Genetic polymorphisms of the <i>IL6</i> and <i>NOD2</i> genes are risk factors for inflammatory reactions in leprosy

<div><p>The pathways that trigger exacerbated immune reactions in leprosy could be determined by genetic variations. Here, in a prospective approach, both genetic and non-genetic variables influencing the amount of time before the development of reactional episodes were studied using Kaplan–Meier survival curves, and the genetic effect was estimated by the Cox proportional-hazards regression model. In a sample including 447 leprosy patients, we confirmed that gender (male), and high bacillary clinical forms are risk factors for leprosy reactions. From the 15 single nucleotide polymorphisms (SNPs) at the 8 candidate genes genotyped (<i>TNF</i>/<i>LTA</i>, <i>IFNG</i>, <i>IL10</i>, <i>TLR1</i>, <i>NOD2</i>, <i>SOD2</i>, and <i>IL6)</i> we observed statistically different survival curves for rs751271 at the <i>NOD2</i> and rs2069845 at the <i>IL6</i> genes (log-rank p-values = 0.002 and 0.023, respectively), suggesting an influence on the amount of time before developing leprosy reactions. Cox models showed associations between the SNPs rs751271 at <i>NOD2</i> and rs2069845 at <i>IL6</i> with leprosy reactions (HR_GT = 0.45, p = 0.002; HR_AG = 1.88, p = 0.0008, respectively). Finally, IL-6 and IFN-γ levels were confirmed as high, while IL-10 titers were low in the sera of reactional patients. Rs751271-GT genotype-bearing individuals correlated (p = 0.05) with lower levels of IL-6 in sera samples, corroborating the genetic results. Although the experimental size may be considered a limitation of the study, the findings confirm the association of classical variables such as sex and clinical forms with leprosy, demonstrating the consistency of the results. From the results, we conclude that SNPs at the <i>NOD2</i> and <i>IL6</i> genes are associated with leprosy reactions as an outcome. <i>NOD2</i> also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients.</p></div

Graphical abstract to illustrate a possible effect of <i>NOD2</i> rs751271 SNP in leprosy reactions.

<p>Patients with the rs751271-GT genotype had lower IL-6 levels, which could influence the inflammatory balance and the susceptibility to or protection against leprosy reactions. NS: Not statistically significant.</p

Clinical characteristics of leprosy patients according to leprosy reaction outcome.

<p>Clinical characteristics of leprosy patients according to leprosy reaction outcome.</p

Serum dosage of IL-6, IFN-γ, and IL-10 and in leprosy patients that did not develop (No Reaction) or developed (Reaction) a reaction.

<p>(A) IL-6 dosage; No Reaction, N = 46; Reaction, N = 31. (B) IFN-γ dosage; No Reaction, N = 44; Reaction, N = 34. (C) IL-10 dosage; No Reaction, N = 41; Reaction, N = 23. The values were converted to a logarithmic scale. Cytokine production (pg/mL) was evaluated by ELISA and the median values were compared by a Mann–Whitney <i>t</i> test.</p