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A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden.
Umea Univ, Dept Clin Sci Obstet & Gynecol, SE-90187 Umea, Sweden.
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2014 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 1, 190-198 p.Article in journal (Refereed) Published
Abstract [en]

In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide-related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case-control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65-0.82; P = 1.6 × 10(-7)), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19-1.49; P = 5.8 × 10(-7)), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68-0.94; P = 6.7 × 10(-3)) and MICA-A5 (OR = 0.60, 95% CI = 0.50-0.72; P = 3.0 × 10(-8)) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer.

Place, publisher, year, edition, pages
2014. Vol. 3, no 1, 190-198 p.
Keyword [en]
Cervical cancer, cis-eQTL, frameshift mutation, HLA-DRB1, MICA
National Category
Basic Medicine Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-238030DOI: 10.1002/cam4.183ISI: 000348218200020PubMedID: 24403192OAI: oai:DiVA.org:uu-238030DiVA: diva2:769848
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2014-12-09 Created: 2014-12-09 Last updated: 2017-12-05Bibliographically approved

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Chen, DanHammer, JoannaGyllensten, Ulf

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