Genome, HLA and polygenic risk score analyses for prevalent and persistent cervical human papillomavirus (HPV) infections
Sally N. Adebamowo, Adebowale Adeyemo, Amos Adebayo, Peter Achara, Bunmi Alabi, Rasheed Bakare, Ayo Famooto, Kayode Obende, Richard Offiong, Olayinka Olaniyan, Sanni Ologun, Charles N. Rotimi, Saurayya S. Abdullahi, Maryam Abdulsalam, Ruxton Adebiyi, Victor Adekanmbi, Bukunmi Adelekun, Segun Adeyemo, Gerald Akabueze, Bernice Akpobome, Stella Akpomiemie, Gabriel O. Alabi, Chinyere Anichebe, Claire Anyanwu, Miriam C. Ayogu, Dorcas J. Bako, Patience Bamisaiye, Nkechi U. Blessing, Osa A. Chinye, Patrick Dakum, Eileen Dareng, Grace Dwana, Juliet I. Erhunmwonsere, Emelda O. Eze, Tolani A. Fagbohun, Temitope Filade, Toluwalope Gbolahan, Gloria C. Anaedobe, Stella Ibezim, Racheal Iwaloye, Jesse James, Dayo Kehinde, Fiyinfoluwa Makinde, Jessica Mase, Charles Mensah, Florence A. Nwoko, Kayode Obende, George Odonye, Folake O. Odubore, Funmi Odunyemi, Michael K. Odutola, Uzoamaka Oguama, Tochukwu Oguoma, Temitayo E Oladimeji, Toyosi Olawande, Temitope Olukomogbon, Sefunmi Oluwole, Gladys Omenuko, Nkiruka Onwuka, Yinka Owoade, Thelma C. Ugorji, Syntyche Yohanna, İbrahim Yusuf, Clement Adebamowo
Abstract
Genetic variants that underlie susceptibility to cervical high-risk human papillomavirus (hrHPV) infections are largely unknown. We conducted discovery genome-wide association studies (GWAS), replication, meta-analysis and colocalization, generated polygenic risk scores (PRS) and examined the association of classical HLA alleles and cervical hrHPV infections in a cohort of over 10,000 women. We identified genome-wide significant variants for prevalent hrHPV around LDB2 and for persistent hrHPV near TPTE2, SMAD2, and CDH12, which code for proteins that are significantly expressed in the human endocervix. Genetic variants associated with persistent hrHPV are in genes enriched for the antigen processing and presentation gene set. HLA-DRB1*13:02, HLA-DQB1*05:02 and HLA-DRB1*03:01 were associated with increased risk, and HLA-DRB1*15:03 was associated with decreased risk of persistent hrHPV. The analyses of peptide binding predictions showed that HLA-DRB1 alleles that were positively associated with persistent hrHPV showed weaker binding with peptides derived from hrHPV proteins and vice versa. The PRS for persistent hrHPV with the best model fit, had a P-value threshold (PT) of 0.001 and a p-value of 0.06 (-log10(0.06) = 1.22). The findings of this study expand our understanding of genetic risk factors for hrHPV infection and persistence and highlight the roles of MHC class II molecules in hrHPV infection.