Low-carbohydrate, high-protein score and mortality in a northern Swedish population-based cohort.

BACKGROUND/OBJECTIVE: Long-term effects of carbohydrate-restricted diets are unclear. We examined a low-carbohydrate, high-protein (LCHP) score in relation to mortality. SUBJECTS/METHODS: This is a population-based cohort study on adults in the northern Swedish county of Västerbotten. In 37,639 men (1460 deaths) and 39,680 women (923 deaths) from the population-based Västerbotten Intervention Program, deciles of energy-adjusted carbohydrate (descending) and protein (ascending) intake were added to create an LCHP score (2-20 points). Sex-specific hazard ratios (HR) were calculated by Cox regression. RESULTS: Median intakes of carbohydrates, protein and fat in subjects with LCHP scores 2-20 ranged from 61.0% to 38.6%, 11.3% to 19.2% and 26.6% to 41.5% of total energy intake, respectively. High LCHP score (14-20 points) did not predict all-cause mortality compared with low LCHP score (2-8 points), after accounting for saturated fat intake and established risk factors (men: HR for high vs low 1.03 (95% confidence interval (CI) 0.88-1.20), P for continuous = 0.721; women: HR for high vs low 1.10 (95% CI 0.91-1.32), P for continuous = 0.229). For cancer and cardiovascular disease, no clear associations were found. Carbohydrate intake was inversely associated with all-cause mortality, though only statistically significant in women (multivariate HR per decile increase 0.95 (95% CI 0.91-0.99), P = 0.010). CONCLUSION: Our results do not support a clear, general association between LCHP score and mortality. Studies encompassing a wider range of macronutrient consumption may be necessary to detect such an association.

Combined effect of low-penetrant SNPs on breast cancer risk.

BACKGROUND: Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status. METHODS: Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression. RESULTS: Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10(-20) and 1.5 × 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10(-4)). CONCLUSION: The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.

Postmenopausal circulating levels of 2- and 16α-hydroxyestrone and risk of endometrial cancer.

BACKGROUND: It has been suggested that the relative importance of oestrogen-metabolising pathways may affect the risk of oestrogen-dependent tumours including endometrial cancer. One hypothesis is that the 2-hydroxy pathway is protective, whereas the 16α-hydroxy pathway is harmful. METHODS: We conducted a case-control study nested within three prospective cohorts to assess whether the circulating 2-hydroxyestrone : 16α-hydroxyestrone (2-OHE1 : 16α-OHE1) ratio is inversely associated with endometrial cancer risk in postmenopausal women. A total of 179 cases and 336 controls, matching cases on cohort, age and date of blood donation, were included. Levels of 2-OHE1 and 16α-OHE1 were measured using a monoclonal antibody-based enzyme assay. RESULTS: Endometrial cancer risk increased with increasing levels of both metabolites, with odds ratios in the top tertiles of 2.4 (95% CI=1.3, 4.6; P(trend)=0.007) for 2-OHE1 and 1.9 (95% CI=1.1, 3.5; P(trend)=0.03) for 16α-OHE1 in analyses adjusting for endometrial cancer risk factors. These associations were attenuated and no longer statistically significant after further adjustment for oestrone or oestradiol levels. No significant association was observed for the 2-OHE1 : 16α-OHE1 ratio. CONCLUSION: Our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16α-OH pathway, protects against endometrial cancer.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

So far, studies on dietary antioxidant intake, including beta-carotene, vitamin C and vitamin E, and breast cancer risk are inconclusive. Thus, we addressed this question in the European Prospective Investigation into Cancer and Nutrition. During a median follow-up time of 8.8 years, 7,502 primary invasive breast cancer cases were identified. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). All analyses were run stratified by menopausal status at recruitment and, additionally, by smoking status, alcohol intake, use of exogenous hormones and use of dietary supplements. In the multivariate analyses, dietary intake of beta-carotene, vitamin C and E was not associated with breast cancer risk in premenopausal [highest vs. lowest quintile: HR, 1.04 (95% CI, 0.85-1.27), 1.12 (0.92-1.36) and 1.11 (0.84-1.46), respectively] and postmenopausal women [0.93 (0.82-1.04), 0.98 (0.87-1.11) and 0.92 (0.77-1.11), respectively]. However, in postmenopausal women using exogenous hormones, high intake of beta-carotene [highest vs. lowest quintile; HR 0.79 (95% CI, 0.66-0.96), P (trend) 0.06] and vitamin C [0.88 (0.72-1.07), P (trend) 0.05] was associated with reduced breast cancer risk. In addition, dietary beta-carotene was associated with a decreased risk in postmenopausal women with high alcohol intake. Overall, dietary intake of beta-carotene, vitamin C and E was not related to breast cancer risk in neither pre- nor postmenopausal women. However, in subgroups of postmenopausal women, a weak protective effect between beta-carotene and vitamin E from food and breast cancer risk cannot be excluded.

Influence of education level on cancer survival in Sweden.

BACKGROUND: While cancer survival at several sites has historically been shown to vary by education level, a current comprehensive assessment of survival following a cancer diagnosis in Sweden, a country with universal health care and cancer screening, has yet to be carried out. METHODS: Using the 2006 update of the Swedish Family-Cancer Database and Cox's proportional hazards regression methods, we calculate the adjusted hazard ratio (HR) and 95% confidence interval to estimate the influence of education level on site-specific cancer survival. RESULTS: Significant positive associations between education level and cancer survival were observed following a diagnosis of upper aerodigestive track cancer, colon cancer, pancreatic cancer, lung cancer, kidney cancer, urinary bladder cancer, melanoma, non-Hodgkin's lymphoma, breast cancer, endometrial cancer, cervical cancer, prostate cancer, and testicular cancer. Although the HRs differed between cancer sites, compared with women and men completing <9 years of education, university graduates were associated with a significant 40% improved survival for all cancer sites combined. CONCLUSIONS: Survival differences by education level were observed for both indolent and aggressive malignancies.

Polymorphisms in the genes of the urokinase plasminogen activation system in relation to colorectal cancer.

BACKGROUND: Extracellular matrix degradation, mediated by the urokinase plasminogen activation (uPA) system, is a critical step in tumor invasion and metastasis. High tumor levels of uPA and its inhibitor PAI-1 have been correlated with poor cancer prognosis. We examined four single nucleotide polymorphisms (SNPs) with a potential effect on expression of genes in the uPA system for their role in colorectal cancer susceptibility and prognosis. PATIENTS AND METHODS: We genotyped the SNPs in 308 Swedish incident colorectal cancer patients with up to 16 years of follow-up and in 585 age- and sex-matched controls. We evaluated the associations between genotypes and colorectal cancer and Dukes' stage. Survival probabilities were compared between different subgroups. RESULTS: Patients with PAI-1 -675 5G/5G genotype had better survival than patients with 4G/4G or 4G/5G genotypes when they had Dukes' stage A or B tumors (P = 0.023 and P = 0.015, respectively). No statistically significant association was observed between the SNPs and the risk of colorectal cancer or Dukes' stage. CONCLUSIONS: Our results suggest a role for the PAI-1 genotype in colorectal cancer prognosis, but further studies are needed to evaluate the impact of our finding in the clinic.

Survival from invasive breast cancer among interval cases in the mammography screening programmes of northern Sweden.

The aim of this study was to estimate breast cancer survival according to detection mode for 5120 women with invasive breast cancer, in particular for those detected in the screening intervals. We found a significant survival difference in favour of women with cancer detected in the screening intervals (n=729) compared with those uninvited (n=1879) during the 13-year follow-up. Detection mode was proven to modify the prognostic effect of stage. Women with stage I interval cancer had shorter survival and those with stage II had longer survival than expected. It is suggested that interval cancers might consist of two subgroups with different behaviour: one of fast-growing tumours presenting as stage I cases and another of slow-growing tumours presenting as stage II+ cases. A hypothesis related to this observation is discussed.

Age at menarche in relation to adult height: the EPIC study.

In the last two centuries, age at menarche has decreased in several European populations, whereas adult height has increased. It is unclear whether these trends have ceased in recent years or how age at menarche and height are related in individuals. In this study, the authors first investigated trends in age at menarche and adult height among 286,205 women from nine European countries by computing the mean age at menarche and height in 5-year birth cohorts, adjusted for differences in socioeconomic status. Second, the relation between age at menarche and height was estimated by linear regression models, adjusted for age at enrollment between 1992 and 1998 and socioeconomic status. Mean age at menarche decreased by 44 days per 5-year birth cohort (beta = -0.12, standard error = 0.002), varying from 18 days in the United Kingdom to 58 days in Spain and Germany. Women grew 0.29 cm taller per 5-year birth cohort (standard error = 0.007), varying from 0.42 cm in Italy to 0.98 cm in Denmark. Furthermore, women grew approximately 0.31 cm taller when menarche occurred 1 year later (range by country: 0.13-0.50 cm). Based on time trends, more recent birth cohorts have their menarche earlier and grow taller. However, women with earlier menarche reach a shorter adult height compared with women who have menarche at a later age.

Early breast cancer deaths in women aged 40-74 years diagnosed during the first 5 years of organised mammography service screening in north Sweden.

The aim of this study was to analyse individual cases of lethal breast cancer and not to evaluate the screening programme. Women aged 40-74 years who were diagnosed with breast cancer in 1990-94 and died on or before 31 December 1998, during the gradual introduction of organised mammography service screening in north Sweden, were included in the study. Out of 342 breast cancer deaths, 280 (82%) were in symptomatic patients whose cancers were clinically detected. Most breast cancers that proved fatal were already in an advanced stage and/or of high histological grade at the time of detection. A shift towards a lower stage was seen among screen-detected and interval-detected fatal cases. In a few of the cases with fatal outcome, in patients primarily presenting with histological grade I tumours of various sizes or small screen-detected tumours less than 10mm in size, early diagnosis by mammography followed by state-of-the-art treatment did not seem to have been enough to prevent death.

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.

Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women.

OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

Service screening with mammography. Long-term effects on breast cancer mortality in the county of Gävleborg, Sweden.

In the current study the long-term effects of a pilot service screening programme in the Swedish county of Gävleborg were studied. Women aged 40-64 years in 13 sub-areas were followed from start of screening between 1974 and 1979. Two control groups were used for comparison; the neighbouring counties and all of Sweden. A reference period prior to the study period was used to facilitate an adjustment for possible differences in baseline breast cancer mortality. Only deaths from breast cancer diagnosed after the first invitation to screening were analysed. Two outcome measures were used for breast cancer mortality; the underlying cause of death and excess mortality. Using the neighbouring counties as a control group, the relative risk, after 22 years of follow-up, of 10 years of screening was estimated at 0.84 (95% CI 0.71-1.00) using excess mortality. Due to lead time bias the relative risk was overestimated by 4%. Hence, a significant 20% reduction of breast cancer excess mortality was found.

Service screening with mammography of women aged 50-69 years in Sweden: effects on mortality from breast cancer.

OBJECTIVES: To estimate the effect of the population based service screening programme in Sweden on mortality from breast cancer among women aged 50-69. SETTING; In 1986, population based service screening with mammography started in Sweden, and by 1997 screening had been introduced in all counties. Half of the counties invite women from 40 years of age whereas women 50 and older are invited in the other counties. The upper age limit was either 69 or 74. Women in the age group 50-69 years are thus invited to screening in all counties. METHODS: The counties which started with mammographic screening in 1986-87 constituted the study group and were compared with the counties which started in 1993 or later. In 1987 the mean number of women aged 50-69 was 161,986 and 98,608 in the study and control groups, respectively. Refined excess mortality (smoothed with the Lowess method) from breast cancer and refined cause specific mortality from breast cancer were used as effect measures. To adjust for geographical differences in mortality from breast cancer a reference period was used. Allowance was made for two potential biases: (a) inclusion bias implying the inclusion of cases diagnosed before invitation to screening in the first screening round, and (b) lead time bias. RESULTS: After a mean follow up time of 10.6 years since the start of screening and a mean individual follow up time of 8.4 years, a non-significant reduction in refined excess mortality for breast cancer was estimated as relative risk (RR) 0.84 (95% confidence interval (95% CI) 0.67 to 1.05). After adjustment for inclusion and lead time biases the RR was 0.80 (20% reduction). Only 27% of the deaths from breast cancer in the total mortality for women aged 50-79 at death consisted of women aged 50-69 at diagnosis who were diagnosed after the start of screening. This figure has important implications for judgement of the impact of screening on age specific national breast cancer mortalities. CONCLUSIONS: A non-significant reduction in mortality from breast cancer was found in counties performing service screening with mammography in Sweden. Adjustment for possible biases changed the result towards a larger effect of screening. The results do not contradict the effects found in the Swedish randomised mammography trials.

Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer.

Human papillomaviruses type 16 and 18 are the major cause of cervical cancer. However, genetic factors contribute to the propensity of persistent HPV infection and cervical carcinoma. Allelic variants of the human leukocyte genes have shown to be associated with cervical neoplasia. The strongest associations have been found with the genes in the HLA class II region. The aim of this study was to analyze the association of two non-HLA class II markers with invasive cervical cancer. Microsatellite polymorphism of the TNFA gene located in the class III region and a short tandem repeat polymorphism of the MICA gene located in the centromeric end of the HLA class I region were analyzed. Eighty-five patients and 120 matched control individuals from a population-based cohort from Northern Sweden participated in this nested case-control study. MICA was not associated with cervical carcinoma. TNFa-11 frequency was increased in the HPV18 DNA positive patients (OR = 2.84, p = 0.0481, CI = 1.04-7.78, pc = NS). TNFa-11 was not associated with susceptibility to HPV16 infection, but it increased the risk for cervical cancer with the HLA DQ6 (DQA 1*0102-DQB 1*0602) haplotype. Our findings indicate that the association of TNFA with cervical cancer is different with CIN. The extended HLA DQ6-TNFa-11 haplotype is increasing the risk for development of cervical cancer significantly (OR = 3.08, p = 0.0104, CI = 1.30-7.31).

Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden.

OBJECTIVE: Using a nested case-referent design we evaluated the relationship between plasma levels of six carotenoids, alpha-tocopherol, and retinol, sampled before diagnosis, and later breast cancer risk. METHODS: In total, 201 cases and 290 referents were selected from three population-based cohorts in northern Sweden, where all subjects donated blood samples at enrolment. All blood samples were stored at -80 degrees C. Cases and referents were matched for age, age of blood sample, and sampling centre. Breast cancer cases were identified through the regional and national cancer registries. RESULTS: Plasma concentrations of carotenoids were positively intercorrelated. In analysis of three cohorts as a group none of the carotenoids was found to be significantly related to the risk of developing breast cancer. Similarly, no significant associations between breast cancer risk and plasma levels of alpha-tocopherol or retinol were found. However, in postmenopausal women from a mammography cohort with a high number of prevalent cases, lycopene was significantly associated with a decreased risk of breast cancer. A significant trend of an inverse association between lutein and breast cancer risk was seen in premenopausal women from two combined population-based cohorts with only incident cases. A non-significant reduced risk with higher plasma alpha-carotene was apparent throughout all the sub-analyses. CONCLUSION: In conclusion, no significant associations were found between plasma levels of carotenoids, alpha-tocopherol or retinol and breast cancer risk in analysis of three combined cohorts. However, results from stratified analysis by cohort membership and menopausal status suggest that lycopene and other plasma-carotenoids may reduce the risk of developing breast cancer and that menopausal status has an impact on the mechanisms involved.

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.

Service screening with mammography in Sweden--evaluation of effects of screening on breast cancer mortality in age group 40-49 years.

The aim of the study was to develop a model for estimating the effect of the nation-wide service screening program with mammography on breast cancer mortality in Sweden. In 1997, the introduction of population-based service screening had been completed in all 26 counties. In approximately half of the counties suitable for evaluation, the lower age limit for invitation was 40 years (study population) and in the other half the age limit was 50 years (control population). The numbers of females aged 40 49 years for the two populations were 202,152 and 237,279, respectively (1988). The study and control populations were compared for the period 1986-1996 with regard to refined breast cancer mortality. To adjust for geographical differences, the period 1976 1986 was used as reference. With a mean follow-up time of 8 years, the estimated relative risk of breast cancer death in relation to invitation to service screening among women aged 40-49 years at breast cancer diagnosis was 0.91 (95% confidence interval 0.72-1.15). These findings were compatible with those presented in the previous overview of the Swedish randomized studies.

Tumor necrosis factor a-11 and DR15-DQ6 (B*0602) haplotype increase the risk for cervical intraepithelial neoplasia in human papillomavirus 16 seropositive women in Northern Sweden.

HLA genes have been shown to be associated with cervical intraepithelial neoplasia (CIN), a precursor of cervical cancer. The human papillomaviruses (HPV) types 16 and 18 are the major environmental cause of this disease. Because the immune system plays an important role in the control of HPV infection, the association of polymorphic HLA could lead to a different immune response to control the development of cervical cancer. The aim of this study was to analyze the association between CIN and a microsatellite polymorphism of tumor necrosis factor (TNFa) taking HPV exposure and CIN-associated HLA haplotypes into account. In a nested case-control study in northern Sweden, 64 patients and 147 controls matched for age and sex and derived from the same population-based cohort were typed for TNFA, HLA-DR, and DQ and assayed for antibodies to HPV types 16 and 18. TNFa polymorphism was not associated with CIN per se. However, there was a significant increase in the frequency of TNFa-11 among HPV16-positive and HLA DR15-DQ6 (B*0602) patients compared with HPV16- and HLA-DQ6-negative patients (odds ratios, 5.4 and 9.3, respectively). The relative risk for CIN conferred by the combination of TNFa-11, HLA-DQ6, and HPV 16 positivity was 15. Our study suggests that the TNFa-11 allele is associated with HPV16 infection and associated with CIN in combination with HLA-DQ6 but not by itself.

Type specificity and significance of different isotypes of serum antibodies to human papillomavirus capsids.

Isotype-specific serum antibody responses against human papillomavirus (HPV) type 16 were evaluated by use of cross-sectional, prospective, and population-based seroepidemiologic studies. IgG1 and IgA were the most abundant isotypes. No sample contained IgG2, and <25 samples contained IgG3 or IgM. Total IgG, IgA, and IgG1 were HPV type specific and were associated with HPV-16 DNA (odds ratios [ORs], 5.4, 5.0, and 5.9, respectively; P<.001) but not with other HPV DNA (ORs, 1.2, 1.2, and 0.8, respectively; P value was not significant). Total IgG and IgG1 were strongly associated with number of lifetime sex partners (P<.001); IgA was only associated with number of recent sex partners and lifetime sex partners among younger women. Total IgG, IgG1, and IgA were associated with cervical intraepithelial neoplasia type III and also predicted risk of future cervical neoplasia. IgG and IgG1 appeared to mark lifetime cumulative exposure, whereas IgA may mark recent or ongoing infection.