Slc11a1 gene variants influence over host response patterns and periodontal diseases resistance and susceptibility phenotypes

Abstract

Abstract Genetic variants in Slc11a1 are shown to be associated with different infectious diseases in humans. This study aimed to correlate the Slc11a1 genetic polymorphisms rs2290708 and rs3731865 with periodontal diseases resistance/susceptibility profiles in humans, and to evaluate impact of Slc11a1 hypo/hyperresponsive variants on experimental periodontitis in mice. Genotypic analysis was performed in 45 patients with chronic periodontitis (CP), 476 healthy individuals (H) and 207 individuals with chronic gingivitis (CG), and subgroups were analyzed for analysis of possible correlations between expression/genotype and in vitro tests. The polymorphisms rs2290708 and rs3731865 were associated with periodontitis risk, with a higher frequency of the genotypes CT+TT and GC+CC and the alleles T and C in the CP group in the control case approach. The analysis of the putative SNPs functionality demonstrated that polymorphic T (rs2290708) and C (rs37371865) alleles were associated with increased TNF-α, IL-1β, IL-6, RANKL and RANKL/OPG ratio in periodontal lesions. In vitro results reinforced the potential hyper-reactive nature of the polymorphic alleles T and C, since macrophages bearing such alleles presented an increased the production the same cytokines cited above. The hyperreactive variants of Slc11a1, prevalent in AIRmax mice when compared with hyporeactive AIRmin strain, were associated with increased alveolar bone loss, leukocyte influx and production of proinflammatory cytokines in experimental periodontitis. Therefore, polymorphisms in the Slc11a1 influence host response patterns and periodontal diseases phenotypes in experimental and human periodontitis. Supported by grants from FAPESP (2019/12120-7 and 2015/24637-3)