Circumcision and human papillomavirus infection in men: a site-specific comparison.

BACKGROUND: Lack of circumcision has been identified as a risk factor for male genital human papillomavirus (HPV) infection, although this association has not been consistently supported. METHODS: Specimens for HPV testing were collected from a cohort of 379 (primarily heterosexual) adult males. HPV prevalence in the glans penis and coronal sulcus, penile shaft, scrotum, semen, and urine was compared by circumcision status. RESULTS: Overall, HPV DNA prevalence ranged from 6% in semen to 52% in the penile shaft. The prevalence of any HPV infection in the glans/corona was significantly higher in uncircumcised men (46%) than in circumcised men (29%) (odds ratio [OR], 1.96 [95% confidence interval (CI), 1.02-3.75], adjusted for demographic characteristics and sexual history). Uncircumcised men also had an increased risk of oncogenic HPV infection (adjusted OR, 2.51 [95% CI, 1.11-5.69]) and infection with multiple HPV types (adjusted OR, 3.56 [95% CI, 1.50-8.50]). Among uncircumcised men, HPV prevalence in the foreskin (44%) was comparable to that in the glans/corona, and type-specific positivity was observed between the 2 sites (kappa=0.52). CONCLUSIONS: Uncircumcised men have an increased risk of HPV infection, including with oncogenic HPV, specifically localized to the glans/corona, possibly because of its proximity to the foreskin, which may be particularly vulnerable to infection.

Comparison of physician- and self-collected genital specimens for detection of human papillomavirus in men.

There is currently no consensus regarding the most appropriate methods of sampling for the detection of genital human papillomavirus (HPV) in men. We employed a recently developed collection method involving abrasion and moistened swabbing of the genital skin surface for the detection of HPV in a cohort of 136 university-affiliated males in Hawaii. Genital specimens collected by physicians using this method were compared with self-collected specimens from the same individuals obtained 24 h later. Self-collected specimens yielded a greater proportion of sufficient specimens than physician-collected specimens. HPV detection was comparable in physician- and self-collected specimens; detection was highest in the penile shaft (51.2% and 51.5%, respectively, P = 0.96), followed by the scrotum (41.2% and 46.2%, P = 0.43), the glans/coronal sulcus (31.9% and 33.1%, P = 0.84), and the foreskin (33.3% and 28.6%, P = 0.74). Site-specific agreement in HPV detection between paired physician- and self-collected samples ranged from 67.2% (kappa = 0.34) for the penile shaft to 95.0% (kappa = 0.89) for the foreskin. There was a high degree of concordance in HPV genotypes in HPV-positive pairs. The most common type was HPV type 84, which comprised approximately 15% of the specimens. The emery paper-swab method offers an efficient sampling method for genital HPV DNA detection in men that could be used both within and outside of the clinical setting.

Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia.

Epidemiological studies have been inconsistent regarding a role for folate in the etiology of cervical dysplasia. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, which is involved in the methylation of homocysteine to methionine. A common variant of this enzyme, resulting from a 677C-->T (Ala-->Val) substitution in the gene, has been shown to have reduced activity and is associated with mild hyperhomocysteinemia. A multiethnic case-control study was used to examine the association of dietary folate and MTHFR genotype with the odds ratios (ORs) for cervical dysplasia among women identified from several clinics on Oahu, Hawaii, between 1992 and 1996. We collected blood samples for DNA extraction, cervical smears for cytological diagnosis, exfoliated cervical cells for human papillomavirus (HPV) DNA testing, and personal interviews from 150 women with squamous intraepithelial lesions (SILs) and from 179 women with cytologically normal (Pap) smears. We found a positive, monotonic trend (P = 0.02) in the ORs for cervical SILs associated with the number of variant MTHFR T alleles, after multivariate adjustment. Women with the heterozygous CT genotype had twice the risk of cervical SILs [OR, 2.0; 95% confidence interval (CI), 1.1-3.7], and women with the homozygous TT genotype had almost three times the risk of SILs (OR, 2.9; 95% CI, 1.0-8.8) compared to women with the homozygous MTHFR CC genotype. The dietary intakes of folate, vitamin B(6), and vitamin B(12) were inversely related to the ORs for cervical SILs, after adjustment for HPV DNA and other confounders. The OR among women in the highest quartile compared with women in the lowest quartile of folate intake was 0.3 (95% CI, 0.1-0.7; P for trend = 0.002). Women with the variant T allele and folate intakes below the median were at significantly elevated risk of cervical SILs (OR, 5.0; 95% CI, 2.0-12.2) compared to women with CC alleles and folate intakes above the median. HPV infection was a strong risk factor for cervical dysplasia, particularly among women with the variant T allele (OR, 46.6; 95% CI, 15.9-136.2). All associations of MTHFR genotype with the ORs for cervical SILs were independent of other risk factors under study. These findings suggest that the MTHFR T allele and reduced dietary folate may increase the risk for cervical SILs.

CYP1A1, GSTM1, and GSTT1 polymorphisms and the risk of cervical squamous intraepithelial lesions in a multiethnic population.

OBJECTIVE: In this investigation, we explored the hypothesis that genetic polymorphisms in the cytochrome P4501A1 (T3801C) and glutathione S-transferase classes mu and theta (GSTM1 and GSTT1) gene deletions promote the development of cervical dysplasia by moderating the activation and detoxification of polycyclic hydrocarbons and other compounds that influence oxidative stress and DNA adduct formation. METHODS: A multiethnic, case-control study of 131 women with biopsy-confirmed cervical squamous intraepithelial lesions (SIL) and 180 controls with cytologically normal cervical (Pap) smears was conducted between 1992 and 1996 in Honolulu, Hawaii. We collected in-person interviews, a blood sample to extract genomic DNA, and an exfoliated cervical cell sample to determine the presence and type of human papillomavirus (HPV) using PCR dot-blot hybridization. Genotyping for the CYP1A1 MspI allelic variant and deletion of the GSTM1 and GSTT1 gene loci followed a PCR method. RESULTS: Women who were homozygous, but not heterozygous, for the CYP1A1 MspI variant allele were at significantly increased risk of cervical SIL (odds ratio (OR) = 3.4; 95% confidence interval (CI) = 1.1-10.7) compared to women who were homozygous for the wild-type allele. Subjects with the GSTM1 null genotype had a nonsignificant elevated risk of cervical SIL (OR = 1.6; 95% CI = 0.8-3.0) compared to women with the gene present. No difference in the risk of cervical disease was associated with the GSTT1 null genotype. The combination of the CYP1A1 homozygous variant and the GSTM1 null genotypes increased the odds ratio for cervical SIL to 5.1 (95% CI = 1.3-20.7). There was no evidence for an interaction between genotype and exposure to tobacco smoke, alcohol drinking, or HPV DNA positivity. CONCLUSIONS: These findings, although based on a small number of subjects, suggest that the CYP1A1 MspI polymorphism may be a susceptibility factor for early, premalignant changes in the cervical epithelium.

Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism.

Steroid hormones, such as estrogens, appear to be associated with ovarian carcinogenesis, but the precise biological mechanisms are unclear. Polymorphisms in genes that regulate the concentration of estrogens and their metabolites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influencing ovarian cancer susceptibility associated with ovulation and reproduction. We conducted a population-based, case-control study of primary ovarian cancer between 1993 and 1999 in Hawaii to test several genetic and related hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes that regulate steroid hormone metabolism and catecholestrogen formation. Multivariate unconditional logistic regression was used to model the association of each genetic polymorphism separately after adjusting for age, ethnicity, and other covariates. The high-activity Val432 allele of the CYP1B1 gene, which may be linked to oxidative stress through elevated 4-hydroxylated catecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu/Leu genotype (P = 0.005). Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alleles were at significantly increased risk of ovarian cancer compared to never-smokers with CYP1A1 (MspI) ml/ml, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction (P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, oral contraceptive pill use) or gene-gene interactions were statistically significant. Although not significant, there was a suggestion that the effect of the CYP1B1 Val allele was reduced substantially in the presence of the high-activity COMT Met allele. These findings suggest that the CYP1B1-Val allele and perhaps other genetic polymorphisms in combination with environmental or hormonal exposures are susceptibility factors for ovarian cancer.

Case-control study of plasma folate, homocysteine, vitamin B(12), and cysteine as markers of cervical dysplasia.

BACKGROUND: An association between B-complex vitamins and related compounds with the development of cervical neoplasia is biologically plausible, yet to the authors' knowledge epidemiologic investigations of these potential biomarkers are limited. METHODS: A case-control study was designed to examine the relation between plasma folate, homocysteine, vitamin B(12), and cysteine and early, premalignant changes in cervical epithelial cells among women identified from several clinics on Oahu, Hawaii, between 1992 and 1996. Fasting blood samples for plasma nutrient analysis, cervical smears for cytologic diagnosis, exfoliated cervical cells for human papillomavirus DNA testing by polymerase chain reaction, and a personal interview were obtained from 185 women with atypical squamous cells of undetermined significance (ASCUS) of the cervix, 147 women with squamous intraepithelial lesions (SIL), and 191 women with cytologically normal (Papanicolaou) smears. RESULTS: Age-adjusted and ethnicity-adjusted mean plasma concentrations of cysteine, but not other nutrients, were significantly lower among ASCUS cases (P = 0.006) and SIL cases (P = 0.01) than controls. A positive trend in the odds ratio for SIL but not ASCUS was found for increased plasma homocysteine concentrations, but this finding was not statistically significant. High plasma levels of cysteine were associated with a reduced risk of ASCUS (P value for trend = 0.006), with an odds ratio of 0.3 (95% confidence interval, 0.2-0.7) for the highest compared with the lowest quartile of cysteine concentration. A weak, negative relation between cysteine and the development of low grade SIL (LSIL) but not high grade SIL (HSIL) also was found. CONCLUSIONS: The results of the current study do not support the hypothesis that folate, homocysteine, or B(12) are markers of cervical dysplasia risk. A possible inverse association between plasma cysteine concentrations and the risk of cervical dysplasia needs further study.

The association of plasma micronutrients with the risk of cervical dysplasia in Hawaii.

Limited data from hematological studies suggest that certain nutrients, including carotenoids, tocopherols, and vitamin C, may protect against malignant change in cervical tissue. Recognizing that human papillomavirus (HPV) infection induces most neoplastic transformation of cervical tissue, the authors conducted a case-control study to examine the association of plasma micronutrient concentrations with the risk of cervical dysplasia after careful adjustment for HPV infection, using a sensitive and reliable HPV detection method. The sample included 147 multiethnic women, between 18 and 65 years of age, with biopsy-confirmed squamous intraepithelial lesions (SILs) of the cervix and 191 clinic controls identified between 1992 and 1996. Cases were identified through cytology and pathology logs in three clinics on Oahu, Hawaii. Controls were selected randomly from admission logs of the participating clinics. In-person interviews were conducted in the subjects' homes, and a fasting blood sample was drawn to measure plasma levels of lutein, lycopene, cryptoxanthin, total carotene, retinol, tocopherol, ascorbic acid, and cholesterol. The presence and type of HPV was determined in exfoliated cell samples using PCR dot blot hybridization. Mean plasma lycopene, total cryptoxanthin, and alpha-cryptoxanthin levels were lower among cases than controls. We found an inverse dose-response of alpha-cryptoxanthin, total tocopherol, and alpha-tocopherol to the odds ratios for cervical SIL after adjustment for HPV and other confounders. The odds ratio among women in the highest compared with the lowest quartile was 0.3 (95% confidence interval, 0.1-0.7) for alpha-cryptoxanthin and 0.3 (95% confidence interval, 0.1-0.8) for alpha-tocopherol. Negative trends in the odds ratios were suggested for other carotenoids and vitamin C, but these were weak, and confidence intervals were wide. Our results support existing evidence that high plasma levels of antioxidants may reduce the risk of cervical SILs independent of HPV infection. These findings are significant because diet is potentially modifiable, and nutrition education and dietary intervention might be targeted at specific high-risk groups.

Diet, body size, physical activity, and the risk of endometrial cancer.

Endometrial cancer is associated with increased weight and body size, diabetes, and other conditions that may result from an excess in calories or lack of physical activity. Although a few studies have explored the effect of dietary constituents on the risk of endometrial cancer, the nature of the joint association of these constituents and obesity, energy intake, or energy expenditure with risk is unknown. A population-based case-control study was conducted in Hawaii to examine the association of diet, body size, and physical activity with the risk of endometrial cancer. Subjects included 332 histologically confirmed, primary endometrial cancer cases and 511 controls identified between 1985 and 1993. Cases and controls were residents of Oahu, Hawaii who were between 18 and 84 years of age and were from one of the following ethnic groups: Japanese, Caucasian, Native Hawaiian, Filipino, and Chinese. Cases were identified through the Hawaii Tumor Registry and matched to the controls on age (+/-2.5 years) and ethnicity. In-person interviews, conducted in the subjects' homes, included dietary, reproductive, menstrual, and medical histories and use of exogenous hormones, physical activity, and other lifestyle variables. Weight, girth, and skinfold measurements were taken at the time of the interview. We found a strong dose-response relation of increased body size to the development of endometrial cancer after adjustment for energy intake. The odds ratio (OR) for endometrial cancer among women in the highest quartile of body mass index (BMI; kg/m2) was more than four times that among women in the lowest quartile. Waist, hip, midarm, and wrist girths were positively associated with the estimated risk of endometrial cancer after adjustment for total calories and other nondietary risk factors, although the trends in the ORs were attenuated after adjustment for BMI. Physically active women had a modest reduction in their risk of disease compared with inactive women. Cases consumed a greater percentage of their calories from fat and a lower percentage of their calories from carbohydrates than did controls. Adjustment for BMI reduced the ORs for the highest compared with the lowest quartile of fat calorie intake from 2.0 (95% confidence interval, 1.3-3.2) to 1.6 (95% confidence interval, 1.0-2.6), suggesting that part of the association is explained by obesity. There was a differential effect of fat on endometrial cancer according to BMI. For all components of fat, the associations with endometrial cancer were either minimal or absent among leaner women (i.e., those with BMI below the median), whereas, among more obese women, two-fold differences in risk were observed between women above and below the median of fat intake. Foods that are high in fat and cholesterol, such as red meat, margarine, and eggs, were positively associated with endometrial cancer, whereas cereals, legumes, vegetables, and fruits, particularly those high in lutein, were inversely associated. These findings suggest that women who avoid being overweight and who consume a diet low in plant and animal fats and high in complex carbohydrates are at a reduced risk of endometrial cancer.