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, Ying Pu Sun, Paul J. Leo

Research output: Contribution to journalArticle

Abstract

Background. Cervical 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 recognized 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. Methods. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13 858 healthy controls of European decent. Results. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [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 ). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions. Our 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 (US)
Pages (from-to)2006-2015
Number of pages10
JournalJournal of Infectious Diseases
Volume218
Issue number12
DOIs
StatePublished - Jan 1 2018

Keywords

  • Cervical neoplasia
  • HPV16-related cervical neoplasia
  • Human leukocyte antigens (HLA)
  • Killer immunoglobulin-like receptors (KIRs)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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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. Journal of Infectious Diseases, 218(12), 2006-2015. https://doi.org/10.1093/infdis/jiy483