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

Related Articles Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study. PLoS Genet. 2017 Aug;13(8):e1006866 Authors: Leo PJ, Madeleine MM, Wang S, Schwartz SM, Newell F, Pettersson-Kymmer U, Hemminki K, Hallmans G, Tiews S, Steinberg W, Rader JS, Castro F, Safaeian M, Franco EL, Coutlée F, Ohlsson C, Cortes A, Marshall M, Mukhopadhyay P, Cremin K, Johnson LG, Garland S, Tabrizi SN, Wentzensen N, Sitas F, Little J, Cruickshank M, Frazer IH, Hildesheim A, Brown MA 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. PMID: 28806749 [PubMed - indexed for MEDLINE]

SNP associations are reported as filled-in dots, HLA amino-acid associations as hollow diamonds (P-values are for omnibus test of association at specific amino-acid positions). Colours represent extent of linkage disequilibrium with the HLA amino-acid(s) or SNP stated in the figure. (A) The linkage disequilibrium with amino acids at positions 13 and 71 that form part of the p4-pocket of HLA-DRB1. Reading from the p-telomere the HLA loci at which amino-acid constituents have been imputed are HLA-A, -C, -B, -DRB1, -DQA1, -DQB1, -DPA1 and–DPB1. Allele-specific HLA type associations are given in the right hand plot. (B) Cervical neoplasia MHC association results having conditioned on amino acid positions 13 and 71 in HLA-DRB1. Linkage disequilibrium with the next largest association amino acid position 156 at HLA-B is shown. (C) Cervical neoplasia MHC association results having conditioned on amino acid positions 13 and 17 in HLA-DRB1 and 156 in HLA-B. No significant association remains.

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