Inside the pocket: Critical elements of HLA-mediated susceptibility to cervical precancerous lesions

Human papillomavirus (HPV) infection is a necessary cause for cervical cancer (CC), but it also depends on genetic factors, such as HLA polymorphism. However, few reports addressed the role of amino acids residues at the HLA peptide-binding cleft in HPV-related cervical disease. Therefore, we aimed to investigate the association between HLA-B, HLA-C, and HLA-DRB1 polymorphism and amino acid residues composing the pockets of the peptide-binding cleft of the respective polypeptide chains with cervical intraepithelial neoplasia (CIN II/III). HLA typing was performed by PCR-SSOP in 184 women with CIN II/III and 174 controls from South Brazil. Associations were estimated by multivariate logistic regression. FDR test was performed to correct the p-value for multiple comparisons. HLA-DRB1*13:01 was associated with protection against CIN II/III, while HLA-C*03:04 was associated with susceptibility. The amino acid residues isoleucine, tyrosine, and leucine at positions 95, 116, and 163 of HLA-C, respectively, were associated with CIN II/III susceptibility. In contrast, serine at positions 11 and 13 of HLA-DRB1 was associated with protection against the disease. Our results confirm previously reported associations between HLA and cervical diseases caused by HPV and suggest a role for amino acid residues at different positions of HLA-C and HLA-DRB1 in CIN II/III. This finding may be further explored to better understand the genetic risk and the influence of immune response to CC development.