The main findings of the present study are that IL17A (rs3819024 and rs3819025) and IL17RA (rs2241043, rs2241049 and rs6518661) genetic variants were not associated with the susceptibility to UC. Aside from that, the IL17A GA genotype of the rs3819024 variant was associated with higher IL-17A plasma levels in UC patients but not in healthy controls. Additionally, AG + GG genotypes of IL17RA rs2241049 variant were associated with a 2.94-fold increased chance of developing moderate/severe illness. Our data demonstrated that UC patients had higher IL-17A plasma levels than healthy controls. Upregulation of the pleiotropic proinflammatory IL-17A cytokine has also been reported in patients with UC [17], UC and active Crohn’s disease (CD) [11]. However, our study did not demonstrate that the IL-17A levels were associated with disease severity.
IL-17A was abundantly detected in inflamed IBD mucosa and its identification represented a hallmark in IBD immunology by revealing a novel pathway for the interaction between innate and adaptive immune response. Th17-related cytokines are elevated in the intestinal mucosa of IBD patients, suggesting that Th17 cells play a major role in disease activity and mucosal destruction [18]. However, Th17 cells in the intestines of disease-free mice appeared to enhance intestinal barrier function by stimulating the development of tight junctions and antimicrobial peptides [19]. Thus, the pathogenicity of Th17 cells in IBD is unknown, and the role of Th17 response in the bowel is heterogeneous, with the capacity to be either protective or inflammatory [3].
In the current study, two SNVs of IL17A (rs3819024 and rs3819025) and three SNVs of IL17RA (rs2241043, rs2241049, and rs6518661) in UC patients that could impact IL-17A concentration or biological effects were examined. The IL17A rs3819024 genetic variant is situated in an upstream region (-444 A > G), whereas the IL17A rs3819025, IL17RA rs2241043, IL17RA rs2241049, and IL17RA rs6518661 variants are located in intronic (non-coding) regions. There was no association between IL17A rs3819024 and IL17A rs3819025 variants and UC susceptibility. Senhaji et al. [11] investigated 10 SNVs in five genes, including the IL17A rs3819024, in IBD patients and healthy controls and found no significant association between these variants and the development of UC. Our results are consistent with those of Senhaji et. al. [11]; however, are conflict with those reported by Mc Govern et al. [20] who investigated 10 SNVs in patients with CD and controls and found that IL17A haplotypes were associated with both risk and protection. These authors showed that the H2 haplotype (rs2275913, rs3819025, rs10484879, and rs1974226) was protective in Jewish individuals with CD while was risky in non-Jewish patients. Consequently, it is possible that haplotypes of other IL17A variants are related with UC susceptibility [20].
To our knowledge, the IL17A variant rs3819025 as well as the IL17RA variants rs2241043 and rs6518661 have not been examined in patients with UC but have been studied in patients with other autoimmune disorders [21, 22]. Catanoso et al. [21] demonstrated that the rs2241043, rs2241049, rs3819025, and rs6518661 variants were not related with psoriatic arthritis susceptibility. Moreover, Kim et al. [22] investigated IL17RA (rs2241049) and IL17A (rs3819025) variants and found no association between these variants with psoriasis susceptibility.
We found that the AG genotype of IL17A variant (rs3819024) was related with elevated IL-17A plasma levels in UC patients but not in healthy controls. It is possible that the small number of participants with the GG genotype limited us from finding an association. There are no studies that associated this IL17A variant to IL-17 plasma levels or the severity of UC. In addition, patients with the AG genotype of IL17A variant (rs3819025) had a statistical tendency toward elevated IL-17A plasma levels when compared to patients with other genotypes, but only in UC patients and not in controls. A previous study found an association between rs3819025 and increased IL-17A serum levels in breast cancer in the presence of G allele [23].
In the present study, the association between AG genotype and IL-17A plasma levels, but not other genotypes, was intriguing. However, an important observation must be made regarding molecular heterosis, which occurs when subjects heterozygous for a particular genetic polymorphism exhibit a significantly greater effect (positive heterosis) or a significantly smaller effect (negative heterosis) than subjects homozygous for each allele [24]. Interactions between multimeric protein products are believed to be a common source of overdominance, which is anticipated to be quite common. Moreover, intermediate expression levels may be optimum for specific functions [25].
In relation to IL17RA variants, we did not find any association between the studied variants and the UC susceptibility. Nevertheless, AG + GG genotypes (dominant model) (rs2241049) were associated with a more severe phenotype of UC disease, as assessed by the Mayo score. Limited studies are found to discuss our results. One study [26] evaluated patients submitted to lung transplant and found an association between the GG genotype of the IL17RA rs2241049 variant and the risk of primary graft dysfunction, most likely due to an increase in IL-17RA and the proliferation and differentiation of IL-17 producing cells, cytokines, and growth factors.
There are a number of considerations that must be taken into account when comparing our results to those of others, including the design of the research, the sample size, and the variability of variation frequency within ethnically distinct cohorts. It is essential to underline the extremely diverse ethnic traits of the Brazilian people as a whole. In addition, the complicated interplay between genotypes analyzed and disease severity in UC merits additional exploration.
Some limitations of this study should be considered, as the small sample size of participants in the group of UC, which could explain some statistical trends. This is also a case–control design, which does not allow inferences on causal relationship. Other limitation is that probably other factors may affect the susceptibility for UC, as well as disease activity, such as other genetic variants coding proinflammatory molecules, epigenetic, and environmental factors. However, this study has some strengths, such as the adjustment of variables for many confounding variables including sex, ethnicity, smoking, and BMI, as well as the high sensitivity and specificity of the immunofluorimetric assay used to measure the IL-17 plasma levels. In addition, to our knowledge, this is the first study to investigate the relationship between IL17A rs3819025 and IL17RA rs2241043 and rs6518661 variants in UC patients.
In conclusion, IL17A GA genotype (rs3819024) was associated with elevated IL-17A plasma levels only in UC patients but not in controls. In addition, AG + GG genotypes of the IL17RA (rs2241049) variant were associated with moderate/severe endoscopic activity of UC. In addition, we cannot ignore the possibility of a hidden interaction between the IL17A variant (rs3819024) and other genetic, epigenetic or environmental variables that could exert some effects in the IL-17A levels modulation of the patients with UC and absent in controls.