Human Papillomavirus
Human Papillomavirus. Credit: University of Maryland School of Medicine

A study led by University of Maryland researchers has identified genetic mutations associated with persistent human papillomavirus (HPV) infection that could help identify women at risk for cervical cancer.

“We found certain genetic variants were associated with having high-risk HPV infections, while other variants and human leukocyte antigen (HLA) genes were associated with persistent infections, which increase the risk of developing cervical cancer,” said study leader Sally Adebamowo, associate professor of epidemiology & public health at the University of Maryland School of Medicine. “This is a critical finding that suggests genetic underpinnings for cervical cancer risk. It is the first sufficiently powered genome-wide association study of cervical high-risk HPV infections.”

HPV is the second most common cancer-causing virus worldwide, accounting for 690,000 cervical and other cancers each year. More than 80% of women will have an HPV infection in their lifetime, but over 90% of cases are cleared by the immune system within two years.

Adebamowo told Inside Precision Medicine that although the HPV vaccine is highly effective for the prevention cervical cancer “its accessibility remains limited, particularly in low-resource settings, where improvements in distribution, affordability, and education are needed. Moreover, these vaccines don’t cover all carcinogenic HPV types.”

Previous studies have suggested a role for genetic factors in HPV prevalence but exact genetic variants that underlie susceptibility to cervical high-risk HPV infections are largely unknown, the researchers note in the European Journal of Human Genetics.

“Identifying genetic factors associated with HPV provides valuable insights into the biological pathways of HPV infection and its carcinogenic progression,” Adebamowo remarked.

To address this, Adebamowo and the team conducted comprehensive genome-wide association and HLA allele studies of the risks for prevalent and persistent cervical high-risk HPV infections in a cohort of over 10,000 women, whose data were collected as part of the African Collaborative Center for Microbiome and Genomics Research (ACCME) cohort study.

At the start of the study, 903 participants had a prevalent high-risk HPV infection. During the nine-month follow-up period, 224 of these infections resolved and 679 persisted.

The investigators found that, compared with the 9846 women who remained HPV-negative throughout the study, those with a prevalent infection at baseline were more likely to carry a variant in the LDB2 gene, a protein coding-gene which is expressed regionally, particularly in the uterus and cervix.

In addition, variants near TPTE2, SMAD2, and CDH12, which also code for proteins that are significantly expressed in the human endocervix, were significantly associated with persistent high-risk HPV.

The HLA allele studies identified specific HLA alleles associated with persistent high-risk HPV infection. These included HLA-DRB1*13:02, HLA-DQB1*05:02, and HLA-DRB1*03:01 which were associated with an increased risk, and HLA-DRB1*15:03 was associated with decreased risk.

HLA molecules are involved with antigen processing and presentation, which is the first step in the activation of the immune response, the researchers explain. They found that HLA-DRB1*13:02 and HLA-DRB1*03:01 were significantly associated with weaker binding with peptides derived from high-risk HPV proteins in comparison with other alleles.

“This finding suggests that [high-risk] HPV persistence may be associated with a diminished immune response due to weaker binding of hrHPV epitopes, a hypothesis that obtains support from the finding that the ‘nonpersistence’ or ‘clearance’ allele (HLA-DRB1*15:03) displays stronger peptide binding predictions,” the authors write.

Adebamowo said: “Our results can be used to develop polygenic risk score models in diverse populations, which can help predict an individual’s disease risk. Such investigations would pave the way for more effective prevention and monitoring strategies, including the identification of novel therapeutic targets and personalized medicine approaches for those at higher risk of developing cervical cancer.”

Indeed, the team are now conducting replication studies in other populations and are in the process of developing and testing such polygenic risk score models using various statistical methods and computational methods.

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