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1.  Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HIM Study 
Sexually transmitted diseases  2013;40(6):508-515.
Background
Studies in women indicate that some sexually transmitted infections promote human papillomavirus (HPV) persistence and carcinogenesis. Little is known about this association in men, therefore we assessed whether Chlamydia trachomatis (CT) infection and herpes simplex virus type 2 (HSV-2) serostatus are associated with genital HPV prevalence, an early event in HPV related pathogenesis.
Methods
Genital exfoliated cells, first-void urine and blood from 3,971 men recruited in the USA, Mexico, and Brazil, were tested for HPV, CT, and HSV-2 antibodies, respectively. Multivariable logistic regression was used to assess the association of CT infection and HSV-2 serostatus with four HPV outcomes (any, oncogenic, non-oncogenic only, and multiple infections).
Results
A total of 64 (1.6%) men were CT positive and 811 (20.4%) men were HSV-2 seropositive. After adjustment for potential confounders, CT was associated with any HPV (aOR 2.19, 95%CI: 1.13–4.24), oncogenic HPV (aOR 3.10, 95%CI: 1.53–6.28), and multiple HPV (aOR 3.43, 95%CI: 1.69-6.95) prevalence. HSV-2 serostatus was associated with any HPV (aOR 1.25, 95%CI: 1.02-1.52), non-oncogenic HPV only (aOR 1.38, 95%CI: 1.08-1.75), and multiple HPV (aOR 1.33, 95%CI: 1.06-1.68) prevalence. In analyses stratified by sexual behaviour, CT infection was significantly associated with HPV detection among men reporting ≥2 recent sexual partners, while HSV-2 serostatus was significantly associated with HPV detection in men reporting 0-5 lifetime sexual partners.
Conclusion
In this population, CT infection and HSV-2 serostatus were associated with prevalent genital HPV infection. Future prospective studies should investigate whether these infections influence HPV acquisition and/or persistence.
doi:10.1097/OLQ.0b013e318289c186
PMCID: PMC3904659  PMID: 23680908
Men; genital; sexually transmitted infection; Human papillomavirus; Chlamydia trachomatis; herpes simplex virus type 2
2.  Proceedings of the Modeling Evidence in HPV Pre-Conference Workshop 
Clinical therapeutics  2010;32(8):1546-1564.
All published and active HPV modelers from around the world were invited to Malmo, Sweden for the inaugural Modeling Evidence in HPV (MEHPV) Pre-Conference Workshop, May 9 and 10, 2009. This workshop—held for the 2 days preceding the 25th International Papillomavirus Conference—provided a unique opportunity for open discussion on HPV modeling and the related scientific and methodological issues. From over a dozen countries and a variety of settings, 34 participants (representing 82% of the HPV modeling literature) exchanged ideas on the field’s fundamental questions. The proceedings, based on the 217-page transcript, was assembled by the Scientific Committee for the explicit purpose of objectively summarizing these ideas in a de-identified, readable fashion. It represents the work and opinions of session participants as recorded and does not constitute official positions of the participants as a whole or individually, the scientific committee, or any sponsoring organization or entity. Through transparency and broad dissemination, this introspective proceedings further characterizes prominent, contemporaneous issues in the state of HPV modeling.
doi:10.1016/j.clinthera.2010.06.017
PMCID: PMC4095755  PMID: 20728767
3.  Telomere Length, Telomere-Related Genes, and Breast Cancer Risk: The Breast Cancer Health Disparities Study 
Genes, chromosomes & cancer  2013;52(7):10.1002/gcc.22056.
Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER−/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER−/PR− tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry.
doi:10.1002/gcc.22056
PMCID: PMC3807250  PMID: 23629941
4.  Genetic Variation in Bone Morphogenetic Proteins and Breast Cancer Risk in Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study 
Bone morphogenetic proteins (BMP) are thoughtx to be important in breast cancer promotion and progression. We evaluated genetic variation in BMP-related genes and breast cancer risk among Hispanic (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women who participated in the 4-Corner’s Breast Cancer Study, the Mexico Breast Cancer Study, and the San Francisco Bay Area Breast Cancer Study. BMP genes and their receptors evaluated include ACVR1, AVCR2A, ACVR2B, ACVRL1, BMP1, BMP2, BMP4, BMP6, BMP7, BMPR1A, BMPR1B, BMPR2, MSTN and GDF10. Additionally, 104 ancestral informative markers were assessed to discriminate between European and Native American ancestry. The importance of estrogen on BMP-related associations was suggested through unique associations by menopausal status and estrogen (ER) and progesterone (PR) receptor status of tumors. After adjustment for multiple comparisons ACVR1 (8 SNPs) was modestly associated with ER+PR+ tumors [odds ratios (ORs between 1.18 and 1.39 padj< 0.05]. ACVR1 (3 SNPs) and BMP4 (3 SNPs) were associated with ER+PR− tumors (ORs 0.59 to 2.07 padj< 0.05). BMPR2 was associated with ER−PR+ tumors (OR 4.20, 95% CI 1.62, 10.91 padj< 0.05) as was GDF10 (2 SNPs ORs 3.62 and 3.85 padj< 0.05). After adjustment for multiple comparisons several SNPs remained associated with ER−PR− tumors (padj< 0.05) including ACVR1 BMP4, and GDF10 (ORs between 0.53 and 2.12). Differences in association also were observed by percentage of Native ancestry and menopausal status. Results support the hypothesis that genetic variation in BMPs is associated with breast cancer in this admixed population.
doi:10.1002/ijc.27960
PMCID: PMC3653321  PMID: 23180569
BMP; ACVR1; BMPRIB; breast cancer; Hispanic; genetic admixture; survival; ER status
5.  Differences between Hispanic and non-Hispanic White Women with Breast Cancer for Clinical Characteristics and their Correlates 
Annals of epidemiology  2013;23(4):227-232.
PURPOSE
Body size and ethnicity may influence breast cancer tumor characteristics at diagnosis. We compared Hispanic and non-Hispanic white cases for stage of disease, estrogen receptor status, tumor size, and lymph node status, and the associations of these with body size in the 4-Corners Breast Cancer Study (4-CBCS).
METHODS
1,527 Non-Hispanic white and 798 Hispanic primary incident breast cancer cases diagnosed between October 1999 and May 2004 were included. Odds ratios (OR) and 95% Confidence Intervals (CI) were calculated by multiple logistic regression.
RESULTS
Hispanic women were more likely to have larger (>1cm), ER- tumors, and >4 positive lymph nodes (p < 0.003). Lymph node status was not associated with body size. However, among non-Hispanic white women, obesity (BMI >30) and increased waist circumference (> 38.5 inches) were significantly, positively associated with ER- tumor status; ORs = 1.87, 95% CI 1.24–2.81 and 2.59, 95% CI 1.58–4.22, respectively. In contrast, among Hispanic women, obesity and waist circumference had inverse associations with ER- status (OR = 0.49, 95% CI 0.29–0.84) and (0.56, 95% CI 0.30–1.05), respectively.
CONCLUSIONS
Hispanic ethnicity may modify the association of body size and composition with ER- breast cancer. This finding could have relevance to clinical treatment and prognosis.
doi:10.1016/j.annepidem.2012.12.013
PMCID: PMC3605206  PMID: 23369848
Breast Neoplasms; Hispanic Americans; Obesity
6.  Seroprevalence of Human Papillomavirus (HPV) Type 6 and 16 Vary by Anatomic Site of HPV Infection in Men 
Background
It is largely unknown if anti-HPV serum antibody responses vary by anatomic site of infection in men.
Methods
This study assessed type-specific anti-HPV serum antibody prevalence associated with corresponding HPV DNA detection in the external genitalia and the anal canal of 1587 heterosexual men and 199 men who have sex with men (MSM).
Results
We observed that HPV 6 and 16 seroprevalence was higher in the presence of same HPV type infection in the anal canal compared to the presence in the external genitalia only, and among MSM compared to heterosexual men. Seropositivity to HPV 6 was strongly associated with HPV 6 DNA detection in the anal canal but not in the external genitalia alone among both heterosexual men (Adjusted Prevalence Ratio (APR), anal+/genital+ vs. anal-/genital-: 4.2 [95% CI: 11.7-10.5]; anal+/genital- vs. anal-/genital-: 7.9 [95% CI: 3.7-17.0]) and MSM (APR, anal+/genital+ vs. anal-/genital-: 5.6 [95% CI: 2.7-11.9]; anal+/genital- vs. anal-/genital-: 3.2 [95% CI: 2.1-4.9]). Similar associations between seropositivity to HPV 16 and anal HPV 16 DNA detection were only observed in MSM (anal+/genital+ vs. anal-/genital-: 3.1 [95% CI: 2.0-5.0]; anal+/genital- vs. anal-/genital-: 2.2 [95% CI: 1.3-3.5]).
Conclusion
Our data demonstrated that seroprevalence varied by anatomic site of HPV infection, suggesting differences in epithelium type present at these anatomic sites may be relevant.
Impact
Our finding is instrumental in advancing our understanding of immune mechanism involved in anatomic site-specific antibody response.
doi:10.1158/1055-9965.EPI-12-0483
PMCID: PMC3466057  PMID: 22761306
Human Papillomavirus (HPV); heterosexual men; men who have sex with men (MSM); seroprevalence; external genitalia; anal canal
7.  Prevention of Invasive Cervical Cancer in the United States: Past, Present, and Future 
Over the past several decades, invasive cervical cancer (ICC) incidence in the United States has declined dramatically. Much of this decline has been attributed to widespread use of cytology screening followed by treatment of precancerous lesions. Despite available technologies to prevent ICC and screening programs targeting high-risk women, certain populations in the United States experience disproportionately high rates of ICC (e.g., racial/ethnic minorities and rural women). Limited access to and use of screening/follow-up services underlie this disparity. The licensure of the human papillomavirus (HPV) vaccine in 2006 introduced an additional method of ICC prevention. Unfortunately, dissemination of the vaccine to age-eligible females has been lower than expected (32% have received all 3 recommended doses). Decreasing the burden of HPV infection and HPV-related diseases in the United States will require greater dissemination of the HPV vaccine to adolescents and young adults, along with successful implementation of revised ICC screening guidelines that incorporate HPV and cytology cotesting. While a future without ICC is possible, we will need a comprehensive national health care program and innovative approaches to reduce ICC burden and disparities.
doi:10.1158/1055-9965.EPI-11-1158
PMCID: PMC3556792  PMID: 22556273
8.  Race and prevalence of human papillomavirus infection among men residing in Brazil, Mexico, and the United States 
HPV causes anal, penile and oropharyngeal cancers in men. Genital HPV prevalence in men appears to vary by world region with men residing in Asia having among the lowest prevalence. Unfortunately, there is little information on prevalence of HPV infection in men by race. The purpose of this study was to examine HPV prevalence by race across three countries. 3,909 men ages 18–70 years enrolled in an ongoing prospective cohort study of the natural history of HPV in men (The HIM Study) were included in the analysis. Participants completed risk factor questionnaires and samples were taken from the penile epithelium and scrotum for HPV detection. HPV testing of the combined DNA extract was conducted using PCR and genotyping. Asian/Pacific Islanders had the lowest HPV prevalence of 42.2% compared to Blacks (66.2%), and Whites (71.5%). The Asian/Pacific Islander race was strongly protective in univariate analysis (prevalence ratio(PR)= 0.59; 95% confidence interval(CI):0.48 – 0.74) and multivariate analysis for any HPV infection (PR= 0.65; 95% CI:0.52 – 0.8). Stratified analysis by lifetime number of female partners also showed strong inverse associations with the Asian/Pacific Islander race. We consistently observed the lowest prevalence of HPV infection among Asian/Pacific Islanders with moderate inverse associations even after various adjustments for potential confounding factors. Unmeasured behavioral factors, sexual mixing with low risk women, and/or race-specific differences in the frequency of germline variations among immune regulating genes may underlie these associations. Further studies among Asian populations that incorporate measures of immuno-genetics are needed to understand this phenomenon.
doi:10.1002/ijc.27397
PMCID: PMC3458422  PMID: 22161806
9.  Dietary Consumption of Antioxidant Nutrients and Risk of Incident Cervical Intraepithelial Neoplasia 
Gynecologic oncology  2010;118(3):289-294.
Objective
Women with human papillomavirus (HPV) infections are at risk for developing squamous intraepithelial lesions (SIL) of the cervix; however, other factors are required for infections to progress to SIL. We hypothesize that consumption of fruits and vegetables high in antioxidant nutrients may prevent, in part, the development of HPV-associated SIL.
Methods
This study is a nested case-control study of 265 HPV-positive women (93 SIL cases and 172 cytologically normal controls) in the Ludwig-McGill Cohort Study, Sao Paulo, Brazil. Diet was assessed by a self-administered food frequency questionnaire. The association between food and nutrient intake of antioxidants and incident SIL was determined by logistic regression and multinomial regression when comparing LSIL and HSILs.
Results
Higher reported consumption of papaya was inversely associated with risk of SIL (p trend=0.01) and strongest for ≥1 time/week (adjusted odds ratios (AORs)=0.19; 95%CI, 0.08-0.49). Risk of SIL was reduced among women reporting consumption of oranges ≥1 time/week (AOR=0.32; 95%CI, 0.12-0.87; p-trend = 0.02). Nutrient intakes of ß-cryptoxanthin and α-carotene were marginally protective against SIL.
Conclusions
Frequent consumption of fruits high in antioxidant nutrients appears to be associated with reduced risk of incident SIL among Brazilian women.
doi:10.1016/j.ygyno.2010.05.022
PMCID: PMC3691953  PMID: 20691333
cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; diet; antioxidant nutrient
10.  Male circumcision and the incidence and clearance of genital human papillomavirus (HPV) infection in men: the HPV Infection in men (HIM) cohort study 
Background
Reported associations of male circumcision (MC) with human papillomavirus (HPV) infection in men have been inconsistent.
Methods
4,033 healthy men were examined every six months for a median of 17.5 months. In each study visit, exfoliated cell specimens from the coronal sulcus/glans penis, penile shaft, and scrotum were collected and combined into one sample per person for HPV DNA detection. Samples were tested for 37 HPV types. Cox proportional hazards models were used to evaluate the association between MC and the incidence and clearance of HPV infections and specific genotypes.
Results
The overall incidence of new HPV infections did not differ by MC status (for any HPV, adjusted hazard ratio (aHR) 1.08, 95% confidence interval (CI) 0.91-1.27). However, incidence was significantly lower among circumcised versus uncircumcised men for HPV types 58 (p = 0.01), 68 (p < 0.001), 42 (p = 0.01), 61 (p < 0.001), 71 (p < 0.001), 81 (p = 0.04), and IS39 (p = 0.01), and higher for HPV types 39 (p = 0.01) and 51 (p = 0.02). Despite the lack of an overall association in the risk of HPV clearance by MC (for any HPV, aHR 0.95, 95% CI 0.88-1.02), median times to clearance were significantly shorter among circumcised than uncircumcised men for HPV types 33 (p = 0.02) and 64 (p = 0.04), and longer for HPV types 6 (p < 0.001), 16 (p < 0.001), and 51 (p = 0.02).
Conclusions
MC is not associated with the incidence and clearance of genital HPV detection, except for certain HPV types. The use of a single combined sample from the penis and scrotum for HPV DNA detection likely limited our ability to identify a true effect of MC at the distal penis.
doi:10.1186/1471-2334-14-75
PMCID: PMC3925013  PMID: 24517172
Male circumcision; Genital; HPV; Incidence; Clearance
11.  Cognitive and Emotional Responses to Human Papillomavirus Test Results in Men 
Background
HPV infection has been associated with a wide range of psychosocial responses among women; however, few studies have examined emotional responses among men.
Purpose
To examine psychosocial differences among self-reported HPV-positive and HPV-negative Florida men who were tested for HPV.
Method
Men (n=536) in a natural history study of HPV completed a cross-sectional psychosocial survey between 2007 and 2010.
Results
Most participants were White, non-Hispanic, unmarried and had some college education. HPV knowledge was high, with no statistically significant differences between groups. Significantly higher negative emotional responses and perceived threat scores were found among HPV-positive men (p<0.05). The majority of men (91%) reported they were very likely or likely to get the HPV vaccine if it became available for men, but identified barriers as factors to consider. HPV-negative men were significantly more likely to tell a sex partner their test results than HPV-positive men.
Conclusions
Men experienced a range of negative emotions after receiving HPV test results, but most disclosed their test result to their sexual partner and reported high intentions to receive the HPV vaccine in the future. Findings should be considered when implementing health-related interventions among men to assist in decreasing psychosocial sequalae associated with HPV.
doi:10.5993/AJHB.36.6.5
PMCID: PMC3904642  PMID: 23026036
12.  The Optimal Anatomic Sites for Sampling Heterosexual Men for Human Papillomavirus (HPV) Detection: The HPV Detection in Men Study 
The Journal of infectious diseases  2007;196(8):1146-1152.
Background
Human papillomavirus (HPV) infection in men contributes to infection and cervical disease in women as well as to disease in men. This study aimed to determine the optimal anatomic site(s) for HPV detection in heterosexual men.
Methods
A cross-sectional study of HPV infection was conducted in 463 men from 2003 to 2006. Urethral, glans penis/coronal sulcus, penile shaft/prepuce, scrotal, perianal, anal canal, semen, and urine samples were obtained. Samples were analyzed for sample adequacy and HPV DNA by polymerase chain reaction and genotyping. To determine the optimal sites for estimating HPV prevalence, site-specific prevalences were calculated and compared with the overall prevalence. Sites and combinations of sites were excluded until a recalculated prevalence was reduced by <5% from the overall prevalence.
Results
The overall prevalence of HPV was 65.4%. HPV detection was highest at the penile shaft (49.9% for the full cohort and 47.9% for the subcohort of men with complete sampling), followed by the glans penis/coronal sulcus (35.8% and 32.8%) and scrotum (34.2% and 32.8%). Detection was lowest in urethra (10.1% and 10.2%) and semen (5.3% and 4.8%) samples. Exclusion of urethra, semen, and either perianal, scrotal, or anal samples resulted in a <5% reduction in prevalence.
Conclusions
At a minimum, the penile shaft and the glans penis/coronal sulcus should be sampled in heterosexual men. A scrotal, perianal, or anal sample should also be included for optimal HPV detection.
doi:10.1086/521629
PMCID: PMC3904649  PMID: 17955432
13.  Male Human Papillomavirus Prevalence and Association With Condom Use in Brazil, Mexico, and the United States 
The Journal of Infectious Diseases  2012;205(8):1287-1293.
Background. Reported associations of condom use and human papillomavirus (HPV) infection have been inconsistent. We investigated self-reported frequency of condom use and detection of genital HPV among men.
Methods. A cross-sectional analysis was conducted in men aged 18–70 years from Brazil, Mexico, and the United States. Men completed questionnaires on sexual history, condom use, and sociodemographic characteristics. Among 2621 men reporting recent vaginal sex, prevalence of any HPV, any oncogenic type, and nononcogenic types only was estimated by frequency of condom use (“always” or “not always”). Multivariable models were used to estimate prevalence ratios (PRs) for HPV according to frequency of condom use.
Results. The prevalence of any HPV was 70.5%; any oncogenic type, 34%, and nononcogenic types only, 22.2%. The adjusted PR for always vs not always using condoms was 0.87 (95% confidence interval [CI], .77–.97) for all countries combined. The association was stronger in the United States (PR, 0.70; CI, .55–.90) than in Brazil (PR, 0.84; CI, .71–1.01) or Mexico (PR, 1.05; CI, .89–1.25) (P for interaction = .025).
Conclusions. HPV prevalence was high even among those who reported always using condoms, and its associations with always using condoms varied among countries.
doi:10.1093/infdis/jis181
PMCID: PMC3308908  PMID: 22396601
14.  Risk Factors for Anogenital Human Papillomavirus Infection in Men 
The Journal of infectious diseases  2007;196(8):10.1086/521632.
Background
Human papillomavirus (HPV) is strongly associated with cervical and other anogenital cancers. Identification of risk factors for HPV infection in men may improve our understanding of HPV transmission and prevention.
Methods
HPV testing for 37 types was conducted in 463 men 18–40 years old recruited from 2 US cities. The entire anogenital region and semen were sampled. A self-administered questionnaire was completed. Multivariate logistic regression aided the identification of independent risk factors for any HPV type, oncogenic HPV types, and nononcogenic HPV types.
Results
Prevalence was 65.4% for any HPV, 29.2% for oncogenic HPV, and 36.3% for nononcogenic HPV. Factors significantly associated with any HPV were smoking ≥10 cigarettes per day (odds ratio [OR], 2.3 [95% confidence interval {CI}, 1.0–5.3]) and lifetime number of female sex partners (FSPs) (OR for ≥21, 2.5 [95% CI, 1.3–4.6]), and factors significantly associated with oncogenic HPV were lifetime number of FSPs (OR for ≥21, 7.4 [95% CI, 3.4–16.3]) and condom use during the past 3 months (OR for more than half the time, 0.5 [95% CI, 0.3–0.8]). For nononcogenic HPV, a significant association was found for number of FSPs during the past 3 months (OR for ≥2, 2.9 [95% CI, 1.4–6.3]).
Conclusions
Lifetime and recent number of FSPs, condom use, and smoking were modifiable risk factors associated with HPV infection in men.
doi:10.1086/521632
PMCID: PMC3877918  PMID: 17955431
15.  Prevalent Serum Antibody Is Not a Marker of Immune Protection against Acquisition of Oncogenic HPV16 in Men 
Cancer research  2011;72(3):676-685.
In women, naturally induced anti–human papilloma virus (HPV) serum antibodies are a likely marker of host immune protection against subsequent HPV acquisition and progression to precancerous lesions and cancers. However, it is unclear whether the same is the case in men. In this study, we assessed the risk of incident genital infection and 6-month persistent genital infection with HPV16 in relation to baseline serostatus in a cohort of 2,187 men over a 48-month period. Genital swabs were collected every 6 months and tested for HPV presence. Incidence proportions by serostatus were calculated at each study visit to examine whether potential immune protection attenuated over time. Overall, incidence proportions did not differ statistically between baseline seropositive and seronegative men at any study visit or over the follow-up period. The risk of incident and 6-month persistent infection was not associated with baseline serostatus or baseline serum antibody levels in the cohort. Our findings suggest that baseline HPV seropositivity in men is not associated with reduced risk of subsequent HPV16 acquisition. Thus, prevalent serum antibodies induced by prior infection may not be a suitable marker for subsequent immune protection against genital HPV16 acquisition in men.
doi:10.1158/0008-5472.CAN-11-0751
PMCID: PMC3474343  PMID: 22123925
16.  Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study 
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, functions in cellular processes essential to the development of cancer. Overexpression of EGFR in primary breast tumors has been linked with poor prognosis. We investigated the associations between 34 EGFR tagging SNPs and breast cancer risk and breast cancer-specific mortality in 4,703 Hispanic and 3,030 non-Hispanic white women from the Breast Cancer Health Disparities Study. We evaluated associations with risk of breast cancer defined by estrogen/progesterone receptor (ER/PR) tumor phenotype. Only one association remained statistically significant after adjusting for multiple comparisons. Rs2075112GA/AA was associated with reduced risk for ER-/PR+ tumor phenotype (odds ratio (OR), 0.34; 95% confidence interval (CI) 0.18-0.63, p adj=0.01). All additional results were significant prior to adjustment for multiple comparisons. Two of the EGFR polymorphisms were associated with breast cancer risk in the overall study population (rs11770531TT: OR, 0.56, 95% CI 0.37-0.84; and rs2293348AA: OR, 1.20, 95% CI 1.04-1.38) and two polymorphisms were associated with risk among Hispanics: rs6954351AA: OR, 2.50, 95% CI 1.32-4.76; and rs845558GA/AA: OR, 1.15, 95% CI 1.01-1.30. With regard to breast cancer-specific mortality, we found positive associations with rs6978771TT hazard ratio (HR), 1.68; 95% CI 1.11-2.56; rs9642391CC HR, 1.64; 95% CI 1.04-2.58; rs4947979AG/GG HR, 1.36; 95% CI 1.03-1.79; and rs845552GG HR, 1.62; 95% CI 1.05-2.49. Our findings provide additional insight for the role of EGFR in breast cancer development and prognosis. Further research is needed to elucidate EGFR’s contribution to ethnic disparities in breast cancer.
PMCID: PMC3852643  PMID: 24319539
Breast cancer; Hispanic; epidermal growth factor receptor; polymorphisms; tumor phenotype
17.  SEPP1 Influences Breast Cancer Risk among Women with Greater Native American Ancestry: The Breast Cancer Health Disparities Study 
PLoS ONE  2013;8(11):e80554.
Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.
doi:10.1371/journal.pone.0080554
PMCID: PMC3835321  PMID: 24278290
18.  The Human Papillomavirus Infection in Men Study: Human Papillomavirus Prevalence and Type Distribution among Men Residing in Brazil, Mexico, and the United States 
Male sexual behavior influences the rates of cervical dysplasia and invasive cervical cancer, as well as male human papillomavirus (HPV) infection and disease. Unfortunately, little is known regarding male HPV type distribution by age and across countries. In samples combined from the coronal sulcus, glans penis, shaft, and scrotum of 1,160 men from Brazil, Mexico, and the United States, overall HPV prevalence was 65.2%, with 12.0% oncogenic types only, 20.7% nononcogenic types only, 17.8% both oncogenic and nononcogenic, and 14.7% unclassified infections. Multiple HPV types were detected in 25.7% of study participants. HPV prevalence was higher in Brazil (72.3%) than in the United States (61.3%) and Mexico (61.9%). HPV16 (6.5%), HPV51 (5.3%), and HPV59 (5.3%) were the most commonly detected oncogenic infections, and HPV84 (7.7%), HPV62 (7.3%), and HPV6 (6.6%) were the most commonly detected nononcogenic infections. Overall HPV prevalence was not associated with age. However, significant associations with age were observed when specific categories of HPV, nononcogenic, and unclassified HPV infections were considered. Studies of HPV type distribution among a broad age range of men from multiple countries is needed to fill the information gap internationally with respect to our knowledge of HPV infection in men.
doi:10.1158/1055-9965.EPI-08-0151
PMCID: PMC3471778  PMID: 18708396
19.  Associations between serum carotenoids and tocopherols and type-specific HPV persistence: The Ludwig-McGill cohort study 
Although oncogenic HPV infections have been established as the necessary cause of cervical cancer, most HPV infections are transient and rarely progress to cervical lesions. Current research is focused on identifying factors associated with viral persistence and clearance, such as nutritional status. We evaluated the association between serum antioxidant nutrients (retinol, 10 carotenoids and 3 tocopherols) and type-specific HPV persistence over 4 visits among 405 women participating in the Ludwig-McGill cohort study. We measured circulating carotenoids and tocopherol at 4 different clinical visits for each woman. We report the results from different analytic approaches (a case–control approach at both the woman and viral level, and a prospective approach based on persistent events) that examined the association between these micronutrients and type-specific oncogenic and nononcogenic HPV persistence. In the case–control analysis at the viral level, midcirculating levels of α-tocopherol were inversely associated with nononcogenic HPV persistent infection (adjusted odds ratio (AOR) = 0.28, 95% CI 0.14–0.57), while high levels were marginally associated (AOR = 0.59, 95% CI 0.28–1.19). Similarly, utilizing generalized estimating equation models, circulating levels of α- and δ-tocopherol in the middle or upper tertiles were inversely associated with type-specific nononcogenic HPV persistence (AOR = 0.44, 95% CI 0.19–0.97 and AOR = 0.46, 95% CI 0.19–1.11, respectively). Our study among Brazilian women suggests that serum levels of tocopherols may be protective against nononcogenic HPV persistence. However, we did not find a strong protective effect (as hypothesized) of other serum antioxidant nutrients and type-specific oncogenic HPV persistence measured over 4 clinical visits.
doi:10.1002/ijc.22346
PMCID: PMC3458424  PMID: 17096322
human papillomavirus; persistence; carotentoid; tocopherol
20.  Provider Factors Associated with Disparities in HPV Vaccination among Low-Income 9–17-Year-Old Girls 
Cancer  2012;119(3):621-628.
Background
Many women who develop cervical cancer are eligible for or are participants of Medicaid. Providing human papillomavirus (HPV) vaccination to girls enrolled in Medicaid may reduce cervical cancer disparities in low-income and minority women. This study evaluated provider characteristics associated with HPV vaccination among 9–17-year-old female Medicaid enrollees.
Methods
A random sample of 800 providers from the Florida Medicaid Master Provider File was mailed a survey in October 2009 that evaluated demographic and practice characteristics, HPV information and knowledge, barriers to HPV vaccination, vaccine practices, and vaccine recommendation practices. To measure HPV vaccination, Medicaid claims data were used to calculate the proportion of eligible patients who received at least one dose of the vaccine from participating providers within the study period. Provider factors associated with vaccination at the bivariate level were evaluated in a multiple linear regression model.
Results
The response rate was 68.3% (N = 485). After excluding ineligible respondents, the current analysis included 433 providers. HPV vaccination prevalence ranged from 0% to 61.9% (M = 20.4, SD = 14.5). HPV vaccination rates were higher among providers who: were Pediatricians, had a private practice, practiced in a single specialty setting, were VFC providers, saw primarily non-Hispanic White patients, used ≥2 strategies for vaccine series completion, and did not refer out for HPV vaccination.
Conclusions
Despite financial coverage for Medicaid-eligible girls, HPV vaccination rates are low. Study findings can be used to target health services interventions to providers least likely to administer HPV vaccine to female Medicaid enrollees.
doi:10.1002/cncr.27735
PMCID: PMC3800018  PMID: 23341308
human papillomavirus; HPV vaccine; cancer vaccine; cervix cancer; low-income population; Medicaid; physician
21.  Do Florida Medicaid Providers’ Barriers to HPV Vaccination Vary Based on VFC Program Participation? 
Maternal and child health journal  2013;17(4):609-615.
Objectives
This study aimed to determine if physicians’ perceived barriers to HPV vaccination were associated with participation in the federal Vaccines for Children (VFC) program.
Methods
A sample of 800 Florida Medicaid providers was randomly selected from the Florida Medicaid Master Provider File. A cross-sectional study was conducted using a 27-item survey that included 13 potential barriers to immunizing Medicaid patients against HPV, including concerns about vaccine safety and efficacy, discussing sexuality, vaccinated teens practicing riskier sexual behaviors, cost and reimbursement, ensuring 3-dose series completion, and school attendance requirements associated with HPV vaccination. Pearson Chi-square tests were conducted to investigate differences between each barrier and VFC program participation. Data were analyzed for 449 physicians.
Results
Compared to non-VFC providers, VFC providers were significantly less likely to somewhat or strongly agree that the following were barriers to vaccination: the cost of stocking the HPV vaccine (p = 0.0011), lack of adequate reimbursement for HPV vaccination (p < 0.0001), and lack of timely reimbursement for HPV vaccination (p < 0.0001). After adjusting for provider specialty and number of years since completion of residency training, VFC status remained significantly associated with the barrier regarding lack of adequate reimbursement for vaccination such that non-VFC providers had a 2.6-fold (95% confidence interval, 1.1–5.8) greater odds of somewhat or strongly agreeing that this barrier applied to them.
Conclusions
Increasing participation in the VFC program may decrease physicians’ cost-related barriers, which may increase the number of children vaccinated on time according to the recommended schedule.
doi:10.1007/s10995-012-1036-5
PMCID: PMC3795412  PMID: 22569945
22.  ADRB2 G–G haplotype associated with breast cancer risk among Hispanic and non-Hispanic white women: interaction with type 2 diabetes and obesity 
Cancer causes & control : CCC  2012;23(10):1653-1663.
Introduction
Polymorphisms in the beta-2-adrenergic receptor (ADRB2) gene have been studied in relation to risk of type 2 diabetes and obesity, risk factors that have received increased attention in relation to breast cancer. We evaluated the hypothesis that ADRB2 variants (rs 1042713, rs1042714) are associated with breast cancer risk in non-Hispanic white (NHW) and Hispanic (H) women using data from a population-based case–control study conducted in the southwestern United States.
Methods
Data on lifestyle and medical history, and blood samples, were collected during in-person interviews for incident primary breast cancer cases (1,244 NHW, 606 H) and controls (1,330 NHW, 728 H). ADRB2 genotypes for rs1042713(G/A) and rs1042714(G/C) were determined using TaqMan assays. The associations of each variant and corresponding haplotypes with breast cancer were estimated using multivariable logistic regression.
Results
Two copies compared to one or zero copies of the ADRB2 G–G haplotype were associated with increased breast cancer risk for NHW women [odds ratio (OR), 1.95; 95 % confidence interval (95 % CI), 1.26–3.01], but with reduced risk for H women [OR, 0.74; 95 % CI, 0.50–1.09]. Effect estimates were strengthened for women with a body mass index (BMI) ≥25 kg/m2 [H: OR, 0.50; 95 % CI, 0.31–0.82; NHW: OR, 3.85; 95 % CI, 1.88–7.88] and for H women with a history of diabetes [H: OR, 0.32; 95 % CI, 0.12–0.89].
Conclusions
These data suggest that ethnicity modifies the association between the ADRB2 G–G haplotype and breast cancer risk, and being overweight or obese enhances the divergence of risk between H and NHW women.
doi:10.1007/s10552-012-0043-6
PMCID: PMC3794465  PMID: 22864926
Breast cancer; Hispanic; Beta-2-adrenergic receptor; Haplotypes; Obesity; Diabetes
23.  Human Papillomavirus (HPV) 6, 11, 16, and 18 Seroprevalence Is Associated with Sexual Practice and Age: Results from the Multinational HPV Infection in Men Study (HIM Study) 
Background
Few human papillomavirus (HPV) serology studies have evaluated type-specific seroprevalence of vaccine HPV types in men. This study investigates seroprevalence of HPV 6, 11, 16, and 18, and associated risk factors in men residing in three countries (United States, Mexico, and Brazil).
Methods
Data from 1,477 men aged 18 to 70 enrolled in the HPV Infection in Men Study (HIM Study) were analyzed. Serum antibody testing was performed with virus-like particle-based ELISA. Potential risk factors were assessed for individual HPV types by the use of logistic regression.
Results
Overall, HPV-6, 11, 16, and 18 seroprevalence was 14.8%, 17.3%, 11.2%, and 5.8%, respectively. Thirty-four percent of men were seropositive to one or more HPV types. When examined by sexual practice, 31.2% of men who had sex with women, 65.6% of men who had sex with men (MSM), and 59.4% of men who had sex with both men and women (MSMW) were seropositive to one or more HPV types. Seroprevalence increased with age among young-to-middle-aged men with significant upward age trends observed for HPV 11, 16, and 18. Men with multiple lifetime male anal sex partners were 2 to 4 times more likely to be HPV 6 or 11 seropositive and 3 to 11 times more likely to be HPV 16 or 18 seropositive.
Conclusion
Our data indicate that exposures to vaccine HPV types were common in men and highly prevalent among MSM and MSMW.
Impact
Our study provides strong evidence that the practice of same-sex anal intercourse is an independent risk factor for seroprevalence of individual vaccine HPV types. Examination of antibody responses to HPV infections at various anatomic sites in future studies is needed to elaborate on the mechanism.
doi:10.1158/1055-9965.EPI-10-1160
PMCID: PMC3232028  PMID: 21378268
24.  Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study 
Lancet  2011;377(9769):932-940.
Summary
Background
Human papillomaviruses (HPVs) cause genital warts and cancers in men. The natural history of HPV infection in men is largely unknown, and that information is needed to inform prevention strategies. The goal in this study was to estimate incidence and clearance of type-specific genital HPV infection in men, and to assess the associated factors.
Methods
Men (aged 18–70 years), residing in Brazil, Mexico, and the USA, who were HIV negative and reported no history of cancer were recruited from the general population, universities, and organised health-care systems. They were assessed every 6 months for a median follow-up of 27·5 months (18·0–31·2). Specimens from the coronal sulcus, glans penis, shaft, and scrotum were obtained for the assessment of the status of HPV genotypes.
Findings
In 1159 men, the incidence of a new genital HPV infection was 38·4 per 1000 person months (95% CI 34·3–43·0). Oncogenic HPV infection was significantly associated with having a high number of lifetime female sexual partners (hazard ratio 2·40, 1·38–4·18, for at least 50 partners vs not more than one partner), and number of male anal-sexual partners (2·57, 1·46–4·49, for at least three male partners vs no recent partners). Median duration of HPV infection was 7·52 months (6·80–8·61) for any HPV and 12·19 months (7·16–18·17) for HPV 16. Clearance of oncogenic HPV infection decreased in men with a high number of lifetime female partners (0·49, 0·31–0·76, for at least 50 female partners vs not more than one partner), and in men in Brazil (0·71, 0·56–0·91) and Mexico (0·73, 0·57–0·94) compared with the USA. Clearance of oncogenic HPV was more rapid with increasing age (1·02, 1·01–1·03).
Interpretation
The data from this study are useful for the development of realistic cost-effectiveness models for male HPV vaccination internationally.
Funding
National Cancer Institute.
doi:10.1016/S0140-6736(10)62342-2
PMCID: PMC3231998  PMID: 21367446
25.  Genital Human Papillomavirus (HPV) Concordance in Heterosexual Couples 
The Journal of Infectious Diseases  2012;206(2):202-211.
Background. Few studies have assessed genital human papillomavirus (HPV) concordance and factors associated with concordance among asymptomatic heterosexual couples.
Methods. Genotyping for HPV was conducted with male and female sex partners aged 18–70 years from Tampa, Florida. Eligibility included no history of HPV-associated disease. Type-specific positive concordance (partners with ≥1 genotype in common) and negative concordance (neither partner had HPV) were assessed for 88 couples. Factors associated with concordance were assessed with Fisher exact tests and tests for trend.
Results. Couples reported engaging in sexual intercourse for a median of 1.7 years (range, 0.1–49 years), and 75% reported being in the same monogamous relationship for the past 6 months. Almost 1 in 4 couples had type-specific positive concordance, and 35% had negative concordance for all types tested, for a total concordance of 59%. Concordance was not associated with monogamy. Type-specific positive concordance was associated with an increasing difference in partners’ lifetime number of sex partners and inversely associated with an increasing difference in age. Negative concordance was inversely associated with both the couple's sum of lifetime number of sex partners and the difference in the partners’ lifetime number of sex partners.
Conclusions. Genital HPV concordance was common. Viral infectiousness and number of sex partners may help explain concordance among heterosexual partners.
doi:10.1093/infdis/jis327
PMCID: PMC3490693  PMID: 22539815

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