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. AUTHOR SUMMARY Around 1% of women with cervical human papillomavirus (HPV) infection progress to cervical cancer. Previous studies had indicated that a person’s genetic makeup could predispose to HPV-associated cervical cancer, and that some of the genes likely to be involved include the immune-related human leukocyte antigen (HLA) genes among the major histocompatibility complex (MHC). However, it has been difficult to determine which alleles might be associated with cervical pre-cancer or cancer due to the complex and high level of co-inheritance of MHC alleles. Here, we performed a genome-wide association study that assessed the correlation of genetic variants among those with cervical cancer and healthy controls. We show that host genetics is a major determinant of HPV-associated cervical cancer, with 36% of liability due to common genetic variants in the population, and identify both risk and protective HLA alleles. Our study was also sufficiently powerful to identify particular residue variants on a number of the immune-related proteins that provide risk or protection, providing further insight into the biological basis for cervical cancer development. Our findings could lay the foundation for screening for people at increased risk of developing cancer following HPV infection, and aid in the treatment and prognosis of cervical cancer.