The Epidemiology and Genetics Behind Condylomata Acuminata

Condylomata acuminata (CA) are a sexually transmitted disease (STD) caused by human papillomavirus (HPV), most often with the low-risk HPV subtypes 6 and 11. Although, the incidence has decreased recently due to implementation of national vaccination programs, the disease is still common and associated with impaired quality of life. The treatment of CA is challenging with high recurrence rates. Therefore, identification of biological pathways as suggested by host genetic variations may be valuable for future research on antiviral therapies and for risk estimation and preventive initiatives.

Previous research on the comorbidities and genetic risk factors of HPV infections has largely been limited to HPV-related malignancies caused by high-risk subtypes of HPV. Thus, this thesis aims to elucidate factors associated with development of the benign, yet clinically important form of HPV infection – condylomata acuminata. More specifically, the three studies of this thesis illustrate epidemiological findings on lifestyle factors, comorbidities, and genetic variants associated with CA.

Study I showed that development of CA is associated with depressive symptoms, high alcohol intake, smoking, and self-reported use of recreational drugs in Danish blood donors. Blood donors are generally healthy individuals, who may not exhibit certain risk behavior related to blood borne infections. Therefore, the demonstrated associations between CA and lifestyle factors, i.e. alcohol and drug use, were somewhat surprising, even though associations between severe mental illness, drug use, and STDs have been reported previously in high-risk populations. Although alcohol intake is not directly linked to risk of blood borne infections, it may illustrate a general inclination to take risks. The association between alcohol intake and CA even seemed to exhibit a dose- response effect. The study cohort included 128,048 blood donors of which 1,786 (1.4%) developed CA after study inclusion. Cases and controls were defined using registry data on relevant diagnosis and treatment.

Malignancies associated with HPV infections are extensively described. However, comorbidities of CA and their temporal relations are understudied. Hence, Study II used a nation-wide cohort of 7.2 million Danes observed for 24 years to demonstrate
that patients with CA are prone to psychiatric disease both prior to and after acquiring the condyloma diagnosis. In addition, patients with CA exhibit a general infection tendency illustrated by pharyngitis and other infections prior to the condyloma diagnosis. As expected, the study also demonstrated associations with cervical cancer, as co-infection with high-risk HPV is common in patients with CA. Furthermore, Study II demonstrated that cervical cancer was followed by female infertility. The implications of Study II include that healthcare providers should pay special attention to the mental health of patients with CA and refer them to psychiatric treatment if needed. In addition, psychiatrists should be aware of STDs in psychiatric patients to limit sequelae such as infertility.

Study III was conducted within the Danish Blood Donor Study similarly with Study I. A total of 84,412 blood donors were included in a genome-wide association study (GWAS) of CA as defined by registry data on diagnosis and treatment. The study revealed that two novel associations to genetic variants in the introns of the genes DAB1 and FHIT were associated with altered risk of CA adjusted for sex, year of birth, body mass index, smoking, and principal components. The DAB1 gene on chromosome 1 is a suggested tumor suppressor gene associated with brain development. The DAB1 variant in our study increased the risk of CA with an odds ratio (OR) of 5.17 (95% confidence interval: 3.02–8.85). The FHIT gene on chromosome 3 is also involved in control of cell cycle and apoptosis, and the gene is associated with cervical cancer and a biomarker of renal cancer prognosis. The FHIT variant in our study decreased the risk of CA, OR 0.19 (95% confidence interval: 0.10–0.35). Lastly, fine-mapping of chromosome 6 showed associations between CA and 19 different alleles of the human leukocyte antigen (HLA) system (OR 1.11–1.38 of the risk alleles, and OR 0.43–0.80 of the protective alleles). Fifteen of the 19 associated HLA alleles have been associated with other HPV manifestations than CA in accordance with our findings.