Association of Metabolic Syndrome With Neuroimaging and Cognitive Outcomes in the UK Biobank.

OBJECTIVE: Metabolic syndrome (MetS) has been linked to dementia. In this study, we examined the association of MetS with neuroimaging and cognition in dementia-free adults, offering insight into the impact of MetS on brain health prior to dementia onset. RESEARCH DESIGN AND METHODS: We included 37,395 dementia-free adults from the UK Biobank database. MetS was defined as having at least three of the following components: larger waist circumference; elevated levels of triglycerides, blood pressure, HbA1c; or reduced HDL cholesterol levels. Multivariable-adjusted linear regression was used to assess associations of MetS with structural neuroimaging and cognitive domains. RESULTS: MetS was associated with lower total brain (standardized ß: -0.06; 95% CI -0.08, -0.04), gray matter (ß: -0.10; 95% CI -0.12, -0.08) and hippocampal (for left side, ß: -0.03, 95% CI -0.05, -0.01; for right side, ß: -0.04, 95% CI -0.07, -0.02) volumes, and greater white matter hyperintensity (WMH) volume (ß: 0.08; 95% CI 0.06, 0.11). Study participants with MetS performed poorer on cognitive tests of working memory (ß: -0.10; 95% CI -0.13, -0.07), verbal declarative memory (ß: -0.08; 95% CI -0.11, -0.05), processing speed (ß: -0.06; 95% CI -0.09, -0.04), verbal and numerical reasoning (ß: -0.07; 95% CI -0.09, -0.04), nonverbal reasoning (ß: -0.03; 95% CI -0.05, -0.01), and on tests of executive function, where higher scores indicated poorer performance (ß: 0.05; 95% CI 0.03, 0.08). More MetS components were also associated with less brain volume, greater WMH, and poorer cognition across all domains. CONCLUSIONS: MetS was associated poorer brain health in dementia-free adults, characterized by less brain volume, greater vascular pathology, and poorer cognition. Further research is necessary to understand whether reversal or improvement of MetS can improve brain health.

New role of fat-free mass in cancer risk linked with genetic predisposition.

Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E-17 and 1.78E-11) and WBFFM (p = 2.88E-08 and 8.24E-12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass.

Prospective study design and data analysis in UK Biobank.

Population-based prospective studies, such as UK Biobank, are valuable for generating and testing hypotheses about the potential causes of human disease. We describe how UK Biobank's study design, data access policies, and approaches to statistical analysis can help to minimize error and improve the interpretability of research findings, with implications for other population-based prospective studies being established worldwide.

Association between metabolic syndrome and risk of incident dementia in UK Biobank.

INTRODUCTION: The association between metabolic syndrome (MetS) and incident dementia remains inconclusive. METHODS: In 176,249 dementia-free UK Biobank participants aged ≥60 years at baseline, Cox proportional-hazards models were used to investigate the association between MetS and incident dementia. MetS was defined as the presence of ≥3 of the following: elevated waist circumference, triglycerides, blood pressure, blood glucose, and reduced high-density lipoprotein cholesterol. RESULTS: Over 15 years of follow-up (median = 12.3), 5255 participants developed dementia. MetS was associated with an increased risk of incident dementia (hazard ratio [HR]: 1.12, 95% confidence interval [CI]: 1.06, 1.18). The association remained consistent when restricting to longer follow-up intervals: >5 to 10 years (HR: 1.17, 95% CI: 1.07, 1.27) and >10 years (HR: 1.22, 95% CI: 1.12, 1.32). Stronger associations were observed in those with ≥4 MetS components and in apolipoprotein-E (APOE)-ε4 non-carriers. DISCUSSION: In this large population-based prospective cohort, MetS was associated with an increased risk of dementia. HIGHLIGHTS: MetS was associated with a 12% increased risk of incident all-cause dementia. Associations remained similar after restricting the analysis to those with longer follow-up. The presence of four or five MetS components was significantly associated with dementia. Stronger associations were observed in those with a low genetic risk for dementia.

Central Adiposity Increases Risk of Kidney Stone Disease through Effects on Serum Calcium Concentrations.

SIGNIFICANCE STATEMENT: Kidney stone disease is a common disorder with poorly understood pathophysiology. Observational and genetic studies indicate that adiposity is associated with an increased risk of kidney stone disease. However, the relative contribution of general and central adipose depots and the mechanisms by which effects of adiposity on kidney stone disease are mediated have not been defined. Using conventional and genetic epidemiological techniques, we demonstrate that general and central adiposity are independently associated with kidney stone disease. In addition, one mechanism by which central adiposity increases risk of kidney stone disease is by increasing serum calcium concentration. Therapies targeting adipose depots may affect calcium homeostasis and help to prevent kidney stone disease. BACKGROUND: Kidney stone disease affects approximately 10% of individuals in their lifetime and is frequently recurrent. The disease is linked to obesity, but the mechanisms mediating this association are uncertain. METHODS: Associations of adiposity and incident kidney stone disease were assessed in the UK Biobank over a mean of 11.6 years/person. Genome-wide association studies and Mendelian randomization (MR) analyses were undertaken in the UK Biobank, FinnGen, and in meta-analyzed cohorts to identify factors that affect kidney stone disease risk. RESULTS: Observational analyses on UK Biobank data demonstrated that increasing central and general adiposity is independently associated with incident kidney stone formation. Multivariable MR, using meta-analyzed UK Biobank and FinnGen data, established that risk of kidney stone disease increases by approximately 21% per one standard deviation increase in body mass index (BMI, a marker of general adiposity) independent of waist-to-hip ratio (WHR, a marker of central adiposity) and approximately 24% per one standard deviation increase of WHR independent of BMI. Genetic analyses indicate that higher WHR, but not higher BMI, increases risk of kidney stone disease by elevating adjusted serum calcium concentrations (ß=0.12 mmol/L); WHR mediates 12%-15% of its effect on kidney stone risk in this way. CONCLUSIONS: Our study indicates that visceral adipose depots elevate serum calcium concentrations, resulting in increased risk of kidney stone disease. These findings highlight the importance of weight loss in individuals with recurrent kidney stones and suggest that therapies targeting adipose depots may affect calcium homeostasis and contribute to prevention of kidney stone disease.

Multi-morbidity and its association with common cancer diagnoses: a UK Biobank prospective study.

BACKGROUND: Whilst multi-morbidity is known to be a concern in people with cancer, very little is known about the risk of cancer in multi-morbid patients. This study aims to investigate the risk of being diagnosed with lung, colorectal, breast and prostate cancer associated with multi-morbidity. METHODS: We investigated the association between multi-morbidity and subsequent risk of cancer diagnosis in UK Biobank. Cox models were used to estimate the relative risks of each cancer of interest in multi-morbid participants, using the Cambridge Multimorbidity Score. The extent to which reverse causation, residual confounding and ascertainment bias may have impacted on the findings was robustly investigated. RESULTS: Of the 436,990 participants included in the study who were cancer-free at baseline, 21.6% (99,965) were multi-morbid (≥ 2 diseases). Over a median follow-up time of 10.9 [IQR 10.0-11.7] years, 9,019 prostate, 7,994 breast, 5,241 colorectal, and 3,591 lung cancers were diagnosed. After exclusion of the first year of follow-up, there was no clear association between multi-morbidity and risk of colorectal, prostate or breast cancer diagnosis. Those with ≥ 4 diseases at recruitment had double the risk of a subsequent lung cancer diagnosis compared to those with no diseases (HR 2.00 [95% CI 1.70-2.35] p for trend < 0.001). These findings were robust to sensitivity analyses aimed at reducing the impact of reverse causation, residual confounding from known cancer risk factors and ascertainment bias. CONCLUSIONS: Individuals with multi-morbidity are at an increased risk of lung cancer diagnosis. While this association did not appear to be due to common sources of bias in observational studies, further research is needed to understand what underlies this association.

UK Biobank: a globally important resource for cancer research.

UK Biobank is a large-scale prospective study with deep phenotyping and genomic data. Its open-access policy allows researchers worldwide, from academia or industry, to perform health research in the public interest. Between 2006 and 2010, the study recruited 502,000 adults aged 40-69 years from the general population of the United Kingdom. At enrolment, participants provided information on a wide range of factors, physical measurements were taken, and biological samples (blood, urine and saliva) were collected for long-term storage. Participants have now been followed up for over a decade with more than 52,000 incident cancer cases recorded. The study continues to be enhanced with repeat assessments, web-based questionnaires, multi-modal imaging, and conversion of the stored biological samples to genomic and other '-omic' data. The study has already demonstrated its value in enabling research into the determinants of cancer, and future planned enhancements will make the resource even more valuable to cancer researchers. Over 26,000 researchers worldwide are currently using the data, performing a wide range of cancer research. UK Biobank is uniquely placed to transform our understanding of the causes of cancer development and progression, and drive improvements in cancer treatment and prevention over the coming decades.

Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses.

BACKGROUND: Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined. RESULTS: In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer. CONCLUSIONS: Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer. IMPACT: The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk.

Reproducible disease phenotyping at scale: Example of coronary artery disease in UK Biobank.

IMPORTANCE: A lack of internationally agreed standards for combining available data sources at scale risks inconsistent disease phenotyping limiting research reproducibility. OBJECTIVE: To develop and then evaluate if a rules-based algorithm can identify coronary artery disease (CAD) sub-phenotypes using electronic health records (EHR) and questionnaire data from UK Biobank (UKB). DESIGN: Case-control and cohort study. SETTING: Prospective cohort study of 502K individuals aged 40-69 years recruited between 2006-2010 into the UK Biobank with linked hospitalization and mortality data and genotyping. PARTICIPANTS: We included all individuals for phenotyping into 6 predefined CAD phenotypes using hospital admission and procedure codes, mortality records and baseline survey data. Of these, 408,470 unrelated individuals of European descent had a polygenic risk score (PRS) for CAD estimated. EXPOSURE: CAD Phenotypes. MAIN OUTCOMES AND MEASURES: Association with baseline risk factors, mortality (n = 14,419 over 7.8 years median f/u), and a PRS for CAD. RESULTS: The algorithm classified individuals with CAD into prevalent MI (n = 4,900); incident MI (n = 4,621), prevalent CAD without MI (n = 10,910), incident CAD without MI (n = 8,668), prevalent self-reported MI (n = 2,754); prevalent self-reported CAD without MI (n = 5,623), yielding 37,476 individuals with any type of CAD. Risk factors were similar across the six CAD phenotypes, except for fewer men in the self-reported CAD without MI group (46.7% v 70.1% for the overall group). In age- and sex- adjusted survival analyses, mortality was highest following incident MI (HR 6.66, 95% CI 6.07-7.31) and lowest for prevalent self-reported CAD without MI at baseline (HR 1.31, 95% CI 1.15-1.50) compared to disease-free controls. There were similar graded associations across the six phenotypes per SD increase in PRS, with the strongest association for prevalent MI (OR 1.50, 95% CI 1.46-1.55) and the weakest for prevalent self-reported CAD without MI (OR 1.08, 95% CI 1.05-1.12). The algorithm is available in the open phenotype HDR UK phenotype library (https://portal.caliberresearch.org/). CONCLUSIONS: An algorithmic, EHR-based approach distinguished six phenotypes of CAD with distinct survival and PRS associations, supporting adoption of open approaches to help standardize CAD phenotyping and its wider potential value for reproducible research in other conditions.

Human Cytomegalovirus and Risk of Incident Cardiovascular Disease in United Kingdom Biobank.

BACKGROUND: Previous studies have yielded conflicting results on the association between human cytomegalovirus (HCMV) and cardiovascular disease (CVD). This study examined associations between HCMV and incident CVD, ischaemic heart disease (IHD) and stroke. METHODS: This study included 8531 women and men of predominantly white ethnic background, aged 40-69 without prevalent CVD from the population-based UK Biobank study, recruited between 2006-2010 with HCMV antibody levels measured. CVD was ascertained via linkage to health administrative records collected until 2020. Multivariate Cox proportional-hazards models were used to determine associations between HCMV seropositivity and incident CVD, IHD and stroke. HCMV seropositive antibody levels in tertiles were used to assess dose-response associations. RESULTS: Over a mean follow-up period of 10.2 years, HCMV seropositivity was not significantly associated with CVD (Cases = 626, Hazard Ratio [HR] =1.01, 95% confidence interval [CI], .86-1.20), IHD (Cases = 539, HR=1.03, 95% CI, .87-1.24) or stroke (Cases = 144, HR = 0.96, 95% CI, .68-1.36). There was no evidence of dose-response associations with any outcome. CONCLUSIONS: We found no significant association between HCMV seropositivity and risk of CVD, IHD or stroke. Further research within understudied populations, such as those of non-white ethnicity, and CVD subtypes is warranted.

Physical activity in relation to circulating hormone concentrations in 117,100 men in UK Biobank.

PURPOSE: Physical activity may reduce the risk of some types of cancer in men. Biological mechanisms may involve changes in hormone concentrations; however, this relationship is not well established. Therefore, we aimed to investigate the associations of physical activity with circulating insulin-like growth factor-I (IGF-I), sex hormone-binding globulin (SHBG, which modifies sex hormone activity), and total and free testosterone concentrations, and the extent these associations might be mediated by body mass index (BMI). METHODS: Circulating concentrations of these hormones and anthropometric measurements and self-reported physical activity data were available for 117,100 healthy male UK Biobank participants at recruitment. Objectively measured accelerometer physical activity levels were also collected on average 5.7 years after recruitment in 28,000 men. Geometric means of hormone concentrations were estimated using multivariable-adjusted analysis of variance, with and without adjustment for BMI. RESULTS: The associations between physical activity and hormones were modest and similar for objectively measured (accelerometer) and self-reported physical activity. Compared to men with the lowest objectively measured physical activity, men with high physical activity levels had 14% and 8% higher concentrations of SHBG and total testosterone, respectively, and these differences were attenuated to 6% and 3% following adjustment for BMI. CONCLUSION: Our results suggest that the associations of physical activity with the hormones investigated are, at most, modest; and following adjustment for BMI, the small associations with SHBG and total testosterone were largely attenuated. Therefore, it is unlikely that changes in these circulating hormones explain the associations of physical activity with risk of cancer either independently or via BMI.

Metabolic syndrome biomarkers and prostate cancer risk in the UK Biobank.

We investigated the association between metabolic syndrome (MetS) and its components and risk of prostate cancer (PCa) in a cohort of men enrolled in the UK Biobank. Our study cohort included 220 622 PCa-free men with baseline measurements of triglycerides (TGs), HDL-cholesterol (HDL), glycated hemoglobin (HbA1c), blood pressure (BP), and waist circumference (WC). Multivariable Cox proportional hazards regression was used to analyze associations with PCa for: individual metabolic components (TG, HDL, HbA1c, BP, WC), combinations of two and three components, and MetS overall (three or more components). We conducted mediation analyses to examine potential hormonal and inflammatory pathways (total testosterone [TT], C-reactive protein [CRP], insulin-like growth factor 1 [IGF-1]) through which MetS components may influence PCa risk. A total of 5409 men in the study developed PCa during a median follow-up of 6.9 years. We found no significant association between MetS and PCa risk (hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.92-1.06). No associations were found with PCa risk and individual measurements of TG, HDL, BP, or WC. However, an inverse association was observed with elevated HbA1c (≥42 mmol/mol) (HR = 0.89, 95% CI = 0.79-0.98). Consistent inverse associations were observed between HbA1c and risk of PCa. Mediation analysis revealed TT, CRP, and IGF-1 as potential mediating factors for this association contributing 10.2%, 7.1%, and 7.9% to the total effect, respectively. Overall MetS had no association with PCa risk. However, a consistent inverse association with PCa risk was found for HbA1c. This association may be explained in part through hormonal and inflammatory pathways.

Adiposity and Endometrial Cancer Risk in Postmenopausal Women: A Sequential Causal Mediation Analysis.

BACKGROUND: Adiposity increases endometrial cancer risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); IL6, IL1-receptor antagonist, TNF receptor 1 and 2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); and free estradiol and estrone (estrogen biomarkers) in the adiposity-endometrial cancer link in postmenopausal women. METHODS: We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, and diabetes; did not use oral contraceptives or hormone therapy; and were postmenopausal at recruitment. Mediating pathways from adiposity to endometrial cancer were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. RESULTS: The study included 163 cases and 306 controls. The adjusted OR for endometrial cancer for body mass index (BMI) ≥30 versus ≥18.5-<25 kg/m2 was 2.51 (95% confidence interval, 1.26-5.02). The ORsNIE were 1.95 (1.01-3.74) through all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33% PM); 1.13 (0.71-1.80) through inflammation beyond (the potential influence of) adiponectin (13% PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5% PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21% PM). The ORNDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. CONCLUSIONS: Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated approximately 70% of increased odds of endometrial cancer in women with obesity versus normal weight. IMPACT: If replicated, these results could have implications for identifying targets for intervention to reduce endometrial cancer risk in women with obesity.

Genetic, lifestyle, and health-related characteristics of adults without celiac disease who follow a gluten-free diet: a population-based study of 124,447 participants.

BACKGROUND: The number of gluten-free diet followers without celiac disease (CD) is increasing. However, little is known about the characteristics of these individuals. OBJECTIVES: We address this issue by investigating a wide range of genetic and phenotypic characteristics in association with following a gluten-free diet. METHODS: The cross-sectional association between lifestyle and health-related characteristics and following a gluten-free diet was investigated in 124,447 women and men aged 40-69 y from the population-based UK Biobank study. A genome-wide association study (GWAS) of following a gluten-free diet was performed. RESULTS: A total of 1776 (1.4%) participants reported following a gluten-free diet. Gluten-free diet followers were more likely to be women, nonwhite, highly educated, living in more socioeconomically deprived areas, former smokers, have lost weight in the past year, have poorer self-reported health, and have made dietary changes as a result of illness. Conversely, these individuals were less likely to consume alcohol daily, be overweight or obese, have hypertension, or use cholesterol-lowering medication. Participants with hospital inpatient diagnosed blood and immune mechanism disorders (OR: 1.62; 95% CI: 1.18, 2.21) and non-CD digestive system diseases (OR: 1.58; 95% CI: 1.42, 1.77) were more likely to follow a gluten-free diet. The GWAS demonstrated that no genetic variants were associated with being a gluten-free diet follower. CONCLUSIONS: Gluten-free diet followers have a better cardiovascular risk profile than non-gluten-free diet followers but poorer self-reported health and a higher prevalence of blood and immune disorders and digestive conditions. Reasons for following a gluten-free diet warrant further investigation.

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.

Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two-sample Mendelian randomisation (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis- and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment = 1.34, 1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.

Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank.

BACKGROUND: Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank. METHODS: A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure. RESULTS: After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death. CONCLUSION: We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.

Ovarian Cancer Risk Factor Associations by Primary Anatomic Site: The Ovarian Cancer Cohort Consortium.

BACKGROUND: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites. METHODS: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests. RESULTS: Most associations did not vary by tumor site (P het ≥ 0.05). Associations between first pregnancy (P het = 0.04), tubal ligation (P het = 0.01), and early-adult (age 18-21 years) body mass index (BMI; P het = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer (P het = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases. CONCLUSIONS: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site. IMPACT: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.

Dietary and Circulating Fatty Acids and Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis. RESULTS: A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintileQ5-Q1 = 1.29; 95% confidence interval (CI) = 1.03-1.62; P trend = 0.02, q-value = 0.06]. Dietary intakes of n-6 linoleic acid (HRQ5-Q1 = 1.10; 95% CI = 1.01-1.21; P trend = 0.03) and n-3 α-linolenic acid (HRQ5-Q1 = 1.18; 95% CI = 1.05-1.34; P trend = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertileT3-T1 = 1.39; 95% CI = 0.99-1.94; P trend = 0.06) and α-linolenic acids (ORT3-T1 = 1.30; 95% CI = 0.98-1.72; P trend = 0.06). CONCLUSIONS: Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer. IMPACT: If causal, eliminating industrial trans-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.

Hematologic Markers and Prostate Cancer Risk: A Prospective Analysis in UK Biobank.

BACKGROUND: Risk factors for prostate cancer are not well understood. Red blood cell, platelet, and white blood cell indices may be markers of a range of exposures that might be related to prostate cancer risk. Therefore, we examined the associations of hematologic parameters with prostate cancer risk. METHODS: Complete blood count data from 209,686 male UK Biobank participants who were free from cancer at study baseline were analyzed. Participants were followed up via data linkage. After a mean follow-up of 6.8 years, 5,723 men were diagnosed with prostate cancer and 323 men died from prostate cancer. Multivariable-adjusted Cox regression was used to estimate adjusted HRs and 95% confidence intervals (CI) for prostate cancer incidence and mortality by hematologic parameters, and corrected for regression dilution bias. RESULTS: Higher red blood cell (HR per 1 SD increase = 1.09, 95% CI, 1.05-1.13) and platelet counts (HR = 1.07, 1.04-1.11) were associated with an increased risk of prostate cancer. Higher mean corpuscular volume (HR = 0.90, 0.87-0.93), mean corpuscular hemoglobin (HR = 0.90, 0.87-0.93), mean corpuscular hemoglobin concentration (HR = 0.87, 0.77-0.97), and mean sphered cell volume (HR = 0.91, 0.87-0.94) were associated with a lower prostate cancer risk. Higher white blood cell (HR = 1.14, 1.05-1.24) and neutrophil count (HR = 1.27, 1.09-1.48) were associated with prostate cancer mortality. CONCLUSIONS: These associations of blood indices of prostate cancer risk and mortality may implicate shared common causes, including testosterone, nutrition, and inflammation/infection among several others in prostate cancer development and/or progression. IMPACT: These associations provide insights into prostate cancer development and progression.