The immune system is activated by MHC-peptide complexes, after which it eliminates infected and cancerous cells in various ways. The APM plays crucial roles in the initiation and development of various human diseases. As components of the APM, ERAP1 and ERAP2 are important determinants of the repertoire of peptides ultimately presented by HLA class I molecules (39-42). Moreover, the SNPs in ERAP genes have been shown to affect the function of ERAPs by changing their peptidome or enzymatic activity (29, 30, 43). In cervical cancer, ERAP1 and ERAP2 proteins have been reported to be highly variable, ranging from low to high expression levels (44-46). Although there are inconsistencies among these studies, it is clear that the dysregulated expression of ERAP proteins, which may be induced by ERAP gene SNPs (47, 48), is associated with cervical cancer risk.
In 2007, Mehta et al. found that rs27044 in ERAP1 was associated with cervical cancer risk. In the current study, rs27044 was found to be associated with cervical cancer risk (P = 0.003). The C allele of rs27044 (Q730) was found to be a protective factor for cervical cancer (OR = 0.838, 95% CI: 0.746-0.941) (Table 2), which was consistent with the results of Mehta’s study (24). The SNP, rs27044, a non-synonymous polymorphism, leads to a Q730E substitution in the IV catalysis domain of ERAP1 (33) and may change the substrate length preferences of ERAP1 (49). Therefore, rs27044 may play a role in cervical cancer by affecting ERAP1 function.
The SNP, rs26618, in ERAP1 leads to an amino acid substitution (I276M) and the current study showed that the CC genotype of this SNP may be associated with an increased risk of cervical cancer (OR = 1.53; 95% CI: 1.14-2.05) compared with TT-CT genotypes (Table 4). In 2016, Guasp et al. reported that I276M (rs26618) may affect the peptidome of ERAP1 by destroying peptides with p2 Ala, unless the p1 amino acid was resistant to ERAP1 trimming (43), which indicated that rs26618 may be associated with cervical cancer. However, in a Netherlands population, Mehta et al. reported no association between rs26618 and cervical carcinoma. One of the reasons of inconsistency between our data and Mehta et al. could be the different sample sizes and statistical power. The sample size used by Mehta et al. was 251 individuals and the statistical power of rs26618 is 0.141, while 2,890 individuals were enrolled in the current study and the statistical power of the same SNP is 0.621. In addition, the different population genetic background could be another reason.
In 2007, Mehta et al. reported that the C allele of rs26653 in ERAP1 was associated with a higher cervical cancer risk in a Netherlands population (24). In the current study, the G allele (OR = 0.829; 95% CI: 0.738-0.930) (Table 2), compared to the C allele, and the 2GG+CG genotype, compared to the CC genotype (OR = 0.82; 95% CI: 0.73-0.93) of rs26653, were associated with lower cervical cancer risk (Table 4). In 2014, Stratikos et al. and Alvarez-Navarro et al. reported that rs26653, which is a non-synonymous polymorphism resulting in a P127R substitution, may be associated with ERAP expression (18, 49), and this substitution may also affect the enzymatic activity of ERAP1 in the editing of tumour antigen peptides. This finding may explain the association between rs26653 and cervical cancer risk; however, the mechanisms need to be determined in functional studies.
In the current study, we found an association between rs2287988 in ERAP2, which is responsible for a synonymous polymorphism (Q563Q), and cervical cancer. The G allele may be associated with a higher risk of cervical cancer (P = 0.004; OR = 1.187, 95% CI: 1.057-1.332) (Table 3). Moreover, the GG-GA genotype was associated with an increased risk of cervical cancer (P = 0.002; OR = 1.33, 95% CI: 1.11-1.60) (Table 5). However, association studies of this SNP are rare. Previous studies have found that ERAP2 haplotypes containing rs2287988 affect ERAP2 splicing and expression (50, 51). Thus, additional association studies in different populations are necessary to investigate the role of this polymorphism during the initiation and development of cervical cancer.
ERAPs are markedly polymorphic and ERAP haplotypes whose protein products differ at multiple amino acids may affect peptide editing by ERAPs (29, 30, 52, 53). In the current study, we also analysed haplotypes of ERAP SNPs in LD. The results showed that the ERAP1 haplotype, rs27044C-rs30187T-rs26618T-rs26653G-rs3734016C and the ERAP2 haplotypes, rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T and rs2549782G-rs2548538A-rs2248374A-rs2287988G-rs1056893T may be associated with cervical cancer risk. These results indicated that SNPs in polymorphic genes may have combinatorial effects on disease susceptibility.