Defining the genetic susceptibility to cervical neoplasia—A genome-wide association study

Abstract

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

From HPV Infection to Lesion Progression: The Role of HLA Alleles and Host Immunity

“…Recently, Bahls et al [39] observed that the HLA-B*07 allele was more frequently found in women with HPV infections and high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL), and CC patients (OR 3.87, 95% Cl 1.11–13.52). Leo et al [40] also recently showed HLA-B*07 to increase the risk for cervical squamous cell carcinoma by 1.3-fold, adenocarcinoma by 1.5-fold, HPV16 infection by 1.4-fold, and HPV18 infection by 1.4-fold.…”

“…Other class I HLA alleles that have shown significant association with persistent HPV-infection and CC development are: HLA-A*02 and HLA-A*0201 [41], HLA-A*0301 [42], HLA-A*3101 and HLA-A*3303 [43], HLA-B*3501, HLA-B*37, and B*3701 [41], HLA-B*3901 [43], HLA-B*4402 [42], HLA-B*58 and B*5801 [41], HLA-Cw*0501 [42], HLA-C*0702 [40], HLA-Cw*0704 [42], and HLA-G*010102, G*010103, G*010105, G*010108, and G*0103 [44] (Fig. 3).…”

“…3). The alleles HLA-B*3503 and HLA-C*0303 have shown contradictory results, and more information is needed to characterize the true role of these alleles in the outcome of HPV infections [40, 41, 43, 45]. …”

“…3). HLA-B*15 and B*1501 have both been strongly associated with a reduced risk of precancerous cervical lesions and cervical squamous cell carcinoma (OR range 0.48–0.6) [40, 42, 46]. HLA-B*15 has also decreased the risk for adenocarcinoma (OR 0.73) [40].…”

“…Other class I alleles that have shown to decrease HPV-associated cervical disease are: HLA-B*14 [39], B*2705 [43], HLA-B*3503, B*40, B*4006, B*52 [41], HLA-Cw*0202 and HLA-Cw*0401 [43], HLA-C*03 [40], HLA-G*0103 [47], HLA-C*01 [45], and HLA-C*08 [39] (Fig. 3).…”