Genome-wide association study of prevalent and persistent cervical high-risk human papillomavirus (HPV) infection.

BACKGROUND: Genetic factors may influence the susceptibility to high-risk (hr) human papillomavirus (HPV) infection and persistence. We conducted the first genome-wide association study (GWAS) to identify variants associated with cervical hrHPV infection and persistence. METHODS: Participants were 517 Nigerian women evaluated at baseline and 6 months follow-up visits for HPV. HPV was characterized using SPF10/LiPA25. hrHPV infection was positive if at least one carcinogenic HPV genotype was detected in a sample provided at the baseline visit and persistent if at least one carcinogenic HPV genotype was detected in each of the samples provided at the baseline and follow-up visits. Genotyping was done using the Illumina Multi-Ethnic Genotyping Array (MEGA) and imputation was done using the African Genome Resources Haplotype Reference Panel. Association analysis was done for hrHPV infection (125 cases/392 controls) and for persistent hrHPV infection (51 cases/355 controls) under additive genetic models adjusted for age, HIV status and the first principal component (PC) of the genotypes. RESULTS: The mean (±SD) age of the study participants was 38 (±8) years, 48% were HIV negative, 24% were hrHPV positive and 10% had persistent hrHPV infections. No single variant reached genome-wide significance (p < 5 X 10- 8). The top three variants associated with hrHPV infections were intronic variants clustered in KLF12 (all OR: 7.06, p = 1.43 × 10- 6). The top variants associated with cervical hrHPV persistence were in DAP (OR: 6.86, p = 7.15 × 10- 8), NR5A2 (OR: 3.65, p = 2.03 × 10- 7) and MIR365-2 (OR: 7.71, p = 2.63 × 10- 7) gene regions. CONCLUSIONS: This exploratory GWAS yielded suggestive candidate risk loci for cervical hrHPV infection and persistence. The identified loci have biological annotation and functional data supporting their role in hrHPV infection and persistence. Given our limited sample size, larger discovery and replication studies are warranted to further characterize the reported associations.

Recurrence of cervical intraepithelial lesions after thermo-coagulation in HIV-positive and HIV-negative Nigerian women.

BACKGROUND: The burden of cervical cancer remains huge globally, more so in sub-Saharan Africa. Effectiveness of screening, rates of recurrence following treatment and factors driving these in Africans have not been sufficiently studied. The purpose of this study therefore was to investigate factors associated with recurrence of cervical intraepithelial lesions following thermo-coagulation in HIV-positive and HIV-negative Nigerian women using Visual Inspection with Acetic Acid (VIA) or Lugol's Iodine (VILI) for diagnosis. METHODS: A retrospective cohort study was conducted, recruiting participants from the cervical cancer "see and treat" program of IHVN. Data from 6 sites collected over a 4-year period was used. Inclusion criteria were: age ≥18 years, baseline HIV status known, VIA or VILI positive and thermo-coagulation done. Logistic regression was performed to examine the proportion of women with recurrence and to examine factors associated with recurrence. RESULTS: Out of 177 women included in study, 67.8 % (120/177) were HIV-positive and 32.2 % (57/177) were HIV-negative. Recurrence occurred in 16.4 % (29/177) of participants; this was 18.3 % (22/120) in HIV-positive women compared to 12.3 % (7/57) in HIV-negative women but this difference was not statistically significant (p-value 0.31). Women aged ≥30 years were much less likely to develop recurrence, adjusted OR = 0.34 (95 % CI = 0.13, 0.92). Among HIV-positive women, CD4 count <200cells/mm(3) was associated with recurrence, adjusted OR = 5.47 (95 % CI = 1.24, 24.18). CONCLUSION: Recurrence of VIA or VILI positive lesions after thermo-coagulation occurs in a significant proportion of women. HIV-positive women with low CD4 counts are at increased risk of recurrent lesions and may be related to immunosuppression.

Age-specific prevalence of human papilloma virus infection among Nigerian women.

BACKGROUND: Inconsistent trends in HPV prevalence by age have been described in Africa. We examined the age prevalence pattern and distribution of 37 HPV-DNA types among urban Nigerian women. METHODS: The study population was a sample of 278 women who presented to cervical cancer screening programs in Abuja, Nigeria, between April and August 2012. Using a nurse administered questionnaire, information on demographic characteristics and risk factors of cervical cancer was collected and samples of cervical exfoliated cells were obtained from all participants. Roche Linear Array HPV Genotyping Test® was used to characterize prevalent HPV and log-binomial regression models were used to examine the association between potential correlates and the prevalence of HPV infection. RESULTS: The mean age (SD) of the women enrolled was 38 (8) years. The overall prevalence of HPV was 37%. HPV 35 was the most prevalent HPV type in the study population. Among women age ≤ 30 years, 52% had HPV infection compared to 23% of those women who were older than 45 years (p = 0.006). We observed a significant linear association between age and the prevalence of HPV infections. The prevalence ratio (PR) and 95% confidence interval (CI) was 2.26 (1.17, 4.34) for any HPV infection, 3.83 (1.23, 11.94) for Group 1 HPV (definite carcinogens), and 2.19 (0.99, 4.84) for Group 2a or 2b HPV (probable or possible carcinogens) types, among women aged 18-30 years, compared to women who were older than 45 years. CONCLUSION: The prevalence of HPV infection was highest among younger women and decreased steadily with age among this population of urban Nigerian women.

Genome, HLA and polygenic risk score analyses for prevalent and persistent cervical human papillomavirus (HPV) infections.

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.

HIV associated high-risk HPV infection among Nigerian women.

BACKGROUND: In developed countries, the incidence of cervical cancer has remained stable in HIV+ women but the prevalence and multiplicity of high-risk HPV (hrHPV) infection, a necessary cause of cervical cancer, appears different comparing HIV+ to HIV- women. Little is known about HIV and HPV co-infection in Africa. METHODS: We enrolled women presenting at our cervical cancer screening program in Abuja, Nigeria between April and August 2012, and collected information on demographic characteristics, risk factors of HPV infection and samples of exfoliated cervical cells. We used Roche Linear Array HPV Genotyping Test® to characterize prevalent HPV and logistic regression models to estimate the association between HIV and the risk of hrHPV infection. RESULTS: There were 278 participants, 54% (151) were HIV+, 40% (111) were HIV-, and 6% (16) had unknown HIV status. Of these, data from 149 HIV+ and 108 HIV- women were available for analysis. The mean ages (± SD) were 37.6 (± 7.7) years for HIV+ and 36.6 (± 7.9) years for HIV- women (p-value = 0.34). Among the HIV+ women, HPV35 (8.7%) and HPV56 (7.4%) were the most prevalent hrHPV, while HPV52 and HPV68 (2.8%, each) were the most prevalent hrHPV types among HIV- women. The multivariate prevalence ratio for any hrHPV and multiple hrHPV infections were 4.18 (95% CI 2.05 - 8.49, p-value <0.0001) and 6.6 (95% CI 1.49 - 29.64, p-value 0.01) respectively, comparing HIV + to HIV- women, adjusted for age, and educational level. CONCLUSIONS: HIV infection was associated with increased risk of any HPV, hrHPV and multiple HPV infections. Oncogenic HPV types 35, 52, 56 and 68 may be more important risk factors for cervical pre-cancer and cancer among women in Africa. Polyvalent hrHPV vaccines meant for African populations should protect against other hrHPV types, in addition to 16 and 18.

Cervical cancer risk factors among HIV-infected Nigerian women.

BACKGROUND: Cervical cancer is the third most common cancer among women worldwide, and in Nigeria it is the second most common female cancer. Cervical cancer is an AIDS-defining cancer; however, HIV only marginally increases the risk of cervical pre-cancer and cancer. In this study, we examine the risk factors for cervical pre-cancer and cancer among HIV-positive women screened for cervical cancer at two medical institutions in Abuja, Nigeria. METHODS: A total of 2,501 HIV-positive women participating in the cervical cancer screen-and-treat program in Abuja, Nigeria consented to this study and provided socio-demographic and clinical information. Log-binomial models were used to calculate relative risk (RR) and 95% confidence intervals (95%CI) for the risk factors of cervical pre-cancer and cancer. RESULTS: There was a 6% prevalence of cervical pre-cancer and cancer in the study population of HIV-positive women. The risk of screening positivity or invasive cancer diagnosis reduced with increasing age, with women aged 40 years and older having the lowest risk (RR=0.4; 95%CI=0.2-0.7). Women with a CD4 count of 650 per mm3 or more also had lower risk of screening positivity or invasive cancer diagnosis (RR=0.3, 95%CI=0.2-0.6). Other factors such as having had 5 or more abortions (RR=1.8, 95%CI=1.0-3.6) and the presence of other vaginal wall abnormalities (RR=1.9, 95%CI=1.3-2.8) were associated with screening positivity or invasive cancer diagnosis. CONCLUSION: The prevalence of screening positive lesions or cervical cancer was lower than most previous reports from Africa. HIV-positive Nigerian women were at a marginally increased risk of cervical pre-cancer and cancer. These findings highlight the need for more epidemiological studies of cervical cancer and pre-cancerous lesions among HIV-positive women in Africa and an improved understanding of incidence and risk factors.

Clearance of Type-Specific, Low-Risk, and High-Risk Cervical Human Papillomavirus Infections in HIV-Negative and HIV-Positive Women.

Purpose There is a dearth of data on clearance of cervical human papillomavirus (HPV) infection among women in West Africa. We examined the clearance of low-risk (lr) and high-risk (hr) cervical HPV infections, and the factors associated with these measures in HIV-negative and HIV-positive women. Methods We studied 630 Nigerian women involved in a study of HPV infection using short polymerase chain reaction fragment-10 assay and line probe assay-25. Research nurses used a cervical brush to collect samples of exfoliated cervical cells from all the study participants. Cox proportional hazards models were used to estimate associations between HIV and HPV infections. Results The mean age of the study participants was 38 (standard deviation, ± 8) years; 51% were HIV positive. The rate of clearing any HPV infection was 2.0% per month among all women in the study population, 2.5% per month among HIV-negative women, and 1.6% per month, among HIV-positive women. The clearance rate per 1,000 person-months of observation for any lrHPV infection and any hrHPV infection were 9.21 and 8.83, respectively, for HIV-negative women, and 9.38 and 9.37, respectively, for HIV-positive women. In multivariate models, the hazard ratios for HIV-positive compared with HIV-negative women were 0.85 (95% CI, 0.51 to 1.43; P = .55) and 0.95 (95% CI, 0.54 to 1.65; P = .85) for cleared infections with any lrHPV and any hrHPV, respectively. The hazard ratio for HIV-positive compared with HIV-negative women was 0.39 (95% CI, 0.17 to 0.88; P = .02) for cleared infections with any multiple HPV and 0.13 (95% CI, 0.03 to 0.58; P = .007) for cleared infections with multiple hrHPV. Conclusion In this study population, we observed that HIV-positive women were less likely to clear infections with multiple hrHPV types.

Morphine-alcohol treatment impairs cognitive functions and increases neuro-inflammatory responses in the medial prefrontal cortex of juvenile male rats.

In the developed and developing world, opioid consumption in combination with alcohol has become one of the substances abused. In this experiment, we examined the effects of alcohol, morphine, and morphine+alcohol combination on cognitive functions and neuroinflammatory responses in the medial prefrontal cortex (mPFC) of juvenile male rats. Alcohol (1.0 ml of 15% v/v ethanol twice daily, subcutaneously, 7 hours apart), morphine (0.5 ml/kg of 0.4 mg/kg morphine chlorate twice daily, subcutaneously, 7 hours apart), morphine+alcohol co-treatment (0.5 ml/kg of 0.4 mg/kg morphine chlorate+1.0 ml of 15% v/v ethanol twice daily, subcutaneously, 7 hours apart) were administered for 21 days. Treatment with morphine+alcohol significantly impairs cognition functions in the Morris water maze, passive avoidance, and novel object recognition tests, furthermore, the treatment significantly increased the quantitative count of astrocytic cells and also conferred marked neuronal cell death in the mPFC, which were studied by glial fibrillary acidic protein immunochemistry for astrocytes and Cresyl violet for Nissl's substance distribution in neurons respectively. These results suggest that alcohol, morphine, and morphine+alcohol co-treatment may trigger cognitive deficits and neuroinflammatory responses in the brain.

Qualitative study of barriers to cervical cancer screening among Nigerian women.

OBJECTIVES: To explore the barriers to cervical cancer screening, focusing on religious and cultural factors, in order to inform group-specific interventions that may improve uptake of cervical cancer screening programmes. DESIGN: We conducted four focus group discussions among Muslim and Christian women in Nigeria. SETTING: Discussions were conducted in two hospitals, one in the South West and the other in the North Central region of Nigeria. PARTICIPANTS: 27 Christian and 22 Muslim women over the age of 18, with no diagnosis of cancer. RESULTS: Most participants in the focus group discussions had heard about cervical cancer except Muslim women in the South Western region who had never heard about cervical cancer. Participants believed that wizardry, multiple sexual partners and inserting herbs into the vagina cause cervical cancer. Only one participant knew about the human papillomavirus. Among the Christian women, the majority of respondents had heard about cervical cancer screening and believed that it could be used to prevent cervical cancer. Participants mentioned religious and cultural obligations of modesty, gender of healthcare providers, fear of disclosure of results, fear of nosocomial infections, lack of awareness, discrimination at hospitals, and need for spousal approval as barriers to uptake of screening. These barriers varied by religion across the geographical regions. CONCLUSIONS: Barriers to cervical cancer screening vary by religious affiliations. Interventions to increase cervical cancer awareness and screening uptake in multicultural and multireligious communities need to take into consideration the varying cultural and religious beliefs in order to design and implement effective cervical cancer screening intervention programmes.

Influence of Spirituality and Modesty on Acceptance of Self-Sampling for Cervical Cancer Screening.

INTRODUCTION: Whereas systematic screening programs have reduced the incidence of cervical cancer in developed countries, the incidence remains high in developing countries. Among several barriers to uptake of cervical cancer screening, the roles of religious and cultural factors such as modesty have been poorly studied. Knowledge about these factors is important because of the potential to overcome them using strategies such as self-collection of cervico-vaginal samples. In this study we evaluate the influence of spirituality and modesty on the acceptance of self-sampling for cervical cancer screening. METHODOLOGY: We enrolled 600 participants in Nigeria between August and October 2014 and collected information on spirituality and modesty using two scales. We used principal component analysis to extract scores for spirituality and modesty and logistic regression models to evaluate the association between spirituality, modesty and preference for self-sampling. All analyses were performed using STATA 12 (Stata Corporation, College Station, Texas, USA). RESULTS: Some 581 (97%) women had complete data for analysis. Most (69%) were married, 50% were Christian and 44% were from the south western part of Nigeria. Overall, 19% (110/581) of the women preferred self-sampling to being sampled by a health care provider. Adjusting for age and socioeconomic status, spirituality, religious affiliation and geographic location were significantly associated with preference for self-sampling, while modesty was not significantly associated. The multivariable OR (95% CI, p-value) for association with self-sampling were 0.88 (0.78-0.99, 0.03) for spirituality, 1.69 (1.09-2.64, 0.02) for religious affiliation and 0.96 (0.86-1.08, 0.51) for modesty. CONCLUSION: Our results show the importance of taking cultural and religious beliefs and practices into consideration in planning health interventions like cervical cancer screening. To succeed, public health interventions and the education to promote it must be related to the target population and its preferences.

Validity of colposcopy in the diagnosis of early cervical neoplasia--a review.

This study was conducted to quantify by meta-analysis the validity of colposcopy in the diagnosis of early cervical neoplasia in order to assess the justification of its integral role in this regard. Eight longitudinal studies were selected, which compared correlation of colposcopic impression with colposcopically directed biopsy results. The prevalence of disease in the studies ranged from 40 to 89%. Colposcopic accuracy was 89%, which agreed exactly with histology in 61% of cases. The sensitivity and specificity of colposcopy for the threshold normal versus all cervical abnormalities were 87-99% and 26-87% respectively. For the threshold normal and low grade SIL versus high grade SIL, the values were 30-90% and 67-97%. Likelihood ratios increased with disease severity. Colposcopy performed better in differentiation of high grade from low grade disease than in differentiation of low grade disease from normal cervix. Colposcopy is a valid tool for the diagnosis of early cervical neoplasia. Its integral role in the management of early cervical disease is justified.

RPS19 and TYMS SNPs and Prevalent High Risk Human Papilloma Virus Infection in Nigerian Women.

High risk HPV (hrHPV) infection is a necessary cause of cervical cancer but the host genetic determinants of infection are poorly understood. We enrolled 267 women who presented to our cervical cancer screening program in Abuja, Nigeria between April 2012 and August 2012. We collected information on demographic characteristics, risk factors of cervical cancer and obtained samples of blood and cervical exfoliated cells from all participants. We used Roche Linear Array HPV Genotyping Test® to characterize the prevalent HPV according to manufacturer's instruction; Sequenom Mass Array to test 21 SNPs in genes/regions previously associated with hrHPV and regression models to examine independent factors associated with HPV infection. We considered a p<0.05 as significant because this is a replication study. There were 65 women with and 202 women without hrHPV infection. Under the allelic model, we found significant association between two SNPs, rs2305809 on RPS19 and rs2342700 on TYMS, and prevalent hrHPV infection. Multivariate analysis of hrHPV risk adjusted for age, body mass index, smoking, age of menarche, age at sexual debut, lifetime total number of sexual partners and the total number of pregnancies as covariates, yielded a p-value of 0.071 and 0.010 for rs2305809 and rs2342700, respectively. Our findings in this unique population suggest that a number of genetic risk variants for hrHPV are shared with other population groups. Definitive studies with larger sample sizes and using genome wide approaches are needed to understand the genetic architecture of hrHPV risk in multiple populations.