Associação dos polimorfismos dos genes TLR4 896 A>G (rs4986790) e iNOS -1173 C>T (rs9282799) com o câncer do colo uterino em mulheres infectadas pelo HPV em uma amostra da população de Alagoas, Brasil: um estudo caso-controle e meta-análise

Abstract

Cervical cancer is one of the leading causes of death among women in the world, representing the fourth most frequent and fourth leading cause of cancer death in the female population worldwide. This malignant neoplasm mainly affects socioeconomically vulnerable women and approximately 90% of cases are associated with high-risk HPV infection. In addition, immunological and genetic factors such as Single Nucleotide Polymorphisms (SNPs) present in host genes may play an important role in virus clearance or cervical cancer susceptibility, such as SNPs in Toll-Like Receptor 4 genes (TLR4) and Inducible Nitric Oxide Synthase (iNOS). Thus, the present study aimed to evaluate the association of TRL4 896 A>G (rs4986790) and iNOS -1173 C>T (rs9282799) gene polymorphisms with cervical cancer in women infected with HPV in a sample of the population of Alagoas, Brazil. This is a casecontrol study, where 99 samples were genotyped for the TRL4 896 A>G gene (72 healthy controls, 27 cases of HPV+ cervical cancer) and 120 samples for iNOS -1173 C>T (82 healthy controls, 38 cases of HPV+ cervical cancer) using the real-time Polymerase Chain Reaction (PCR) technique. Additionally, a systematic review and meta-analysis of the TLR4 896 A>G (rs4986790) polymorphism was performed. In the case-control study, the results referring to SNP 896A>G in the TLR4 gene showed a statistically significant difference when comparing allele and genotypic frequencies, where the 896G allele (p=0.01; OR with 95% CI=5.87 [1.41- 24.40]) and 896A/G genotype were associated with increased risk of cervical cancer (p=0.01; OR with 95% CI=6.57 [1.51-28.56]). This demonstrates that when comparing the 896A/A homozygote with the 896A/G heterozygote the presence of a G allele was sufficient to increase the risk. The sampling power was 100% and the population was in agreement with the HardyWeinberg equilibrium (p=0.63). The results of the meta-analysis of the TLR4 896 A>G (rs4986790) polymorphism did not demonstrate significant associations, differing from the results found in the population of Alagoas. This fact can be explained by the scarcity of association studies between the SNP TLR4 896 A>G (rs4986790) and cervical cancer, as well as the low sample size of the studies included in the meta-analysis. In the overall analysis of the association between the polymorphic variant -1173C>T of iNOS and cervical cancer, no association was found. The rare genotype -1173T/T was not identified in any group and the heterozygote -1173T/C had a low frequency in this population. The distribution of genotypic frequencies in the population was in accordance with the Hardy-Weinberg equilibrium (p=0.88). It is concluded that the G allele in the SNP TLR4 896 A>G (rs4986790) represents a risk factor for cervical cancer in the population of Alagoas. In the meta-analysis with other populations, no associations were found. The iNOS -1173 C>T SNP was not associated with cervical cancer in this population. However, the results regarding the polymorphism of the iNOS -1173 C>T gene are inconclusive due to the limited sample size, which presented a low sampling power.