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

Abstract

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 (TNF/LTA, IFNG, IL10, TLR1, NOD2, SOD2, and IL6) we observed statistically different survival curves for rs751271 at the NOD2 and rs2069845 at the IL6 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 NOD2 and rs2069845 at IL6 with leprosy reactions (HRGT = 0.45, p = 0.002; HRAG = 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 NOD2 and IL6 genes are associated with leprosy reactions as an outcome. NOD2 also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients.

Adding MASP1 to the lectin pathway—Leprosy association puzzle: Hints from gene polymorphisms and protein levels

“…Interestingly, among the miRNAs predicted to recognize these polymorphic sites, none bind TG, but miR-3181 preferentially recognizes CG and miR-2861, CA. Both are expressed in the liver [49], with miR-2861 being up-regulated by interleukin 6 [50], a proinflammatory cytokine with a pivotal role in leprosy disease [51]. It is thus conceivable that these regulatory mechanisms operate after disease establishment and activation of the acute phase response (Fig 6).…”

The association of nucleotide‐binding oligomerization domain 2 gene polymorphisms with the risk of asthma in the Chinese Han population

“…suggest that the rs3135500 variant might increase the risk for multiple system atrophy. A previous study found that the rs751271 polymorphism was associated with inflammatory reactions in leprosy (Sales‐Marques et al., ). Weidinger et al., () study found that the rs1077861 T allele decreased the risk of asthma, whereas the rs3135500 A allele was significantly associated with an increased risk of asthma.…”

AddingMASP1to the lectin pathway – leprosy association puzzle: hints from gene polymorphisms and protein levels

“…Interestingly, among the miRNAs predicted to recognize these polymorphic sites, none bind TG , but miR-3181 preferentially recognizes CG and miR-2861, CA . Both are expressed in the liver (56), with miR-2861 being up-regulated by interleukin 6 (57), a proinflammatory cytokine with a pivotal role in leprosy disease (58). It is thus conceivable that these regulatory mechanisms operate after disease establishment and activation of the acute phase response (Fig.…”