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Purpose: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. Design: Meta-analysis of eleven population-based cohort studies of the European Eye Epidemiology (E3) consortium. Participants: A total of 143240 participants were included in the glaucoma analyses and 47177 participants in the IOP analyses. Methods: We examined associations of four categories of systemic medications (antihypertensive medications: beta-blockers, diuretics, calcium channel blockers [CCBs], alpha-agonists, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers; lipid-lowering medications; antidepressants; antidiabetic medications) with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Multivariable regression analyses were carried out in each study and results were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in diabetic participants only. Main Outcome Measures: Glaucoma prevalence and IOP. Results: In the meta-analyses of our maximally-adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR] with corresponding 95% confidence interval [95% CI]: 1.23 [1.08 to 1.39]). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR [95% CI]: 1.96 [1.23 to 3.12]). The use of other antihypertensive medications, lipid-lowering medications, antidepressants or antidiabetic medications were not clearly associated with glaucoma. Use of systemic beta-blockers was associated with a lower IOP (Beta [95% CI]: -0.33 [-0.57 to -0.08] mmHg). Monotherapy of both selective (Beta [95% CI]: -0.45 [-0.74 to -0.16] mmHg) and non-selective (Beta [95% CI]: -0.54 [-0.94 to -0.15] mmHg) systemic beta-blockers was associated with lower IOP. There was a suggestive association between use of high-ceiling diuretics and lower IOP (Beta [95% CI]: -0.30 [-0.47; -0.14] mmHg), but not when used as monotherapy. Use of other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were not associated with IOP. Conclusions: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic beta-blocker use. Both findings are potentially important given that glaucoma patients frequently use systemic antihypertensive medications. Determining whether the CCB association is causal should be a research priority. published

PDF file, 120KB, Supplemental Table 1. Study Descriptions, Design and Sample Size for 19 DENSNP Studies. Caucasian Women Only. Supplemental Table 2. Source and Timing of Reproductive and Anthropometric Variable Collection. Supplemental Table 3. Description of Mammogram View, Side, Film Digitizer and Density Estimation Software for DENSNP Studies. Supplemental Table 4. Genotyping Platform and SNP Call Rates Performed by Each Study.

PDF file, 20KB, Supplemental Table 5a. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Percent Mammographic Density. Supplemental Table 5b. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area. Supplemental Table 5c. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area.

PDF file, 133KB, Supplemental Table 6a. Per-Allele Association (SE) of Breast Cancer Susceptibility Variants with Mammographic Percent Density Stratifying by Case Status, BMI, Menopausal Status and PMH Use. Supplemental Table 6b. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use. Supplemental Table 6c. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use.

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures.Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status.Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07).Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland.Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. Cancer Epidemiol Biomarkers Prev; 21(7); 1156–. ©2012 AACR.

Supplementary Table 2. Associations (95% Confidence Interval (CI) in brackets) between all 77 breast cancer susceptibility variants and percent dense area, dense area, and non-dense area

PDF file - 275K, Significance of the mammographic breast density polygenic risk score (PRS) for the prediction of breast cancer risk, according to percent cut-off of SNPs used in the PRS: sensitivity analysis using imputed case:control genotype dosages.

Supplementary Figures 1-2 from Telomere Length in Prospective and Retrospective Cancer Case-Control Studies

Supplementary Tables 1-2 from Telomere Length in Prospective and Retrospective Cancer Case-Control Studies

Supplementary Table 3. Associations (95% Confidence Interval (CI) in brackets) between breast cancer susceptibility variants and the mammographic measures with adjustment for case-control status

Supplementary Table 1. Mean (95% Confidence Interval (CI)) mammographic density measurements by covariate distribution

BACKGROUND: This cohort study aimed to determine the association between body fat percentage (BF%), incident fractures and calcaneal broadband ultrasound attenuation (BUA). METHODS: Participants were drawn from the EPIC-Norfolk Prospective Population Cohort Study (median follow-up = 16.4 years). Cox models analysed the relationship between BF% and incident fractures (all and hip). Linear and restricted cubic spline (RCS) regressions modelled the relationship between BF% and BUA. RESULTS: 14,129 participants (56.2 % women) were included. There were 1283 and 537 incident all and hip fractures respectively. The participants had a mean (standard deviation) age of 61.5 (9.0) years for women and 62.9 (9.0) years for men. Amongst men, BF% was not associated with incident all fractures. While BF% < 23 % (median) was not associated with hip fractures, BF% > 23 % was associated with increased risk of hip fractures by up to 50 % (hazard ratio (95 % confidence interval) = 1.49 (1.06-2.12)). In women, BF% < 39 % (median) was associated with up to 32 % higher risk of all fractures (1.32 (1.13-1.44)), while BF% > 35 % was not associated with this outcome. Higher BF% was associated with lower risk of incident hip fractures in women. Higher BF% was associated with higher BUA amongst women. Higher BF% up to ~23 % was associated with higher BUA amongst men. CONCLUSIONS: Higher BF% is associated with lower risk of fractures in women. While there was no association between BF% and all fractures in men, increasing BF% >23 % was associated with higher risk of hip fractures in men. This appears to be independent of estimated bone mineral density. Fracture prevention efforts need to consider wider physical, clinical, and environmental factors.

Purpose: Serum lipids are modifiable, routinely collected blood test features associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) with intraocular pressure (IOP). Design: Cross-sectional study in the UK Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohorts. Participants: We included 94 323 participants from the UK Biobank (mean age, 57 years) and 6230 participants from the EPIC-Norfolk (mean age, 68 years) cohorts with data on TC, HDL-C, LDL-C, and triglycerides collected between 2006 and 2009. Methods: Multivariate linear regression adjusting for demographic, lifestyle, anthropometric, medical, and ophthalmic covariables was used to examine the associations of serum lipids with corneal-compensated IOP (IOPcc). Main Outcome Measures: Corneal-compensated IOP. Results: Higher levels of TC, HDL-C, and LDL-C were associated independently with higher IOPcc in both cohorts after adjustment for key demographic, medical, and lifestyle factors. For each 1-standard deviation increase in TC, HDL-C, and LDL-C, IOPcc was higher by 0.09 mmHg (95% confidence interval [CI], 0.06–0.11 mmHg; P < 0.001), 0.11 mmHg (95% CI, 0.08–0.13 mmHg; P < 0.001), and 0.07 mmHg (95% CI, 0.05–0.09 mmHg; P < 0.001), respectively, in the UK Biobank cohort. In the EPIC-Norfolk cohort, each 1-standard deviation increase in TC, HDL-C, and LDL-C was associated with a higher IOPcc by 0.19 mmHg (95% CI, 0.07–0.31 mmHg; P = 0.001), 0.14 mmHg (95% CI, 0.03–0.25 mmHg; P = 0.016), and 0.17 mmHg (95% CI, 0.06–0.29 mmHg; P = 0.003). An inverse association between triglyceride levels and IOP in the UK Biobank (–0.05 mmHg; 95% CI, –0.08 to –0.03; P < 0.001) was not replicated in the EPIC-Norfolk cohort (P = 0.30). Conclusions: Our findings suggest that serum TC, HDL-C, and LDL-C are associated positively with IOP in 2 United Kingdom cohorts and that triglyceride levels may be associated negatively. Future research is required to assess whether these associations are causal in nature.

Background/aimsTo investigate the association of commonly used systemic medications with prevalent age-related macular degeneration (AMD) in the general population.MethodsWe included 38 694 adults from 14 population-based and hospital-based studies from the European Eye Epidemiology consortium. We examined associations between the use of systemic medications and any prevalent AMD as well as any late AMD using multivariable logistic regression modelling per study and pooled results using random effects meta-analysis.ResultsBetween studies, mean age ranged from 61.5±7.1 to 82.6±3.8 years and prevalence ranged from 12.1% to 64.5% and from 0.5% to 35.5% for any and late AMD, respectively. In the meta-analysis of fully adjusted multivariable models, lipid-lowering drugs (LLD) and antidiabetic drugs were associated with lower prevalent any AMD (OR 0.85, 95% CI=0.79 to 0.91 and OR 0.78, 95% CI=0.66 to 0.91). We found no association with late AMD or with any other medication.ConclusionOur study indicates a potential beneficial effect of LLD and antidiabetic drug use on prevalence of AMD across multiple European cohorts. Our findings support the importance of metabolic processes in the multifactorial aetiology of AMD.

This systematic review and meta-analysis summarizes the existing evidence for the association of alcohol use with intraocular pressure (IOP) and open-angle glaucoma (OAG).Understanding and quantifying these associations may aid clinical guidelines or treatment strategies and shed light on disease pathogenesis. The role of alcohol, a modifiable factor, in determining IOP and OAG risk also may be of interest from an individual or public health perspective.The study protocol was preregistered in the Open Science Framework Registries (https://osf.io/z7yeg). Eligible articles (as of May 14, 2021) from 3 databases (PubMed, Embase, Scopus) were independently screened and quality assessed by 2 reviewers. All case-control, cross-sectional, and cohort studies reporting a quantitative effect estimate and 95% confidence interval (CI) for the association between alcohol use and either IOP or OAG were included. The evidence for the associations with both IOP and OAG was qualitatively summarized. Effect estimates for the association with OAG were pooled using random effects meta-analysis. Studies not meeting formal inclusion criteria for systematic review, but with pertinent results, were also appraised and discussed. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.Thirty-four studies were included in the systematic review. Evidence from 10 studies reporting an association with IOP suggests that habitual alcohol use is associated with higher IOP and prevalence of ocular hypertension (IOP21 mmHg), although absolute effect sizes were small. Eleven of 26 studies, comprising 173 058 participants, that tested for an association with OAG met inclusion criteria for meta-analysis. Pooled effect estimates indicated a positive association between any use of alcohol and OAG (1.18; 95% confidence interval [CI], 1.02-1.36; P = 0.03; IAlthough this meta-analysis suggests a harmful association between alcohol use and OAG, our results should be interpreted cautiously given the weakness and heterogeneity of the underlying evidence base, the small absolute effect size, and the borderline statistical significance. Nonetheless, these findings may be clinically relevant, and future research should focus on improving the quality of evidence.

This systematic review summarizes evidence for associations between female reproductive factors (age at menarche, parity, oral contraceptive [OC] use, age at menopause, and postmenopausal hormone [PMH] use) and intraocular pressure (IOP) or open-angle glaucoma (OAG).Understanding the associations between female reproductive factors and glaucoma may shed light on the disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable, which may lead to new therapies.Two reviewers independently extracted articles in MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects aged18 years; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional, or randomized controlled trial design; a reported measure of association, such as the hazard ratio, relative risk, odds ratio, or mean difference, with an associated confidence interval; and a measured exposure of at least 1 of the following variables: age at menarche, parity, OC use, age at menopause, or PMH use.We included a total of 27 studies. Substantial differences in study designs, exposure and treatment levels, treatment durations, and variable reporting precluded a meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and a lower IOP were identified. Estrogen-only PMH use may be associated with lower OAG risk, which may be modified by race. No significant associations were found with combined estrogen-and-progesterone PMH use. No strong associations between parity or age at menarche and glaucoma were found, but a younger age at menopause was associated with an increased glaucoma risk, and adverse associations were identified with a longer duration of OC use, though no overall association with OC use was found.The association between PMH use and lower IOP or OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. Future research should examine associations with IOP specifically and how the relationship between genetic factors and OAG risks may be influenced by female reproductive factors.

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

Objectives Assess the association between marine omega-3 polyunsaturated fatty acid (n-3 PUFA) intake from supplements, mainly cod liver oil, and coronary heart disease (CHD) mortality. Design Prospective cohort study, with three exposure measurements over 22 years. Setting Norfolk-based European Prospective Investigation into Cancer (EPIC-Norfolk, UK). Participants 22 035 men and women from the general population, 39–79 years at recruitment. Exposure Supplement use was assessed in three questionnaires (1993–1998; 2002–2004; 2004–2011). Participants were grouped into non-supplement users (NSU), n-3 PUFA supplement users (SU+n3) and non–n-3 PUFA supplement users (SU-n3). Cox regression adjusted for time-point specific variables: age, smoking, prevalent illnesses, body mass index, alcohol consumption, physical activity and season and baseline assessments of sex, social class, education and dietary intake (7-day diet diary). Primary and secondary outcome measures During a median of 19-year follow-up, 1562 CHD deaths were registered for 22 035 included participants. Results Baseline supplement use was not associated with CHD mortality, but baseline food and supplement intake of n-3 PUFA was inversely associated with CHD mortality after adjustment for fish consumption. Using time-varying covariate analysis, significant associations were observed for SU+n3 (HR: 0.74, 95% CI 0.66 to 0.84), but not for SU-n3 versus NSU. In further analyses, the association for SU+n3 persisted in those who did not take other supplements (HR: 0.83, 95% CI 0.71 to 0.97). Those who became SU+n3 over time or were consistent SU+n3 versus consistent NSU had a lower hazard of CHD mortality; no association with CHD was observed in those who stopped using n-3 PUFA-containing supplements. Conclusions Recent use of n-3 PUFA supplements was associated with a lower hazard of CHD mortality in this general population with low fish consumption. Residual confounding cannot be excluded, but the findings observed may be explained by postulated biological mechanisms and the results were specific to SU+n3.

The tumour suppressor p53 is one of the most commonly altered genes in colorectal cancer (CRC) development. Genetic alterations in p53 may therefore be associated with postulated lifestyle risk factors for CRC, such as red meat consumption. In the European Prospective Investigation into Cancer and Nutrition-Norfolk study, we examined whether detailed estimates of dietary and lifestyle factors measured at baseline related to later development of p53 mutations in CRCs. After 10-year follow-up, there were 185 incident CRCs of which 34% had somatic p53 mutations (p53+). We observed significantly higher mean intakes of alcohol, total meat and red meat, in the group with p53 mutations and advanced Dukes' stage disease (daily alcohol intake was 7 and 12 g for p53- and p53 + cases, respectively, P = 0.04; daily total meat intake was 69 and 100 g for p53- and p53 + cases, respectively, P = 0.03 and daily red meat intake was 39 and 75 g for p53- and p53+ cases, respectively, P = 0.01). Each 50 g/day increment in total meat intake was associated with having p53 mutations in cases with advanced Dukes' stages [odds ratio (OR): 3.43, 95% confidence interval (CI): 1.47-7.96]. Similarly, each 50 g/day increment in red meat intake was also significantly associated with having consistent p53 mutations in cases with advanced Dukes' stages (OR: 2.42, 95 % CI: 1.18-4.96). These effects of total meat or red meat intake and advanced Dukes' stages were independent of age, sex, body mass index, smoking and alcohol intake. Furthermore, P values for interaction between daily total meat or red meat intake and Dukes' stages were statistically significant in multivariable models (Pinteraction < 0.001). Our results suggest that p53 mutations accelerate progression of CRC to advanced Dukes' stage in association with higher meat especially red meat intakes.

Jamie C. Sergeant, Suzanne M. M. Verstappen, Catharine Morgan, Robert N. Luben, Amit Bhaniani, Serena Anuj, RA-MAP consortium, Alex J. MacGregor, Nick Wareham, Deborah P. M. Symmons, Kay-Tee Khaw and Ian N. Bruce Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, Cambridge and Norwich Medical School, University of East Anglia, Norwich, UK

Suzanne M. Verstappen, Jamie C. Sergeant, Robert N. Luben, Amit Bhaniani, Serena Anuj, RA-MAP consortium, Alex J. MacGregor, Nick Wareham, Deborah P. M. Symmons, Kay-Tee Khaw and Ian N. Bruce Arthritis Research UK Centre for Epidemiology, The University of Manchester, NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester, European Prospective Investigation into Cancer and Nutrition, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, Rheumatology, Norfolk and Norwich University Hospital, Manchester, UK

Background Type-2 diabetes is associated with systemic inflammation and higher C-reactive protein (CRP) levels. However, the longitudinal association of CRP and haemoglobin-A1c (HbA1c) has not been described in large prospective studies. Understanding such associations may shed light on the role of inflammation in development of type-2 diabetes and its complications such as cardiovascular diseases. Methods EPIC-Norfolk is a cohort study of men and women aged 40–79 years at time of recruitment (1993–1997). Serum CRP (mg/l) was measured using a high-sensitivity assay at baseline and 13-years follow-up. HbA1c (%) was measured at baseline, 4, and 13 years. Participants were excluded if they were diagnosed with diabetes or were taking diabetes medication. Data on at least one measurement of CRP and HbA1c was available for 14228 participants (55 % of the cohort). Results In the cross-sectional analysis of baseline data, a 1-SD higher loge-CRP (about three-fold higher CRP) was associated with 0.06 (95 % CI 0.04, 0.08) higher HbA1c (%) adjusted for potential confounders. In longitudinal analysis using multivariable linear mixed models, change in CRP over 13 years was to a similar extent positively associated with increase in HbA1c, such that 1-SD higher longitudinal change in loge-CRP was associated with 0.04 (95 % CI 0.02, 0.05) increase in HbA1c. Conclusion In this study we found longitudinal observational evidence suggesting that increase in systemic inflammation is associated with an increase in HbA1c and thus systemic inflammation may have a role in development of type-2 diabetes and its complications.

Cross-sectional studies investigating the relationship between phytoestrogens in diet, urine, or blood with plasma estradiol and sex hormone binding globulin (SHBG) have been inconclusive. We investigated the relationship among phytoestrogen exposure, polymorphisms in the ESR1, COMT, CYP19, and SHBG genes, and plasma estradiol and SHBG levels in 125 free-living postmenopausal women taking part in a cohort study (European Prospective Investigation of Cancer and Nutrition-Norfolk) using three different markers: dietary, urinary, and serum phytoestrogens. Phytoestrogen levels (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) in spot urine and serum were analyzed by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, respectively. Plasma estradiol and SHBG were measured by immunoassays. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = −0.199 to −0.277, P

STK15 is a putative oncogene that codes for a centrosome-associated, serine/threonine kinase, the normal function of which is to ensure accurate segregation of chromosomes during mitosis. Amplification of STK15 has been reported in ovarian tumors, suggesting a role in ovarian cancer pathology. STK15 is polymorphic with two single nucleotide substitutions (449t/a and 527g/a) in evolutionarily conserved regions causing amino acid changes (F31I and V57I). Two other nucleotide substitutions (287c/g and 1891g/c) of unknown significance are in 5′ and 3′ untranslated regions (UTR), respectively. To learn more about the involvement of STK15 in ovarian cancer, we genotyped and haplotyped these polymorphisms in three population-based ovarian cancer case-control studies from the United Kingdom, United States, and Denmark with 1,821 combined cases and 2,467 combined controls and calculated risks for developing ovarian cancer. Genotypes of individual polymorphisms in control groups of the United Kingdom, United States, and Denmark conformed to Hardy-Weinberg equilibrium. In combined cases and combined controls, rare allele frequencies were 0.23 and 0.21 for I31, 0.16 and 0.17 for I57, 0.08 and 0.07 for 5′ UTR g, and 0.25 and 0.24 for 3′ UTR c, respectively. Using FF common homozygotes of F31I as comparator, there was increased ovarian cancer risk to FI heterozygotes (odds ratio, 1.18; 95% confidence interval, 1.01-1.36), II homozygotes (odds ratio, 1.25; 95% confidence interval, 0.89-1.75), and I31 allele carriers (odds ratio, 1.17; 95% confidence interval, 1.02-1.35) in the combined group data. For either V57I, 5′ UTR C/G, or 3′ UTR G/C, all genotypic ovarian cancer risks were essentially in unity relative to their respective common homozygotes, VV, cc, or gg. Haplotype analysis of combined group data revealed seven haplotypes with frequencies between 0.02 and 0.5, with c-F-V-g the most common. None of the haplotype-specific risks significantly differed from unity relative to c-F-V-g. These results suggest a model of dominant inheritance of ovarian cancer risk by the I31 allele of F31I and that the I31 allele may be a common ovarian cancer susceptibility allele of low penetrance.

Subjects of this study consisted of 333 women (aged 45–75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply 13C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13–0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20–45% [log2 odds ratio = 1.34 (1.06–1.70; P = 0.013) for urine equol, 1.46 (1.05–2.02; P = 0.024) for serum equol, and 1.22 (1.01–1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.

Background Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting. We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts. Methods Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications. Results Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio [HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR, 1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95% CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43). Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03). Conclusion Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

Background and Objectives: An elevated white blood cell (WBC) count has been reported to be associated with all-cause mortality and risk of cardiovascular diseases. While the relationship between leukocyte count and coronary heart disease has been well documented, evidence on the association with risk of stroke has been less consistent. The aim of this study was to investigate the relationship between WBC count and incidence of stroke in a large cohort of disease-free men and women, and to assess how far any associations might be explained by traditional risk factors for stroke. Methods: We examined the prospective association between full blood WBC count and incident stroke in 7,392 men and 9,049 women from the general population participating in the European Prospective Investigation into Cancer-Norfolk Study. Participants were aged 39-79 years, without known heart attack, stroke, and cancer at the baseline examination in 1993-1997 and were followed up for incident stroke till March 2008. Results: During the median follow-up of 12 years, 542 incident stroke cases were observed. The age- and sex- adjusted risk of incident stroke increased with the increase of WBC count. Compared to the lowest quartile of WBC count, the age- and sex- adjusted hazard ratios (HRs) and 95% CIs for stroke were 1.11 (0.86-1.45), 1.40 (1.10-1.79), and 1.65 (1.29-2.09) in the second, third, and fourth quartile, respectively. Adjusting for smoking attenuated the results, while further adjustment for socioeconomic and lifestyle risk factors changed the association very little. The association was further attenuated after adjustment for biological risk factors such as systolic blood pressure and a history of diabetes at baseline, but people with the highest quartile of WBC count still had a higher risk of stroke than those in the lowest quartile (HR 1.32, 95% CI 1.02-1.71). Every 2*10 9 /L increase in WBC count was associated with a hazard ratio of 1.14 (95% CI 1.02-1.26) for stroke in the fully-adjusted model which included age, sex, smoking status, BMI, social class, educational level, alcohol intake, physical activity, systolic blood pressure, a history of diabetes at baseline, and total serum cholesterol. Conclusions: A positive association between WBC count and stroke was observed in these middle-aged and older men and women. Adjustment for smoking attenuated the association while multivariate adjustment for other risk factors did not further change the results.

Background The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. Methods 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Results Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). Conclusion These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.

Low circulating levels of testosterone and sex-hormone-binding globulin (SHBG) are associated with increased cardiovascular risk in men. This association may be partially mediated through changes in glucose metabolism, but relatively few data are available on the relationship between sex hormones and markers of long-term glycaemia. We assessed the associations of endogenous testosterone and SHBG with glycated haemoglobin (HbA(1c) ) in men.Cross-sectional study of 1292 men from the Norfolk population of European Prospective Investigation into Cancer (EPIC-Norfolk).Glycated haemoglobin, total testosterone (TT) and SHBG levels were measured, and free testosterone (FT) levels were calculated. Multiple linear regression models were used to assess the associations of TT, SHBG and FT with HbA(1c).Men with diabetes had lower testosterone and SHBG levels. In non-diabetic men, HbA(1c) levels were inversely associated with TT and calculated FT independently of age, body mass index, smoking, alcohol consumption and physical activity. The adjusted change in HbA(1c) was 0·055 (95% CI 0·025; 0·085) per standard deviation (SD) decrease in TT and 0·041 (95% CI 0·010; 0·073) per SD decrease in calculated FT, respectively. SHBG levels were inversely associated with HbA(1c) after multivariable adjustment (β = 0·038 per SD decrease (95% CI 0·004; 0·071)).In middle-aged and older men, low endogenous testosterone and SHBG levels are associated with glycaemia, even below the threshold for diabetes. Further studies are needed to determine the effects of interventions that raise testosterone levels in men having increased HbA(1c) and subnormal testosterone levels.

OBJECTIVE To investigate the association between fish and seafood intake and new-onset type 2 diabetes. RESEARCH DESIGN AND METHODS This was a population-based prospective cohort (European Prospective Investigation of Cancer [EPIC]-Norfolk) study of men and women aged 40–79 years at baseline (1993–1997). Habitual fish and seafood intake (white fish, oily fish, fried fish, and shellfish) was assessed using a semiquantitative food frequency questionnaire and categorized as less than one or one or more portions/week. During a median (interquartile range) follow-up of 10.2 (9.1–11.2) years, there were 725 incident diabetes cases among 21,984 eligible participants. RESULTS Higher total fish intake (one or more versus less than one portions/week) was associated with a significantly lower risk of diabetes (odds ratio [OR] 0.75 [95% CI 0.58–0.96]), in analyses adjusted for age, sex, family history of diabetes, education, smoking, physical activity, dietary factors (total energy intake, alcohol intake, and plasma vitamin C) and obesity (BMI and waist circumference). White fish and oily fish intakes were similarly inversely associated with diabetes risk, but the associations were not significant after adjustment for dietary factors (oily fish) or obesity (white fish). Fried fish was not significantly associated with diabetes risk. Consuming one or more portions/week of shellfish was associated with an increased risk of diabetes (OR 1.36 [1.02–1.81]) in adjusted analyses. CONCLUSIONS Total, white, and oily fish consumption may be beneficial for reducing risk of diabetes, reinforcing the public health message to consume fish regularly. Greater shellfish intake seems to be associated with an increased risk of diabetes, warranting further investigation into cooking methods and mechanisms.

Previous studies on cardiovascular risk profile in different socioeconomic status were focused on younger populations and many of them have not been able to take into account age and sex differences.To investigate the relationship of occupational social class with the prevalence of cardiovascular disease risk factors and cardiovascular diseases in younger (65 years) and older (or=65 years) men and women.A population-based-cross sectional study was conducted in a general community in Norfolk, United Kingdom. Participants were 23,085 men and women aged 40-79 years, recruited from general practice age-sex registers as part of European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk). The prevalence of cardiovascular risk factors and cardiovascular diseases were examined.The prevalence of smoking was significantly higher in those in manual social classes particularly in the younger (65) age group. Younger women in manual social classes were more likely to be smokers compared to older women in the same social class. Being in manual social classes was associated with higher cholesterol levels in women but lower cholesterol levels in men. Manual social class was associated with higher physical activity in those younger than 65 years but this association was reversed in those 65 years or older.Occupational social class is differently related to cardiovascular risk factors in individuals depending on their age and sex. This may reflect differences in behavior at work and leisure, which vary by sex and pre- and postretirement. Interventions to promote health and reduce social inequalities need to take age and gender into account.

There is evidence that transforming growth factor (TGF)beta acts as a suppressor of tumor initiation but also as a promoter of tumor progression when the antiproliferative effect of the TGFbeta signaling pathway has been overridden by other oncogenic mutations. Several somatic mutations that disrupt the TGFbeta-SMAD signaling pathway have been reported in human breast tumors. We have examined the association between single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3987 patients and 3867 controls, median age approximately 50 years, and range 22-92 years. The promoter SNP, C-509T, and the T +29C signal-peptide SNP (encoding Leu10Pro) are in strong linkage disequilibrium. They are both significantly associated with increased incidence of invasive breast cancer in a recessive manner [odds ratios: (TT versus C-carrier), 1.25; 95% confidence intervals 1.06-1.48; P = 0.009 and (ProPro versus Leu-carrier), 1.21; 95% confidence intervals 1.05-1.37; P = 0.01]. The G-800A SNP was not significantly associated with incidence of breast cancer. The C-509T SNP is not contained within a known consensus sequence for a promoter regulatory element and therefore unlikely to affect TGFbeta1 expression, whereas the Leu10Pro signal peptide substitution potentially affects TGFbeta1 secretion. Transfections of HeLa cells with constructs encoding either the Pro or Leu forms of TGFbeta1 and driven by the cytomegalovirus promoter indicate that the signal peptide with Pro at residue 10 causes a 2.8-fold increase in secretion compared with the Leu form. These data indicate that the allele encoding Pro10 is associated with increased rates of TGFbeta1 secretion and with increased incidence of invasive breast cancer for the population samples described. It is estimated that 3% of all breast cancer cases may be attributable to Pro10 homozygosity.