Characteristics of the subjects
Table 1 shows the clinical data of the subjects in the present study. There was no significant difference in age among the control, CIN, and cervical cancer groups (P > 0.05, F = 1.438), as evaluated by one-way ANOVA. In the CIN group, there were 65 patients with low-grade CIN (I/II) and 491 patients with high-grade CIN (III). In the cervical cancer group, there were 151 patients with adenocarcinoma, 903 patients with squamous cell carcinoma, and 18 patients with other pathological types.
Association of the eleven SNPs with CIN and cervical cancer
All 11 SNPs were in HWE in the control group (P > 0.05) (Supplementary Table 1). The allelic and genotypic frequencies of these SNPs are presented in Tables 2 and 3. The results showed that the allelic and genotypic frequencies of rs26618 (P = 0.021 and 0.016, respectively), rs26653 (P = 0.001 and 0.004), rs27044 (P = 0.003 and 0.012) and rs30187 (P = 0.008 and 0.020) in ERAP1 (Table 2) and rs2248374 (P = 0.014 and 0.020) and rs2287988 (P = 0.004 and 0.007) in ERAP2 (Table 3) were significantly different between cervical cancer and control groups. Additionally, the allelic and genotypic distributions of rs2248374 (P = 0.015 and 0.041, respectively) and rs2287988 (P = 0.014 and 0.039) in ERAP2 were significantly different between CIN and cervical cancer groups (Table 3). However, after Bonferroni correction, only rs26653, rs27044, and rs2287988 were associated with cervical cancer risk (P < 0.0045). The results indicated that, in ERAP1, the G allele of rs26653 may be associated with a lower risk of cervical cancer compared with C allele (OR = 0.829; 95% CI: 0.738-0.930) and the G allele of rs27044 may be a risk factor for cervical cancer (OR = 1.193, 95% CI: 1.062-1.340). Moreover, the A allele of rs2287988 in ERAP2 may be associated with a lower risk of cervical cancer (OR = 0.843, 95% CI: 0.751-0.946). There were no SNPs in ERAP1 (Table 2) or ERAP2 (Table 3) that exhibited a significantly different distribution between the CIN and control groups or between the CIN and cervical cancer groups (P > 0.0045).
Inheritance model analysis
To evaluate the genotypic association of the 11 SNPs with CIN and cervical cancer, inheritance analysis was performed among cervical cancer, CIN, and control groups (Table 4, Table 5, and Supplementary Tables 2-5). The CC genotype of rs26618 was a risk factor for cervical cancer, compared with TT-CT genotype (P = 0.004; OR = 1.53, 95%CI: 1.14-2.05) in the recessive model (the best-fit inheritance model for the comparison between control and cervical cancer groups) (Table 4). The 2GG+CG genotype of rs26653 was associated with a lower risk of cervical cancer compared with the CC genotype (P = 0.001, OR = 0.82; 95% CI: 0.73-0.93) in the log-additive model (the best-fit inheritance model for the comparison between control and cervical cancer groups) (Table 4). The 2CC+CG genotype of rs27044 may be a protective factor against cervical cancer compared with the GG genotype (P = 0.003, OR = 0.84; 95% CI: 0.75-0.94) in the log-additive model (the best-fit inheritance model for the comparison between control and cervical cancer groups) (Table 4) and the GG+GA genotype of rs2287988 may be a risk factor for cervical cancer compared with the AA genotype (P = 0.002, OR = 1.33; 95% CI: 1.11-1.60) in the dominant model (the best fit inheritance model for the comparison between control and cervical cancer groups) (Table 5).
LD and haplotype analysis of SNPs in ERAP1 and ERAP2
The results of LD analysis showed that rs26618, rs26653, rs27044, rs30187, and rs3734016 in ERAP1 and rs2248374, rs2549782, rs2287988, rs2548538, and rs1056893 in ERAP2 were in LD (D' > 0.80) (Supplementary Tables 6, 7). Subsequently, we constructed the haplotypes, rs27044-rs30187-rs26618-rs26653-rs3734016 and rs2549782-rs2548538-rs2248374-rs2287988-rs1056893. The distribution of these haplotypes (with a frequency of more than 3%) was compared in a pairwise manner among the cervical cancer, CIN, and control groups (Tables 6 and 7). The ERAP1 haplotype, rs27044C-rs30187T-rs26618T-rs26653G-rs3734016C, was associated with a lower risk of cervical cancer (P = 0.001; OR = 0.804, 95% CI: 0.711-0.910) (Table 6). The distribution of haplotypes rs2549782G-rs2548538A-rs2248374A-rs2287988G-rs1056893T and rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T in ERAP2 (Table 7) were significantly different in the control (P = 0.009 and 0.003, respectively) and CIN (P = 0.006 and 0.009) groups compared with the cervical cancer group. The results indicated that rs2549782G-rs2548538A-rs2248374A-rs2287988G-rs1056893T may be associated with a higher risk of cervical cancer (OR = 1.592, 95% CI: 1.122-2.258) and the progression from CIN to cervical cancer (OR = 2.000, 95% CI: 1.215-3.292). Moreover, rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T may be associated with a lower risk of cervical cancer (OR = 0.835, 95%CI: 0.740-0.942) and the progression from CIN to cervical cancer (OR = 0.817, 95% CI: 0.702-0.951).