Functional Haplotypes in Interleukin 4 Gene Associated with Periodontitis

Abstract

Chronic periodontitis (CP) is an infectious inflammatory disease that affects tooth-supporting structures and in which dental plaque bacteria, immune mechanisms and genetic predisposition play important roles. Interleukin 4 (IL-4) is a key anti-inflammatory cytokine with relevant action in imbalances in inflamed periodontal tissue. Individuals carrying the TCI/CCI genotype (S-haplotype) of the IL-4 gene are 5 times more susceptible to CP, whereas the CTI/TTD genotype (P-haplotype) confers protection against CP. Compared with the S-haplotype, subjects with the P-haplotype produce higher levels of the IL-4 protein after non-surgical periodontal therapy. The present in vitro study aimed to investigate the functionality of IL-4 haplotypes in immune cells to obtain insight into the influence of these genetic variations in regulating immune responses to CP-associated bacteria. Peripheral blood was collected from 6 subjects carrying each haplotype, and their immune cells were challenged with periodontopathogens to compare responses of the different haplotypes with regard to gene expression, protein secretion and the immunophenotype of T helper responses. We found higher IL-4 mRNA and protein levels in the P-haplotype, which also presented higher levels of anti-inflammatory cytokines. In contrast, cells from S-haplotype subjects responded with higher levels of pro-inflammatory cytokines. S-haplotype individuals exhibited significantly greater polarization toward the Th1 phenotype, whereas the P-haplotype was associated with an attenuated response to periodontopathogens, with suggestive skewing toward Th2/M2 phenotypes. In conclusion, IL-4 genetic variations associated with susceptibility to or protection against chronic periodontitis are directly associated with influencing the response of immune cells to periodontopathogens.

Genetic polymorphisms in the Interleukins IL1B, IL4, and IL6 are associated with concomitant periodontitis and type 2 diabetes mellitus in Brazilian patients

“…When considering that SNP of part of a haplotype, Anovazzi et al, 2010 identified a haplotype in the IL4 gene associated with lower risk to periodontitis. In a subsequent study, that named IL4 protection haplotype was associated with high‐production of IL‐4 mRNA and protein levels and higher levels of anti‐inflammatory cytokines, while the susceptible haplotype produced higher levels of pro‐inflammatory cytokines 52 . Interestingly, subsequent studies demonstrated that the IL‐4‐susceptible haplotype was associated with the high levels of periodontopathogens that could, in a synergistic way, contribute to the periodontium infection and development of periodontitis in subjects carrying this haplotype 53,54 .…”

Characteristics of interleukin-4 gene (C-589T, rs2243250) polymorphism in children with bronchial asthma and allergic rhinitis with isolated or allergic rhinitis-induced comorbid malocclusion

“…Furthermore, modern scientific studies have confirmed that the IL-4 gene polymorphism influence IL-4 and other cytokines production regulating immune responses that directly associated with caries and periodontitis development [27][28][29].…”

Evidence Linking PPARG Genetic Variants with Periodontitis and Type 2 Diabetes Mellitus in a Brazilian Population

“…To obtain insight into the influence of the rs1151999 SNP on the expression of PPARG and pro- and anti-inflammatory genes, we recalled some individuals carrying each rs1151999 genotype (GG, GT or TT), and repeated the physical, biochemical and periodontal evaluations. Because we were interested in assessing the potential influence of rs1151999 on gene expression, we calculated the sample size with the DDS Research sample size calculator (SPH Analytics, Alpharetta, GA, USA), utilizing gene expression values from a previous study [ 57 ]. Based on this calculation, we required at least six subjects carrying each genotype (GG, GT, and TT) to have the ability to detect significant (at the 80% confidence level) differences of 0.3 units in the average gene expression values, with an estimated variation of 0.6 units.…”