Two IL-17RA Variants Show No Link to Gastric Cancer in Brazil

In one of the few systematic investigations of interleukin-17 receptor A gene variants in gastric disease, researchers report that two candidate polymorphisms do not appear to influence susceptibility to gastritis or gastric cancer. The study, published in the Egyptian Journal of Medical Human Genetics, analyzed 301 gastric biopsy samples from a Brazilian cohort and found no statistically significant association between the IL-17RA variants rs887796:A>G and rs1468488:T>C and either condition, whether the variants were tested individually, under multiple genetic models, or combined as haplotypes. The only signal that emerged was a familiar one: Helicobacter pylori infection, the bacterium long established as a central carcinogenic driver in the stomach, was significantly more frequent among gastric cancer patients than among controls.

The research team, drawn from institutions including the Clinics Hospital of the Marilia Medical School, São Paulo Hospital of the Federal University of São Paulo, the Mercy Hospital of Marilia, and the Institute of Tropical Pathology and Public Health sector of the Federal University of Goiás, set out to address a gap left by earlier work. Only one prior study, conducted in a Chinese population, had examined these two polymorphisms in the context of gastric cancer, and it had not considered the presence of H. pylori at all. Because the IL-17 signaling pathway sits at the heart of the inflammatory response to H. pylori infection, the Brazilian group reasoned that variants in the receptor gene might modulate who develops gastritis and who progresses toward malignancy — and that any such effect could only be detected properly if infection status were built into the analysis.

The biological rationale was plausible. Gastric cancer is a multifactorial disease in which H. pylori drives carcinogenesis through inflammation mediated by cytokines, including the interleukin-17 family. The IL-17 family comprises six members, IL-17A through F, and five receptors. IL-17RA, located on chromosome 22q11.1, acts as the main mediator of IL-17A-induced signaling and, together with IL-17RC, forms the heteromeric receptor complex responsible for the response to IL-17F. The receptor is expressed in various cell types within the tumor microenvironment, including hematopoietic cells, fibroblasts, and epithelial cells. Both SNPs examined in the study sit in the 3′ untranslated region of the IL17RA gene, a region involved in post-transcriptional regulation: variants there can modify microRNA binding sites and thereby affect mRNA stability and gene expression. Previous bioinformatics analyses had flagged rs887796 and rs1468488 as potential microRNA binding site polymorphisms, and an earlier study had reported that specific genotypes of these SNPs were associated with a significantly lower risk of developing gastric cancer.

To test whether that earlier finding held in a different population, the researchers recruited participants of both sexes who had not received antiparasitic or antibiotic therapy within 30 days before sample collection. The 301 gastric biopsy specimens were stratified into three diagnostic categories based on histopathological examination using the Sydney and Laurén classification systems: a control group of 95 individuals with histologically normal gastric mucosa, a gastritis group of 112 patients, and a gastric cancer group of 94 patients. The control participants had undergone upper gastrointestinal endoscopy for gastrointestinal symptoms, routine clinical evaluation, or preoperative assessment, and no histopathological abnormalities were identified in their biopsies. The cohort included 126 males, with a mean age of 58.61 years, and 175 females, with a mean age of 53.96 years, and no statistically significant differences in age or sex distribution were observed among the three groups. All procedures were approved by the Research Ethics Committee of the Sacred Heart University Center under approval number 1.119.830, and written informed consent was obtained from all participants.

The laboratory workflow combined bacterial detection and genotyping on the same quantitative PCR platform. Gastric biopsy specimens were cryopreserved in liquid nitrogen, and genomic DNA was isolated using the QiAmp DNA Mini Kit, with concentration and purity assessed on a NanoDrop 2000 spectrophotometer. H. pylori was detected with a TaqMan Microbe Detection Assay run in duplicate on an ABI Prism 7500 Fast system, with positive controls using DNA from the J99 strain and negative controls containing nuclease-free water; samples with Ct values below 38 were considered positive. Genotyping of the two IL-17RA SNPs used TaqMan SNP Genotyping Assays with allele-specific probes. Every sample yielded a valid genotype, giving a genotyping rate of 100 percent, with no exclusions due to amplification failure or inconclusive results. Statistical analyses were performed in SNPStats, assessing Hardy-Weinberg equilibrium, odds ratios with 95 percent confidence intervals, and associations under codominant, dominant, recessive, and log-additive inheritance models, with adjustments for H. pylori status. Age and sex were not included as covariates because their distributions did not differ significantly among the groups.

The infection results reinforced the established epidemiology of gastric disease. Overall, 140 of the 301 analyzed individuals carried H. pylori. Infection was present in 37.9 percent of the control group, 47.3 percent of the gastritis group, and 54.3 percent of the gastric cancer group. Compared with controls, the gastritis group showed a higher frequency of infection that did not reach statistical significance, with an odds ratio of 1.47 and a p-value of 0.20. The gastric cancer group, by contrast, showed a significantly higher percentage of H. pylori-positive individuals than controls, with an odds ratio of 1.94, a 95 percent confidence interval of 1.10 to 3.48, and a p-value of 0.03. A sensitivity analysis using G*Power, considering the control-versus-cancer comparison of 189 individuals, alpha of 0.05, and 80 percent statistical power, indicated a minimum detectable effect size of w = 0.204.

Against that backdrop, the genetic findings were uniformly negative. The genotypic distributions of both SNPs were in Hardy-Weinberg equilibrium in all three groups, with p-values ranging from 0.23 to 1.00, supporting the reliability of the genotyping. For rs887796, the association analysis showed no statistically significant differences among the control, gastritis, and gastric cancer groups under the codominant, dominant, or recessive models, nor in the direct comparison between gastritis and cancer. The log-additive model, which evaluates a possible dose-response effect based on the number of variant alleles, likewise showed no trend: p-values of 0.24 for control versus gastritis, 0.38 for control versus cancer, and 0.91 for gastritis versus cancer. The rs1468488 polymorphism told the same story, with log-additive p-values of 0.91, 0.39, and 0.40 for the same three comparisons.

The haplotype analysis added a further layer of rigor. The two SNPs displayed partial linkage disequilibrium with low correlation between the loci — for example, D′ of 0.44 and r of −0.13 in the control-versus-gastritis comparison, D′ of 0.62 and r of −0.18 in the control-versus-cancer comparison, and D′ of 0.52 and r of −0.16 in the gastritis-versus-cancer comparison, all statistically significant — which justified testing the combined variants. Haplotype analysis, however, found no significant association with gastritis or gastric cancer in any comparison, with global haplotype association tests yielding p-values of 0.70, 0.68, and 0.66, respectively. Taken together, the individual and combined analyses indicated that these IL-17RA variants did not show statistically significant associations with either disease, regardless of the genetic model or the groups compared.

The contrast with the earlier Chinese study is instructive. Dong and colleagues, in their 2017 work, evaluated the same two variants in 500 gastric cancer cases and 500 controls and reported a significant association with gastric cancer risk. The Brazilian authors point to several differences that may explain the divergence: ancestry, with an Asian versus a Latin American population; sample size and study design, with the present study including three diagnostic groups rather than a two-way case-control design; and the adjustment for H. pylori infection, which the Chinese analysis did not consider. The authors also note that direct functional evidence demonstrating that either SNP alters IL17RA expression or receptor signaling remains limited, so the biological plausibility of the variants, however well grounded in genomic location and pathway biology, has yet to be established experimentally.

The authors are careful about what the negative result does and does not mean. They lack information on the genetic ancestry or ethnic composition of participants, and given the high degree of miscegenation in the Brazilian population, the influence of population stratification on genotypic frequencies cannot be ruled out. Residual confounding factors not evaluated in the study cannot be completely excluded, and although statistical power analyses indicated adequate power to detect small-to-moderate genetic effects, smaller associations, particularly those involving rare genotypes, may have gone undetected. No functional assays were performed. Their conclusion is accordingly measured: the findings suggest that IL-17RA rs887796 and rs1468488 are not major independent susceptibility markers for gastritis or gastric cancer in this Brazilian cohort, though the limited sample size may reduce power to detect modest genetic effects. Larger and more heterogeneous populations, along with functional analyses of the variants, will be needed to settle the question definitively.

Subject of Research: Association of IL-17RA gene polymorphisms rs887796 and rs1468488 with susceptibility to gastritis and gastric cancer in a Brazilian cohort accounting for H. pylori infection.

Article Title: Interleukin-17RA polymorphisms rs887796 and rs1468488 are not associated with gastric cancer

Article References: Fredi, B. M., Nagahara, M., Brandt, F. A., Coelho, M. M., Fonseca, A. D. S., Almeida, L. A. D., Chen, E. S., Barbosa, M. S., Payao, S. L. M., Rocha, J. C., & Rasmussen, L. T. (2026). Interleukin-17RA polymorphisms rs887796 and rs1468488 are not associated with gastric cancer. Egyptian Journal of Medical Human Genetics, 27(1), Article 77. https://doi.org/10.1186/s43042-026-00909-6

Image Credits: AI Generated

DOI: 10.1186/s43042-026-00909-6

Keywords: gastric cancer, IL-17RA, polymorphisms, Helicobacter pylori, gastritis, SNP genotyping, haplotype analysis, Brazilian cohort, inflammation, cytokines, genetic susceptibility, qPCR