Xiao Bao1,2,3, Aimee L Hanson4,5,6, Margaret M Madeleine7, Sophia S Wang8, Stephen M Schwartz7, Felicity Newell3, Ulrika Pettersson-Kymmer9,10, Kari Hemminki11,12, Sven Tiews13, Winfried Steinberg13, Janet S Rader14, Felipe Castro12,15, Mahboobeh Safaeian16, Eduardo L Franco17, François Coutlée18, Claes Ohlsson19,20, Adrian Cortes4, Mhairi Marshall3, Pamela Mukhopadhyay4, Katie Cremin4, Lisa G Johnson7, Suzanne M Garland21,22,23, Sepehr N Tabrizi21,22,23, Nicolas Wentzensen16, Freddy Sitas24,25,26, Cornelia Trimble27, Julian Little28, Maggie Cruickshank29, Ian H Frazer5,6, Allan Hildesheim16, Matthew A Brown3, Emma L Duncan3, Ying Pu Sun1,2, Paul J Leo3. 1. Center for Reproductive Medicine, First Affiliated Hospital of Zhengzhou University, China. 2. Henan Key Laboratory of Reproduction and Genetics, First Affiliated Hospital of Zhengzhou University, China. 3. Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology. 4. University of Queensland Diamantina Institute, University of Queensland. 5. Faculty of Medicine and Biomedical Sciences, University of Queensland. 6. Translational Research Institute, Princess Alexandra Hospital, Woolloongabba. 7. Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington. 8. Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, California. 9. Department of Pharmacology and Clinical Neuroscience. 10. Department of Public Health and Clinical Medicine, Umeå University, Umeå. 11. Center for Primary Health Care Research, Lund University, Lund. 12. Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg. 13. MHC Laboratory for Cytopathology, Dr Steinberg, Soest, Germany. 14. Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee. 15. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg. 16. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda. 17. Division of Cancer Epidemiology, McGill University. 18. Département de Microbiologie, Infectiologie et Immunologie, Centre Hospitalier de l'Université de Montréal, Montréal, Ottawa, Canada. 19. Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden. 20. Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 21. Western Pacific Regional Human Papillomavirus Laboratory Network, Department of Microbiology and Infectious Diseases. 22. Murdoch Children's Research Institute, Royal Children's Hospital. 23. Department of Obstetrics and Gynaecology, University of Melbourne, Parkville. 24. Cancer Council NSW, Sydney. 25. Sydney School of Public Health, University of Sydney, Camperdown. 26. School of Public Health and Community Medicine, University of New South Wales, Kensington, Australia. 27. Center for Cervical Dysplasia, Johns Hopkins University, Baltimore, Maryland. 28. School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada. 29. Division of Medical Education, University of Aberdeen, United Kingdom.
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 13858 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.
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 13858 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.
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