Joint effects of different human papillomaviruses and Chlamydia trachomatis infections on risk of squamous cell carcinoma of the cervix uteri.

This case-control study based in Nordic serum banks evaluated the joint effects of infections with genital human papillomavirus (HPV) types, and Chlamydia trachomatis in the aetiology of cervical squamous cell carcinoma. Through a linkage with the cancer registries, 144 cases were identified and 420 controls matched to them. Exposure to past infections was defined by the presence of specific IgG antibodies. The odds ratio (OR) for the second-order interaction of HPV16, HPV6/11 and C. trachomatis was small (1.0) compared to the expected multiplicative OR, 57, and the additive OR, 11. The interactions were not materially different among HPV16 DNA-positive squamous cell carcinomas. When HPV16 was replaced with HPV18/33 in the analysis of second-order interactions with HPV6/11 and C. trachomatis, there was no evidence of interaction, the joint effect being close to the expected additive OR. Possible explanations for the observed antagonism include misclassification, selection bias or a true biological phenomenon with HPV6/11 and C. trachomatis exposures antagonizing the carcinogenic effects of HPV16.

Underestimation of the importance of blood pressure and cholesterol for coronary heart disease mortality in old age.

AIMS: To take appropriate account of duration of follow-up in estimating age-specific associations of 'usual' blood pressure and cholesterol with death from coronary heart disease. METHODS AND RESULTS: Blood pressure and cholesterol were measured in 18 841 men at entry to the Whitehall study, and coronary heart disease mortality was recorded during a 26-year period. Biennial re-measurements of these risk factors in the Framingham study were used to obtain period-specific corrections for 'regression dilution'. For coronary heart disease deaths at ages 40-64, 65-74 and 75+ years in the Whitehall study, the mean times since baseline were 9, 15, and 21 years, respectively. In uncorrected analyses of coronary heart disease risk in each age range, a 10 mmHg lower systolic blood pressure at baseline was associated with proportional risk reductions of only 19%, 14% and 10%, respectively (P<0.001 for trend with age). After period-specific correction for regression dilution, a 10 mmHg lower usual systolic blood pressure about 5 years before coronary heart disease death was associated with risk reductions of 25%, 23% and 21%, respectively (trend P=0.1). Similarly, a 1 mmol . l(-1)lower blood cholesterol was associated with proportional reductions in coronary heart disease risk of 21%, 17% and 11% (trend P<0.001) in uncorrected analyses, by contrast with proportional reductions of 27%, 26% and 21% (trend P=0.5) after period-specific correction. CONCLUSIONS: After making appropriate allowance for the longer interval between baseline measurements and death at older ages, reductions in the risk of coronary heart disease death associated with differences in usual levels of blood pressure or cholesterol at some particular fixed time prior to death were about as great in old age as in middle age.

A prospective study of Helicobacter pylori seropositivity and the risk for future myocardial infarction among socioeconomically similar U.S. men.

BACKGROUND: The role of Helicobacter pylori as a determinant of cardiovascular disease is controversial. OBJECTIVE: To determine whether previous exposure to H. pylori is associated with an increased risk for myocardial infarction. DESIGN: Prospective case-control study. SETTING: Physicians' Health Study. PARTICIPANTS: Initially healthy U.S. men. MEASUREMENTS: Titers of IgG antibody against H. pylori and several inflammatory markers were measured in baseline blood samples obtained from 445 men who subsequently had a myocardial infarction (case-patients) and 445 men matched for age and smoking status who remained free of vascular disease (controls) during a mean follow-up of 8.9 years. RESULTS: Baseline seropositivity was similar among case-patients and controls (43.4% vs. 44.3%; rate ratio, 0.96 [95% CI, 0.7 to 1.3]). Minimal evidence of association was found between magnitude of seropositivity and subsequent risk and between seropositivity and levels of the inflammatory biomarkers. CONCLUSION: In a socioeconomically homogeneous population, we found limited evidence of association between H. pylori exposure and risk for future myocardial infarction.

Analgesic use and renal function in men.

CONTEXT: Several case-control studies suggest an association between analgesic use and increased risk of chronic renal disease, but few cohort studies have examined this association. OBJECTIVE: To determine whether analgesic use is associated with risk of renal dysfunction. DESIGN AND SETTING: Cohort study of analgesic use data from the Physicians' Health Study, which lasted 14 years from September 1982 to December 1995 with annual follow-up. PARTICIPANTS: A total of 11 032 initially healthy men who provided blood samples and self-report of analgesic use. MAIN OUTCOME MEASURES: Elevated creatinine level defined as 1.5 mg/dL (133 micromol/L) or higher and a reduced creatinine clearance defined as 55 mL/min (0.9 mL/s) or less, and self-reported use of acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (never [<12 pills]; 12-1499 pills; 1500-2499 pills; and >/=2500 pills). RESULTS: A total of 460 men had elevated creatinine levels (4.2%) and 1258 had reduced creatinine clearance (11.4%). Mean creatinine levels and creatinine clearances were similar among men who did not use analgesics and those who did, even at total intakes of 2500 or more pills. In multivariable analyses adjusted for age; body mass index; history of hypertension, elevated cholesterol, and diabetes; occurrence of cardiovascular disease; physical activity; and use of other analgesics, the relative risks of elevated creatinine level associated with intake of 2500 or more pills were 0.83 (95% confidence interval [CI], 0.50-1.39; P for trend =.05) for acetaminophen, 0.98 (95% CI, 0.53-1.81; P for trend =.96) for aspirin, and 1.07 (95% CI, 0.71-1.64; P for trend =.86) for other nonsteroidal anti-inflammatory drugs. No association was observed between analgesic use and reduced creatinine clearance. CONCLUSIONS: Moderate analgesic use in this cohort study of initially healthy men was not associated with increased risk of renal dysfunction.

Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck.

BACKGROUND: Oncogenic human papillomaviruses (HPVs), especially HPV type 16 (HPV-16), cause anogenital epithelial cancers and are suspected of causing epithelial cancers of the head and neck. METHODS: To examine the relation between head and neck cancers and HPVs, we performed a nested case-control study within a joint Nordic cohort in which serum samples were collected from almost 900,000 subjects. Samples collected at enrollment from 292 persons in whom squamous-cell carcinoma of the head and neck developed, on average, 9.4 years after enrollment and from 1568 matched controls were analyzed for antibodies against HPV-16, HPV-18, HPV-33, and HPV-73 and for cotinine levels as a marker of smoking habits. Polymerase-chain-reaction (PCR) analyses for HPV DNA were performed in tumor tissue from 160 of the study patients with cancer. RESULTS: After adjustment for cotinine levels, the odds ratio for squamous-cell carcinoma of the head and neck in subjects who were seropositive for HPV-16 was 2.2 (95 percent confidence interval, 1.4 to 3.4). No increased risk was observed for other HPV types. Fifty percent of oropharyngeal and 14 percent of tongue cancers contained HPV-16 DNA, according to PCR analysis. CONCLUSIONS: HPV-16 infection may be a risk factor for squamous-cell carcinoma of the head and neck.

Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma.

CONTEXT: Human papillomavirus (HPV) infection has been established as a cause of cervical cancer. Epidemiologic studies suggest that Chlamydia trachomatis infection also confers increased risk for cervical squamous cell carcinoma (SCC). Whether this risk is serotype-specific is unknown. OBJECTIVE: To study the association between exposure to different C trachomatis serotypes and subsequent development of cervical SCC. DESIGN AND SETTING: Longitudinal, nested case-control study within a cohort of 530 000 women who provided samples to serum banks in Finland, Norway, and Sweden. The data files were linked to respective national cancer registries. SUBJECTS: One hundred twenty-eight women who had developed invasive cervical SCC at least 12 months following serum donation. Each case had 3 matched controls. MAIN OUTCOME MEASURE: Risk for the development of cervical SCC by IgG antibodies to 10 different C trachomatis serotypes, adjusted for antibodies to HPV types 16, 18, and 33 and for serum cotinine levels. RESULTS: Of specific C trachomatis serotypes, serotype G was most strongly associated with SCC (adjusted odds ratio [OR], 6.6; 95% confidence interval [CI], 1. 6-27.0). Other serotypes associated with SCC were I (OR, 3.8; 95% CI, 1.3-11.0) and D (OR, 2.7; 95% CI, 1.3-5.6). Presence of serum IgG antibodies to more than 1 serotype increased the adjusted ORs for SCC (P<.001 for trend). CONCLUSIONS: Chlamydia trachomatis serotype G is most strongly associated with subsequent development of cervical SCC. Increasing numbers of exposures to different C trachomatis serotypes also increases risk. Our results strengthen the evidence that there is a link between past C trachomatis infection and cervical SCC.

Epidemiology and factor analysis of obesity, type II diabetes, hypertension, and dyslipidemia (syndrome X) on the Island of Kosrae, Federated States of Micronesia.

OBJECTIVES: Obesity, type II diabetes, hypertension, and dyslipidemia are major causes of morbidity and mortality throughout the world. Though these disorders often cluster in individuals and families and are collectively known as syndrome X, the basis for this aggregation is not well understood. To further understand the pathogenesis of syndrome X, a comprehensive epidemiological study was undertaken on the Pacific Island of Kosrae, Federated States of Micronesia (FSM). METHODS: The entire adult (>20 years of age) population of Kosrae underwent a clinical evaluation that included a questionnaire that noted the participants' sex, family data including listing of biological parents, siblings, and children, smoking status, village of residence, age and health status. The medical evaluation included: anthropometric measures (weight, height, waist, hip), serum chemistries (leptin, fasting blood sugar (FBS), insulin, total cholesterol (TC), triglycerides (TG), and apolipoproteins B and A-I (apo B and apo A-I) and blood pressure (BP) measurements. RESULTS: Obesity (BMI >/=35) was found in 24%, diabetes (FBS >/=126 or 2-hour oral glucose tolerance test >/=200) in 12%, hypertension (SBP >/=140 or DBP >/=90) in 17%, and dyslipidemia (TC >/=240 or TG >/=200 or apo B >/=120 or apo A-I

Joint effect of HPV16 with Chlamydia trachomatis and smoking on risk of cervical cancer: antagonism or misclassification (Nordic countries).

OBJECTIVES: To estimate the joint effects of infections with human papillomavirus type 16 (HPV16) and Chlamydia trachomatis and smoking on the risk of cervical cancer. To study whether the joint effects can be accounted for by misclassification in the HPV serology. METHODS: A nested case-control study with incidence density sampling was conducted in three cohorts of 530,000 women, who donated serum samples to three Nordic serum banks in 1973-1994. The main outcome measure is the odds ratio (OR) of incidence rates of invasive cervical squamous cell carcinoma (SCC) among those seropositive for HPV16 and/or C. trachomatis and/or with increased levels of cotinine in serum compared to those negative for all the three exposures. RESULTS: Two hundred eight women with SCC and 624 matched controls were identified during a mean follow-up of 5 years through linkage to the national cancer registries. Exposure to past infections and smoking was defined by presence of specific IgG antibodies to HPV16 and C. trachomatis and increased levels of serum cotinine. Observed ORs were compared to OR = 20 for HPV16 and accounting the differences for by misclassification bias. OR = 20 was elected as a gold standard on the basis of other studies with PCR-based analyses and a follow-up design. Each of the three exposures was associated with an increased risk of SCC (OR = 5.4 for HPV16, 3.4 for C. trachomatis and 1.8 for cotinine). The interaction was antagonistic (observed OR = 2.5 among those positive for all three exposures as compared to OR = 33 expected on the basis of multiplicative single effects (p = 0.047)). The antagonism could not totally be accounted for by any credible combination of sensitivity and specificity of HPV16 serology. CONCLUSION: HPV16, C. trachomatis, and smoking are likely to be risk factors of SCC with strong antagonistic joint effect. Non-differential misclassification in serology for HPV16 could be ruled out (but only some types of differential) as an alternative explanation for the observed antagonism.

Re-survey of the Whitehall study of London civil servants: changes in risk factors for cardiovascular disease during 29 years of follow-up.

BACKGROUND: Substantial uncertainty persists about the relevance of blood pressure and cholesterol to the risk of cardiovascular disease in the elderly. OBJECTIVE: To investigate the determinants of cardiovascular risk in old age, and the relevance of such risk factors when recorded in middle and old age. METHODS: A re-survey in 1997 of 8537 survivors of a cohort of men who were originally examined in 1967-1970 when aged 40-69 years. RESULTS: Completed questionnaires were received from 7050 (82%) of the survivors, and blood pressure and blood samples from 5427 (64%). The response rate declined with increasing age, was inversely related to markers of socioeconomic status in 1967-70 and in 1997, and was lower in those who had been current smokers or had a higher blood pressure level in 1967-70. After excluding those with reported cardiovascular disease (25% of respondents), the mean levels of total cholesterol and apolipoprotein B were lower in older age groups, whereas apolipoprotein A1 levels did not vary much with age. Among those with risk factors recorded both in 1967-70 and 1997, the prevalence of smoking had declined by two-thirds (32% in 1970 and 12% in 1997), the prevalence of diabetes had increased (0.3% versus 4.5%), and the mean systolic blood pressure had increased by 16 mmHg (130 versus 146 mmHg), but the diastolic blood pressure had not changed materially (80 versus 81 mmHg), and the measured levels of total cholesterol had increased by 0.5 mmol/l (although that change may be artefactual). CONCLUSION: Follow-up of vital status in this cohort should permit an assessment of the relevance of risk factors recorded in middle and old age to cardiovascular disease in old age.

Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators.

BACKGROUND: The original report of a possible association between myocardial infarction and the insertion/deletion (I/D) polymorphism of the gene for the angiotensin-1-converting enzyme (ACE) indicated a risk ratio for myocardial infarction with the DD genotype of 1.34 (95% CI 1.05-1.70), and the association was claimed to be particularly strong in a retrospectively defined low-risk subgroup (3.2 [95% CI 1.7-5.9). Subsequent investigations reached varying conclusions, but all were small, and much larger studies were needed. METHODS: 4629 myocardial infarction cases and 5934 controls were compared. Cases were UK men aged 30-54 years and women aged 30-64 years recruited on presentation to hospital with confirmed myocardial infarction. Controls were aged 30-64 years with no history of cardiovascular disease, but were siblings or children of myocardial infarction survivors, or spouses of such relatives. All risk-ratio calculations allow for this relatedness of some of the controls. An updated meta-analysis of previous studies was also conducted. FINDINGS: The ACE DD genotype was found in 1359 (29.4%) of the myocardial infarction cases and in 1637 (27.6%) of the controls (risk ratio 1.10 [95% CI 1.00-1.21]). The association between myocardial infarction and the DD genotype did not seem to be stronger in the subgroup defined as low risk by previously used criteria (234 [28%] of 836 cases and 911 [28%] of 3253 controls: risk ratio 1.04 [95% CI 0.87-1.24]), or in any other subgroup. Nor was the ACE I/D genotype predictive of subsequent survival. INTERPRETATION: This study involved many more cases than any previously reported study of this question, but did not confirm the existence of any substantial association. In an updated meta-analysis of these results with those of previously published studies, the risk ratio for myocardial infarction with the DD genotype seems to lie in the range 1.0 to about 1.1. Although an increase in risk of up to about 10-15% cannot be ruled out, substantially more extreme risks can be. Moreover, there are not especially strong associations in the subgroups previously selected for emphasis. These findings illustrate the need for some studies of candidate genes to involve much larger populations than is customary, without undue emphasis on retrospectively defined subgroups.

Chlamydia trachomatis infection as a risk factor for invasive cervical cancer.

Cervical carcinoma is a sexually transmitted disease most strongly linked with human-papillomavirus (HPV) infection. We conducted a prospective sero-epidemiologic study to evaluate the role of Chlamydia trachomatis infection in the development of cervical carcinoma, with invasive cancer as an end point. A nested case-control study within a cohort of 530000 Nordic women was performed. Linking data files of 3 Nordic serum banks and the cancer registries of Finland, Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed during a mean follow-up of 5 years after serum sampling. The serum samples of the cases and matched cancer-free controls were analyzed for IgG antibodies to C. trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to C. trachomatis were associated with an increased risk for cervical squamous-cell carcinoma (HPV- and smoking-adjusted OR, 2.2; 95% CI, 1.3-3.5). The association remained also after adjustment for smoking both in HPV16-seronegative and -seropositive cases (OR, 3.0; 95% CI, 1.8-5.1; OR, 2.3, 95% CI, 0. 8-7.0 respectively). No such association was found for C. pneumoniae. Our prospective study provides sero-epidemiologic evidence that infection with C. trachomatis confers an increased risk for subsequent development of invasive squamous-cell carcinoma of the uterine cervix.

Helicobacter pylori infection and early onset myocardial infarction: case-control and sibling pairs study.

OBJECTIVES: To examine the association between coronary heart disease and chronic Helicobacter pylori infection. DESIGN: Case-control study of myocardial infarction at young ages and study of sibling pairs with one member affected and the other not. SETTING: United Kingdom. PARTICIPANTS: 1122 survivors of suspected acute myocardial infarction at ages 30-49 (mean age 44 years) and 1122 age and sex matched controls with no history of coronary heart disease; 510 age and sex matched pairs of siblings (mean age 59 years) in which one sibling had survived myocardial infarction and one had no history of coronary heart disease. MAIN OUTCOME MEASURES: Serological evidence of chronic infection with H pylori. RESULTS: 472 (42%) of the 1122 cases with early onset myocardial infarction were seropositive for H pylori antibodies compared with 272 (24%) of the 1122 age and sex matched controls, giving an odds ratio of 2.28 (99% confidence interval 1.80 to 2.90). This odds ratio fell to 1.87 (1.42 to 2.47; P<0.0001) after smoking and indicators of socioeconomic status were adjusted for and to 1.75 (1.29 to 2.36) after additional adjustment for blood lipid concentrations and obesity. Only 158 of the 510 pairs of siblings were discordant for H pylori status; among these, 91 cases and 67 controls were seropositive (odds ratio 1.33 (0.86 to 2.05)). No strong correlations were observed between H pylori seropositivity and measurements of other risk factors for coronary heart disease (plasma lipids, fibrinogen, C reactive protein, albumin, etc). CONCLUSION: In the context of results from other relevant studies, these two studies suggest a moderate association between coronary heart disease and H pylori seropositivity that cannot be fully accounted for by other risk factors. But even if this association is causal and largely reversible by eradication of chronic infection, very large randomised trials would be needed to show this.

Low levels of serum vitamins A and E in blood and subsequent risk for cervical cancer: interaction with HPV seropositivity.

Nutritional factors have been associated with risk of cervical cancer, but it is unclear whether the associations are of etiological significance or secondary to human papillomavirus (HPV) exposure. A delineation of this question requires a prospective study with invasive cancer as the end point. We conducted a nested case-control study in Finland and Sweden within a joint cohort of 405,000 women followed up for, on average, 4 years. Blood samples from 38 prospective cases of invasive cervical cancer diagnosed between 1985 and 1994 and 116 controls matched for age, country, and sample storage time were available for the study. Levels of retinol or unoxidized alpha-tocopherol in the blood were not risk factors for cervical cancer. However, joint-effect analysis of low levels of retinol disclosed statistically significant (p = 0.023) synergistic (more than multiplicative) interaction with HPV (HPV16, HPV18, or HPV33) seropositivity (observed relative risk = 2.6, 95% confidence interval = 0.7-8.8, expected relative risk = 0.3). Retinol might act as an effect modifier of the HPV-associated risk for cervical cancer; exposed women may require adequate levels for immunologic surveillance of HPV.

Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies.

In prospective studies, disease rates during follow-up are typically analyzed with respect to the values of factors measured during an initial baseline survey. However, because of "regression dilution," this generally tends to underestimate the real associations of disease rates with the "usual" levels of such risk factors during some particular exposure period. The "regression dilution ratio" describes the ratio of the steepness of the uncorrected association to that of the real association. To assess the relevance of the usual value of a risk factor during particular exposure periods (e.g., first, second, and third decades) to disease risks, regression dilution ratios can be derived by relating baseline measurements of the risk factor to replicate measurements from a reasonably representative sample of study participants after an interval equivalent to about the midpoint of each exposure period (e.g., at 5, 15, and 25 years, respectively). This report illustrates the impact of this time interval on the magnitude of the regression dilution ratios for blood pressure and blood cholesterol. The analyses were based on biennial remeasurements over 30 years for participants in the Framingham Study (Framingham, Massachusetts) and a 26-year resurvey for a sample of men in the Whitehall Study (London, England). They show that uncorrected associations of disease risk with baseline measurements underestimate the strength of the real associations with usual levels of these risk factors during the first decade of exposure by about one-third, the second decade by about one-half, and the third decade by about two-thirds. Hence, to correct appropriately for regression dilution, replicate measurements of such risk factors may be required at varying intervals after baseline for at least a sample of participants.

No excess risk of cervical carcinoma among women seropositive for both HPV16 and HPV6/11.

Human papillomavirus (HPV) types 16 and 18 are the major risk factors for cervical carcinoma, whereas HPV types 6 and 11 cause benign genital lesions. We wanted to study the joint effect of simultaneous infections with the oncogenic and non-oncogenic HPV types on risk of subsequent development of cervical carcinoma. A cohort of 530,000 women who had donated blood samples to Nordic serum banks between 1973 and 1994 was followed up by linkage to national cancer registries. We identified 182 prospective cases with invasive cervical carcinoma and selected 538 matched controls at random. HPV 6, 11, 16, 18 and 33 seropositivity was used as a marker for the different HPV infections, and seropositivity for Chlamydia trachomatis and cotinine were used as markers for risk-taking sexual behavior and smoking respectively. The adjusted odds ratio (OR) of cervical squamous-cell carcinoma (SCC) was 2.2 for HPV6/11 among HPV16 seronegatives and 5.5 for HPV16 among HPV6/11 seronegatives. Assuming multiplicative joint effect, the expected OR for seropositivity to both HPV6/11 and HPV16 would have been 12, but the observed OR was 1.0. The antagonistic interaction was statistically significant (p = 0.001) and present also under deterministic considerations of possible misclassification bias. Antagonistic interactions were also detected for combinations of HPV16 and HPV18 and of HPV16 and HPV33. The results are in line with the concept that HPV-specific immunity protects against SCC and support primary prevention of SCC by vaccination against the HPVs.

Design, objectives, and lessons from a pilot 25 year follow up re-survey of survivors in the Whitehall study of London Civil Servants.

DESIGN: To assess the feasibility of conducting a re-survey of men who are resident in the United Kingdom 25 years after enrollment in the Whitehall study of London Civil Servants. METHODS: A random sample of 401 study survivors resident in three health authority areas was selected for this pilot study. They were mailed a request to complete a self administered questionnaire, and then asked to attend their general practice to have their blood pressure, weight, and height measured and a blood sample collected into a supplied vacutainer, and mailed to a central laboratory. Using a 2 x 2 factorial design, the impact of including additional questions on income and of an informant questionnaire on cognitive function was assessed. RESULTS: Accurate addresses were obtained from the health authorities for 96% of the sample. Questionnaires were received from 73% and blood samples from 61% of the sample. Questions on income had no adverse effect on the response rate, but inclusion of the informant questionnaire did. Between 1970 and 1995 there were substantial changes within men in the mean blood pressure and blood total cholesterol recorded, as reflected by correlation coefficients between 1970 and 1995 values of 0.26, and 0.30 for systolic and diastolic blood pressure and 0.38 for total cholesterol. CONCLUSION: This pilot study demonstrated the feasibility of conducting a re-survey using postal questionnaires and mailed whole blood samples. The magnitude of change in blood pressure and blood total cholesterol concentrations within individuals was greater than anticipated, suggesting that such remeasurements may be required at different intervals in prospective studies to help interpret risks associations properly. These issues will be considered in a re-survey of the remaining survivors of the Whitehall study.

A prospective, seroepidemiological study of the role of human papillomavirus in esophageal cancer in Norway.

Infection with the human papillomavirus (HPV), notably HPV type 16, has been associated with esophageal cancer in seroepidemiological studies. To evaluate the consistency of the association, we performed a nested case-control study of HPV seropositivity and risk of esophageal cancer within a prospectively followed cohort of 300,000 Norwegian men and women who had donated blood samples to a serum bank. The data file of the serum bank was linked with the nationwide Cancer Registry of Norway to identify esophageal cancers diagnosed after donation of the serum sample. Fifty-seven cases and 171 matched controls were analyzed for antibodies to specific microorganisms, and odds ratios for developing esophageal cancer were calculated. There was an increased risk of developing esophageal cancer among HPV 16-seropositive subjects (odds ratio = 6.6; 95% confidence interval, 1.1-71) but not among Chlamydia trachomatis-seropositive subjects. Adjustment for the presence of serum cotinine, a marker of smoking habits, did not affect the estimates substantially. The seroepidemiological association between HPV 16 and esophageal cancer seems to be consistent in different countries.

Prospective seroepidemiological study of role of human papillomavirus in non-cervical anogenital cancers.

OBJECTIVE: To evaluate the association between infection with the major oncogenic types of human papillomavirus and the risk of developing non-cervical anogenital cancers in a cohort followed up prospectively. DESIGN: Data from two large serum banks to which about 700,000 people had donated serum samples were followed up for a mean of 8 years. People who developed non-cervical anogenital cancers during follow up were identified by registry linkage with the nationwide cancer registries in Finland and Norway. Within this cohort a nested case-control study was conducted based on the serological diagnosis of infection with human papillomavirus types 16, 18, and 33. SUBJECTS: 81 cases and 240 controls matched for sex, age, and storage time of serum samples. MAIN OUTCOME MEASURES: Odds ratios of developing non-cervical anogenital cancers in presence of IgG antibodies to specific micro-organisms. RESULTS: Subjects seropositive for human papillomavirus type 16 had an increased risk of developing non-cervical anogenital cancers (odds ratio 3.1 (95% confidence interval 1.4 to 6.9)). Subjects seropositive for type 33 also had an increased risk (odds ratio 2.8 (1.0 to 8.3)) but not significantly after adjustment for infection with type 16. Seropositivity for human papillomavirus type 16 was associated with an increased risk of developing vulvar and vaginal cancers (odds ratio 4.5 (1.1 to 22)) and a strongly increased risk of developing preinvasive vulvar and vaginal lesions (odds ratio infinity (3.8 to infinity)). Seropositivity for human papillomavirus type 18 increased the risk of developing preinvasive lesions (odds ratio 12 (1.2 to 590)). High, but non-significant odds ratios for types 16 and 33 were seen for penile cancers. CONCLUSIONS: This study provides prospective seroepidemiological evidence that infection with human papillomavirus type 16 confers an increased risk of developing non-cervical genital cancers, particularly vulvar and vaginal cancers.

Prospective seroepidemiologic study of human papillomavirus infection as a risk factor for invasive cervical cancer.

BACKGROUND: Major risk factors for invasive cervical cancer include infection with human papillomavirus (HPV), infection with other sexually transmitted pathogens (e.g., Chlamydia trachomatis), and smoking. Since exposures to these risk factors can be related, the contribution of any single factor to cervical carcinogenesis has been difficult to assess. We conducted a prospective study to define the role of HPV infection in cervical carcinogenesis, with invasive cancer as an end point. METHODS: A nested case-control study within a joint cohort of 700,000 Nordic subjects was performed. The 182 women who developed invasive cervical cancer during a mean follow-up of 5 years were matched with 538 control women on the basis of age and time of enrollment. Serum samples taken at enrollment were analyzed for evidence of tobacco use (i.e., cotinine levels); for antibodies against HPV types 16, 18, and 33; and for antibodies against C. trachomatis. Relative risks (RRs) were estimated by use of conditional logistic regression. RESULTS: Presence of antibodies against HPV in serum (seropositivity) was associated with an increased risk of cervical cancer, and adjustment for smoking and for C. trachomatis seropositivity did not affect this finding (RR = 2.4; 95% confidence interval [CI] = 1.6-3.7). HPV16 seropositivity was associated primarily with an increased risk of squamous cell carcinoma (RR = 3.2; 95% CI = 1.7-6.2). In contrast, risk associated with HPV18 seropositivity tended to be higher for cervical adenocarcinoma (RR = 3.4; 95% CI = 0.8-14.9). In populations with a low prevalence of antibodies against C. trachomatis, the HPV16-associated risk of cervical cancer was very high (RR = 11.8; 95% CI = 3.7-37.0); in contrast, in populations with a high prevalence of antibodies against C. trachomatis, no excess risk was found. CONCLUSION: Past infection with HPV16 increases the risk of invasive cervical squamous cell carcinoma, most clearly seen in populations with a low prevalence of sexually transmitted diseases.