Determination of NLRP3 (rs4612666) and IL-1B (rs1143634) genetic polymorphisms in periodontally diseased and healthy subjects
Introduction
Chronic periodontitis (CP), an infection-induced inflammatory and progressive disease that leads to tooth-supporting tissues destruction, is one of the most prevalent diseases in the world, and it constitutes the foremost reason of tooth loss in the elderly (Tachi et al., 2003). It results from an imbalance between the levels of potentially pathogenic bacteria in the subgingival microbiota and the immunological potential of the host, which can be modified by several risk factors, including demographic, behavioral, environmental, and systemic aspects (Nunn, 2003). Furthermore, genetic factors may play a role in determining the host's immune response to infection and could account for significant variation in the distribution, severity, and extension of the disease (Nunn, 2003, Zhang, Sun et al., 2011; Laine, Crielaard, & Loos, 2012).
It has been recently demonstrated that one of the factors of innate immune response that might influence the activity of the CP is the activation of the nod-like receptor pyrin domain containing 3 (NLRP3)/apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC)/Caspase-1 multiprotein complex known as NLRP3 inflammasome in response to various bacterial, physical, and chemical agents (Bostanci et al., 2009, Belibasakis and Johansson, 2012; Belibasakis, Guggenheim, & Bostanci, 2013; Park et al., 2014). The formation of the inflammasome leads to the auto-proteolytic maturation of caspase-1, which subsequently results in maturation and extracellular release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 (Dinarello, 2002, Sahdo et al., 2013), that have been associated with inflammatory periodontal tissue destruction (Orozco, Gemmell, Bickel, & Seymour, 2006; Tobón-Arroyave et al., 2008), possibly through a mechanism known as pyroptosis, a form of cell death induced by bacterial pathogens (Strowig, Henao-Mejia, Elinav, & Flavell, 2012), being more potent in its action IL-1β (Dinarello, 1998). Known biological effects of IL-1β include stimulation of T-lymphocytes and cytokine production, proliferation of B-lymphocytes and antibody production (Chiplunkar, Langhorne, & Kaufmann, 1986), fibroblast proliferation, stimulation of prostaglandin E2 (PGE2) release by monocytes and fibroblasts, and release of metalloproteinases that degrade extracellular matrix proteins (Dewhirst, Stashenko, Mole, & Tsurumachi, 1985). IL-1β also promotes osteoclast formation and bone resorption (Gowen & Mundy, 1986), and it affects neutrophil chemotaxis and activation (Westmacott, Wadsworth, & Bloxham, 1987) and endothelial cell function (Goutoudi, Diza, & Arvanitidou, 2004).
Increasing evidence suggests that gain-of-function mutations in the NLRP3 gene lead to a constitutive activation of NLRP3 protein, resulting in an uncontrolled production of IL-1β (Sahdo et al., 2013). Alternatively, it has been postulated that the NLRP3 transcriptional activity can be modulated by single-nucleotide polymorphisms (SNPs) of the NLRP3 gene located on chromosome 1q44. A single base substitution variant (rs4612666) located at intron 7 where a change T > C occurs, is significantly associated with susceptibility to several inflammatory diseases including Crohn disease, psoriatic juvenile idiopathic arthritis, Behçet's syndrome, and rheumatoid arthritis (Day et al., 2008, Villani et al., 2009, Zhang, Zeng et al., 2011, Yüksel et al., 2014, Mathews et al., 2014). However, the association of NLRP3 (rs4612666) SNP with CP has not been described. In addition to the former, the production of IL-1β might be also synchronously modulated by the presence of a functional SNP at the position +3954 of the IL-1B gene (rs1143634) located in the exon 5 of the chromosome 2q13, where a transition between C and T occurs (Pociot, Mølvig, Wogensen, Worsaae, & Nerup, 1992; Nothwang et al., 1997). Nevertheless, the results of association of IL-1B +3954 SNP regarding chronic periodontitis have been conflictive, because while some researchers have found no evidence for association between IL-1B +3954 SNP and CP (Trevilatto, de Souza Pardo, Scarel-Caminaga, Alvim-Pereira, & Alvim-Pereira, 2011; Boukortt et al., 2015, Yücel et al., 2013), others authors have showed a strong association of the CT genotype with disease status in different populations (Shete, Joseph, Vijayan, Srinivas, & Banerjee, 2010; Masamatti, Kumar, Baron, Mehta, & Bhat, 2012; Amirisetty et al., 2015). Therefore, this study aimed to identify if a possible association between NLRP3 (rs4612666) and IL-1B (rs1143634) SNPs may be implicated in the etiopathogenesis of CP in a Colombian population.
Section snippets
Study design, subject recruitment, and inclusion/exclusion criteria
This cross-sectional, observational, analytic study was conducted with a convenience non-probabilistic sample of 205 volunteers from the population of individuals that sought treatment or consultation at the Graduate Periodontics as well as Adult Dental Health Clinics of the University of Antioquia in Medellín (Colombia). The study protocol conformed to the ethical guidelines of the Helsinki Declaration and followed the ethical policy of the Institutional Research Ethics Board. Subsequently,
Post-hoc genetic power calculation and reproducibility of findings
Genetic power calculations suggested that the sample of 124 patients with untreated CP and 81 periodontally HC would provide >93% power to reject the null hypothesis of no association at P < 0.01 when a genotypic relative risk was ≥1.8. Intra-observer reproducibility was excellent for PD (ICC = 0.981 and 0.938 respectively, P < 0.010), and CAL (ICC = 0.978 and 0.999 respectively, P < 0.001) scores in each series of measures recorded per subject by the same examiner. Likewise, inter-observer
Discussion
Over recent decades, immunogenetic studies have provided insight into the individual differences in the pathogenesis of CP and several recent publications have showed that susceptibility to dysbiotic microbial communities with potential for destructive inflammation is based on host genetic factors that may predispose to or protect from disease (Laine et al., 2012, Divaris et al., 2013; Stabholz, Soskolne, & Shapira, 2010; Hajishengallis, 2015). Hence, dysbiosis alone may not necessarily
Acknowledgment
This study has been fully supported by a grant of the Research Development Committee of the University of Antioquia (CODI-Code 2014-481).
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2019, Archives of Oral BiologyCitation Excerpt :In addition, recent studies have indicated that polymorphisms in genes encoding IL-1ß cytokines might be associated with PD susceptibility and severity. Numerous studies have investigated IL-1ß gene polymorphisms in PD patients in various populations, although the results are inconsistent (Armingohar, Jørgensen, Kristoffersen, Schenck, & Dembic, 2014; Boukortt et al., 2015; Iglesias-Linares et al., 2012; Isaza-Guzmán, Hernández-Viana, Bonilla-León, Hurtado-Cadavid, & Tobón-Arroyave, 2016; Tanaka, Miyake, Hanioka, & Arakawa, 2014; Trevilatto et al., 2011; Wu et al., 2015). Some studies suggest an association between IL-1ß gene polymorphisms and the development of PD, and others indicate an influence on disease severity; however, some studies failed to find an association between IL-1ß gene polymorphisms and PD.
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2018, Archives of Oral BiologyCitation Excerpt :For CP, the individual genetic profile is estimated to explain approximately 50% (Michalowicz et al., 2000) of the interindividual susceptibility as well as contributing to the severity and disease progression (Kornman et al., 1997). Apart from individual biological features, like age and gender, external factors also play a major role: the applied orthodontic forces for EARR, the characteristic subgingival dysbiotic microbiome and smoking habits for CP (Al-Qawasmi et al., 2003; Delima, Karatzas, Amar, & Graves, 2002; Hartsfield et al., 2004; Isaza-Guzman, Hernandez-Viana, Bonilla-Leon, Hurtado-Cadavid, & Tobon-Arroyave, 2016; Viecilli, Katona, Chen, Hartsfield, & Roberts, 2009). Despite having a different primary etiology, EARR and CP share molecular pathways involved in inflammation and bone metabolism, namely those dependent on IL1 cytokines.
Association between the rs1143634 polymorphism in interleukin-1B and chronic periodontitis: Results from a meta-analysis composed by 54 case/control studies
2018, GeneCitation Excerpt :A previous meta-analysis with 36 case/control studies indicated a strong association between the aforementioned polymorphism with chronic periodontitis in Asian and Caucasian ethnicities (Deng et al., 2013). But since this year, several others studies have been published in Caucasian (Baldini et al., 2013), African (Wagaiyu et al., 2014; Wagaiyu et al., 2015) and Brazilian ethnicities (Braosi et al., 2012; Medonça et al., 2015), as well as others populations (Isaza-Guzmán et al., 2016), which may bring others results with more power of association. Hence, a better evaluation about these data and ethnicity is required.