HLA and KIR Associations of Cervical Neoplasia

Xiao Bao, Aimee L Hanson, Margaret M Madeleine, Sophia S Wang, Stephen M Schwartz, Felicity Newell, Ulrika Pettersson-Kymmer, Kari Hemminki, Sven Tiews, Winfried Steinberg, Janet S Rader, Felipe Castro, Mahboobeh Safaeian, Eduardo L Franco, François Coutlée, Claes Ohlsson, Adrian Cortes, Mhairi Marshall, Pamela Mukhopadhyay, Katie CreminLisa G Johnson, Suzanne M Garland, Sepehr N Tabrizi, Nicolas Wentzensen, Freddy Sitas, Cornelia Trimble, Julian Little, Maggie Cruickshank, Ian H Frazer, Allan Hildesheim, Matthew A Brown, Emma L Duncan, YingPu Sun, Paul J Leo

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Abstract

BackgroundCervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognised by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk.MethodsHere, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.ResultsFour novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (OR=1.24, P=2.49×10−9), HLA-DRB5*0101 (OR=1.29, P=2.26×10−8), HLA-DRB5*9901 (OR=0.77, P=1.90×10−9) and HLA-DRB3*0301 (OR=0.63, P=4.06×10−5), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).ConclusionsOur findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.
Original languageEnglish
Pages (from-to)2006-2015
Number of pages15
JournalThe journal of infectious diseases
Volume218
Issue number12
Early online date7 Aug 2018
DOIs
Publication statusPublished - 15 Dec 2018

Keywords

  • cervical neoplasia
  • human leukocyte antigens (HLA)
  • killer immunoglobulin-like receptors (KIRs)
  • HPV16-related cervical neoplasia

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    Bao, X., Hanson, A. L., Madeleine, M. M., Wang, S. S., Schwartz, S. M., Newell, F., Pettersson-Kymmer, U., Hemminki, K., Tiews, S., Steinberg, W., Rader, J. S., Castro, F., Safaeian, M., Franco, E. L., Coutlée, F., Ohlsson, C., Cortes, A., Marshall, M., Mukhopadhyay, P., ... Leo, P. J. (2018). HLA and KIR Associations of Cervical Neoplasia. The journal of infectious diseases, 218(12), 2006-2015. https://doi.org/10.1093/infdis/jiy483