Association of the IL1RN gene VNTR polymorphism (rs2234663) with chronic inflammation-associated cancer

One of the main tasks of modern medicine is to identify genetic predisposition to common diseases using molecular markers. This plays a crucial role in enabling early diagnosis and timely prevention. Currently, diseases that are either hereditary or non-hereditary, and which are caused by endogenous and exogenous factors, mutagenesis, and acute or chronic inflammatory processes, are the leading cause of both incidence and mortality. Of particular importance among these are various forms of cancer, which are associated not only with genetic factors but also with chronic inflammation. It is well established that proinflammatory cytokines, their biosynthesis and the proper functioning of signalling pathway components play a key role in the development and regulation of inflammatory processes, particularly chronic ones. In this context, along with agonists of interleukin-1 (IL-1), the interleukin-1 receptor antagonist (IL-1RA) and the gene encoding it (IL1RN) are critically involved in modulating IL-1 activity. The aim of the present study was to determine the association between the VNTR polymorphism (rs2234663) located in the second intron of the IL1RN gene and the risk of cancer presumably associated with chronic inflammation. The study material consisted of genomic DNA isolated from peripheral blood samples of cancer patients (experimental group, EG, n=80) and conditionally healthy individuals (control group, CG, n=84). Genotyping of the IL1RN VNTR polymorphism (rs2234663) was performed using the polymerase chain reaction (PCR) method with specific primers. Allele and genotype frequencies were calculated for both groups. Although all known alleles of the IL1RN gene were detected in the studied cohorts, several genotypes (*2*5, *2*6, *3*4, *3*5, *3*6, *4*5, *4*6, and *5*6) were not observed in either group. In the experimental group, the frequency of the normal allele *1 was approximately 1.4-fold lower, whereas the frequency of the mutant allele *2 was about 1.6-fold higher compared with the control group. Overall, the homozygous mutant genotype (*2*2) occurred approximately 2.1 times more frequently in cancer patients than in controls. To evaluate the strength of association between the IL1RN polymorphism and cancer susceptibility, odds ratios (OR), relative risks (RR), 95% confidence intervals (CI), Z-test statistics, and corresponding P values were calculated. The association between the risk allele *2 and cancer predisposition was statistically significant (OR≈2.2, RR≈1.53, P≈0.001). A pronounced association was also observed for the homozygous genotype *2*2 (OR≈2.84, RR≈2.18, P≈0.004). Notably, compared with heterozygous carriers (*1*2), individuals homozygous for the *2 allele (*2*2) exhibited approximately 2.4-fold higher odds (OR*2*2/OR*1*2) and about 2.0-fold higher relative risk (RR*2*2/RR*1*2) of developing cancer associated with chronic inflammation. Of the analysed genetic models, only the dominant model (*2*2 vs. *1*1 + *1*2) showed a statistically significant association with cancer risk (OR≈2.97, RR≈2.10, P=0.003).