente) de SNPs na experiência de cárie: evidências a partir de revisões sistemáticas e estudos prospectivos

Abstract

It is unquestionable - and the literature strongly supports - that the main factors for the development and progression of caries disease are related to biological, behavioral and socioeconomic factors. However, some individuals exposed to the same risk and/or protective factors may have a different pattern of caries occurrence. Thus, recent studies have investigated the possibility of genetic influence on the occurrence of dental caries, aiming to explain this part of the effect not explained by known risk factors. Therefore, the aim of the present study was to investigate the influence and interaction (epistatic and geneenvironment) of Single Nucluotide Polimorphysm (SNPs) on dental caries experience from systematic reviews and prospective studies in the 1982 Pelotas birth cohort. Systematic reviews and meta-analyzes were conducted to identify genetic polymorphisms and their effects on dental caries experience in adults and children. The search strategy was performed using relevant keywords and between MeSH terms considering the structure of each database (PubMed / MedLine, Scopus, ISI Web of Science, VHL - Virtual Health Library, Scielo). Only human studies were included with cross-sectional and/or longitudinal design. No language restrictions or period of publication were considered. Studies with literature review design, case reports and case series, conference abstracts, letters to the editor, and qualitative studies were excluded. After identifying SNPs and their estimated effects on dental caries experience in reviews, prospective studies were conducted to evaluate the impact and reproduction of the effects of these SNPs on the birth cohort. Thus, a representative sample of all 5,914 live births from the 1982 Pelotas cohort were prospectively investigated and the prevalence of caries was assessed at 15 years (n = 888), 24 (n = 720) and 31 years (n = 539). Group-Based trajectory modeling was used to identify groups with similar trajectories of CPO-D “decayed” component. Genetic material was collected, and SNPs related to genes (TUFT1, MMP20, MMP13, MMP2, DLX3, TIMP2, BMP7, TFIP11, TAS1R3, TAS1R2, CA6, MUC5B, AQP2, AQP5, LTF and MBL2) were genotyped. Genomic ancestry was evaluated using ADMIXTURE. Family income, sugar consumption and frequency and gingival bleeding were also investigated. We investigated epistatic interactions by the Generalized Multifactor Dimensionality Reduction (GMDR) software and gene-environment modification, inserting an interaction term between sugar consumption and genotype / allele. Parametric analysis by G-formula was used to analyze mediation effects. Results of the systematic reviews showed that the main SNPs associated with caries experience were: i) among the genes linked to dental mineral tissues the TFIP11, AMBN, VRD and AMELX ii) among the genes linked to the taste sensitivity genes TAS1R2, TAS1R3 and TAS2R38; iii) among the genes linked to salivary composition and salivary flow CA6, AQP5 and AQP2; iv) among the immune response genes MBL2 and MUC5B. Prospective studies found: i) an epistatic association involving rs243847 (MMP2), rs2303466 (DLX3) and rs388286 (BMP7) capable of increasing the dental caries trajectory (OR=2.51, 95%CI[1.54–4.09]); ii) SNP rs307355 (TAS1R3) was associated with high caries trajectory (OR=4.17, 95%CI[1.21– 14.42]) and showed an epistatic interaction with rs35874116 (TAS1R2) (OR=1.72, 95%CI [1.04-2.84]); iii) rs10875989 (AQP2) was associated with an elegant caries trajectory (OR=1.38, 95%CI [1.07–1.78]) and presented a three locus interaction with rs2274333 (CA6) and rs3759129 (AQP5) which increased the chances of being in the group of high caries trajectory (OR=2.31, 95%CI [1.53–3.47]); g-formula showed that the effect between rs10875989 (AQP2) and caries was mediated by gingival bleeding (p <0.05) rather than sugar consumption (p> 0.05); iv) rs11716497 (LTF) was associated with high caries trajectory (OR=1.61, 95%CI [1.03–2.52]) and an epistatic interaction with rs4547741 (LTF) and rs11716497 (LTF) was also observed. G-formula showed that the association between rs11716497 (LTF) and caries trajectory had a direct effect and was not mediated by sugar intake (p <0.001). Thus, based on the results obtained from the systematic reviews and metaanalyzes added to the findings of prospective studies, we conclude that dental caries has an important genetic component capable of influence the caries experience and trajectory of individuals. In addition, epistatic interactions seem to play an important role in the genetic architecture of dental caries and environmental factors may modify the genetic effect on the phenotype.