| Title: | Genome-Wide Association Analyses of HPV16 and HPV18 Seropositivity Identify Susceptibility Loci for Cervical Cancer |
| Journal: | Journal of Medical Virology |
| Published: | 31 Jan 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39891432/ |
| DOI: | https://doi.org/10.1002/jmv.70195 |
Publication 14464
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Abstract
Infection by high-risk human papillomavirus is known to exacerbate cervical cancer development. The host immune response is crucial in disease regression. Large-scale genetic association studies for cervical cancer have identified few susceptibility variants, mainly at the human leukocyte antigen locus on chromosome 6. We hypothesized that the host immune response modifies cervical cancer risk and performed three genome-wide association analyses for HPV16, HPV18 and HPV16/18 seropositivity in 7814, 7924, and 7924 samples from the UK Biobank, followed by validation genotyping in the German Cervigen case-control series of cervical cancer and dysplasia. In GWAS analyses, we identified two loci associated with HPV16 seropositivity (6p21.32 and 15q26.2), two loci associated with HPV18 seropositivity (5q31.2 and 14q24.3), and one locus for HPV16 and/or HPV18 seropositivity (at 6p21.32). MAGMA gene-based analysis identified HLA-DQA1 and HLA-DQB1 as genome-wide significant (GWS) genes. In validation genotyping, the genome-wide significant lead variant at 6p21.32, rs9272293 associated with overall cervical disease (OR = 0.86, p = 0.004, 95% CI = 0.78-0.95, n = 3710) and HPV16 positive invasive cancer (OR = 0.73, p = 0.005, 95% CI = 0.59-0.91, n = 1431). This variant was found to be a robust eQTL for HLA-DRB1, HLA-DQB1-AS1, C4B, HLA-DRB5, HLA-DRB6, HLA-DQB1, and HLA-DPB1 in a series of cervical epithelial tissue samples. We additionally genotyped twenty-four HPV seropositivity variants below the GWS threshold out of which eleven variants were found to be associated with cervical disease in our cohort, suggesting that further seropositivity variants may determine cervical disease outcome. Our study identifies novel genomic risk loci that associate with HPV type-specific cervical cancer and dysplasia risk and provides evidence for candidate genes at one of the risk loci.</p>
17 Keywords
- Adult
- Aged
- Case-Control Studies
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genotype
- HLA-DQ alpha-Chains
- HLA-DQ beta-Chains
- Human papillomavirus 16
- Human papillomavirus 18
- Humans
- Middle Aged
- Papillomavirus Infections
- Polymorphism, Single Nucleotide
- United Kingdom
- Uterine Cervical Neoplasms
21 Authors
- Theresa Beckhaus
- Linda Kachuri
- Taishi Nakase
- Peter Schürmann
- Rieke Eisenblätter
- Maya Geerts
- Gerd Böhmer
- Hans-Georg Strauß
- Christine Hirchenhain
- Monika Schmidmayr
- Florian Müller
- Peter A. Fasching
- Norman Häfner
- Alexander Luyten
- Matthias Jentschke
- Peter Hillemanns
- Tracy A. O'Mara
- Stephen S. Francis
- John S. Witte
- Thilo Dörk
- Dhanya Ramachandran
1 Application
| Application ID | Title |
|---|---|
| 14105 | Characterizing the Shared Genetic Basis of Common Cancers |
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