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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.

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Perspective on This Article from Anthropometric Measures, Physical Activity, and Risk of Glioma and Meningioma in a Large Prospective Cohort Study

Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case–control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone–binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62–5.23), Ptrend = 0.002; testosterone OR = 2.27 (95% CI: 1.35–3.81), Ptrend = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00–4.46), Ptrend = 0.05; testosterone OR = 2.06 (95% CI: 0.95–4.46), Ptrend = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor–negative as well as receptor–positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors. Cancer Prev Res; 4(10); 1626–35. ©2011 AACR.

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Supplementary Methods from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium

Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 × 10-5], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734–44)

Supplementary Table 1 from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium

Supplementary material and methods: supplementary information on data collection, statistical analyses, and presentation of results in the figures.

Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case–control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from prediagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10 mg/L compared with 10 mg/L was positively associated with risk of mucinous (OR = 9.67; 95% CI = 1.10–84.80) and endometrioid carcinoma (OR = 3.41; 95% CI = 1.07–10.92), and suggestively positive, although not statistically significant, for serous (OR = 1.43; 95% CI = 0.82–2.49) and clear cell carcinoma (OR = 2.05; 95% CI = 0.36–11.57; Pheterogeneity = 0.20). Heterogeneity was observed with oral contraceptive use (Pinteraction = 0.03), where the increased risk was present only among ever users (OR = 3.24; 95% CI = 1.62–6.47). This study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma.Significance:C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be particularly implicated in the etiology of mucinous and endometrioid carcinomas.

Table S1. Association between CRP and ovarian cancer risk by OC3 study Table S2. Association between CRP and ovarian cancer risk for various sensitivity analyses, including exclusion of PLCO, exclusion of women diagnosed within 2 years of blood draw, additional adjustment for aspirin use, and exclusion of women with cardiovascular disease Table S3. Association between CRP and ovarian cancer risk by time between blood draw and diagnosis Figure S1. Restricted cubic splines of the association between CRP and ovarian cancer risk using two approaches to identify CRP outliers Figure S2. Restricted cubic splines of the association between CRP and risk of serous and non-serous ovarian cancer

Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age.Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening.Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited. Cancer Epidemiol Biomarkers Prev; 21(3); 437–44. ©2012 AACR.

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Supplementary Figure Legends for Figures S1-S15.

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Backgrounds: Multiple polymorphisms affecting smoking behavior have been identified through genome-wide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels.Methods: We conducted an analysis in a lung cancer case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of single-nucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13.Results: Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk.Conclusions: 15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation.Impact: This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior. Cancer Epidemiol Biomarkers Prev; 20(10); 2250–61. ©2011 AACR.

Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2 = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes. Cancer Epidemiol Biomarkers Prev; 19(11); 2877–87. ©2010 AACR.

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16–1.43) for IGF-I, 0.81 (0.68–0.96) for IGFBP-1, and 1.25 (1.12–1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288–300. ©2016 AACR.

Supplementary Table 1 from Eighteen Insulin-like Growth Factor Pathway Genes, Circulating Levels of IGF-I and Its Binding Protein, and Risk of Prostate and Breast Cancer

Supplementary tables and figures showing study and assay characteristics, correlations between analytes, and the relationships of the analytes with prostate cancer risk overall, by study and study design, and subdivided by clinical and other characteristics.

Supplementary Table 2 from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between prediagnostic concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. ORs for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest vs. lowest study-specific fifth was 1.22; 95% confidence interval, 1.13–1.31; P trend < 0.001). However, this association varied by disease aggressiveness (Pheterogeneity = 0.014); higher circulating 25(OH)D was associated with a higher risk of nonaggressive disease (OR per 80 percentile increase = 1.24, 1.13–1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78–1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of nonaggressive prostate cancer may be influenced by detection bias.Significance:This international collaboration comprises the largest prospective study on blood vitamin D and prostate cancer risk and shows no association with aggressive disease but some evidence of a higher risk of nonaggressive disease.

Supplementary Tables 1-3 from Pancreatic Cancer Risk and ABO Blood Group Alleles: Results from the Pancreatic Cancer Cohort Consortium

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18–1.62], 1.47 (95% CI, 1.07–2.02), and 1.53 (95% CI, 1.21–1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13–1.58) and 1.61 (95% CI, 1.22–2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14–1.85) and 2.42 (1.28–4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03–3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk. Cancer Res; 70(3); 1015–23

PDF file - 58K, Median concentrations of leptin and sOB-R by tumor stage and cancer location, the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 127K, Relative risks (RR-s)* and 95% confidence intervals (CI-s) of colorectal cancer associated with a doubling in leptin and sOB-R concentrations, by subgroups, the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 101K, Relative risks (RR-s) and 95% confidence intervals (CI-s) of colon, rectal and colorectal cancer according to sex-specific quintiles of baseline soluble leptin receptor (sOB-R) concentrations, in men and women, the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 100K, Relative risks (RR-s) and 95% confidence intervals (CI-s) of colon, rectal and colorectal cancer according to sex-specific quintiles of baseline leptin concentrations, in men and women , the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 80K, Relative risks (RR-s) and 95% confidence intervals (CI-s) of colon, rectal and colorectal cancer according to quintiles of free leptin index (FLI), the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

BackgroundCertain infectious agents are recognised causes of cancer and potentially other chronic diseases. Identifying associations and understanding pathological mechanisms involving infectious agents and subsequent chronic disease risk will be possible through measuring exposure to multiple infectious agents in large-scale prospective cohorts such as UK Biobank.MethodsFollowing expert consensus we designed a Multiplex Serology platform capable of simultaneously measuring quantitative antibody responses against 45 antigens from 20 infectious agents implicated in non-communicable diseases, including human herpes, hepatitis, polyoma, papilloma, and retroviruses, as well asChlamydia trachomatis, Helicobacter pyloriandToxoplasma gondii. This panel was assayed in a random subset of UK Biobank participants (n=9,695) to test associations between infectious agents and recognised demographic and genetic risk factors and disease outcomes.FindingsSeroprevalence estimates for each infectious agent were consistent with those expected from the literature. The data confirmed epidemiological associations of infectious agent antibody responses with sociodemographic characteristics (e.g. lifetime sexual partners withC, trachomatis;P=1·8×10−149), genetic variants (e.g. rs6927022 with Epstein-Barr virus (EBV) EBNA1 antibodies,P=9·5×10−91) and disease outcomes including human papillomavirus-16 seropositivity and cervical intraepithelial neoplasia (odds ratio 2·28, 95% confidence interval 1·38-3·63), and quantitative EBV viral capsid antigen responses and multiple sclerosis through genetic correlation (MHC rG=0·30,P=0·01).InterpretationThis dataset, intended as a pilot study to demonstrate applicability of Multiplex Serology in epidemiological studies, is itself one of the largest studies to date covering diverse infectious agents in a prospective UK cohort including those traditionally under-represented in population cohorts such as human immunodeficiency virus-1 andC. trachomatis. Our results emphasise the validity of our Multiplex Serology approach in large-scale epidemiological studies opening up opportunities for improving our understanding of host-pathogen-disease relationships. These data are available to researchers interested in examining the relationship between infectious agents and human health.

BACKGROUND: Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)−1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. RESULTS: In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22–1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66–2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67–0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. CONCLUSIONS: Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.

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.

An increasing number of people are now living with cardiovascular disease (CVD), with concomitant CVD-related hospitalizations, operations, and prescriptions. To ultimately deliver optimal cardiovascular care, access to population-based biobanks with data on multiomics, phenotypes, and lifestyle risk factors are crucial. UK Biobank is a cohort study that incorporated data between 2006 and 2010 from over half a million individuals (40 to 69 years of age) at recruitment from across the United Kingdom. As one of the most accessible, largest, and in-depth cohort studies in the world, UK Biobank continues to enhance the resource with the addition of data from various omics platforms (eg, genomics, metabolomics, proteomics), multimodal imaging, self-reported risk factors and health outcomes, and linkage to electronic health records. The vision of UK Biobank is to allow as many researchers as possible to apply their expertise and imagination to undertake research to prevent, diagnose, and treat a wide range of chronic conditions, including CVD.

BackgroundKidney stone disease (KSD) is linked to obesity, metabolic syndrome and biochemical alterations including higher serum calcium concentration. The mechanisms by which these phenotypes associate with KSD are uncertain. We aimed to establish the effects of adiposity on KSD using conventional and genetic epidemiological techniques.MethodsWe assessed observational associations between measures of adiposity and incident KSD in 479,405 people from the UK Biobank. To facilitate Mendelian randomization (MR) analyses, we undertook genome-wide association studies (GWAS) of KSD in the UK Biobank in combined and sex-specific subsets. Univariable, multivariable and mediation MR analyses were used to calculate odds ratio (OR) or beta coefficient (ß) for risk of KSD per genetically instrumented higher marker of adiposity, metabolic syndrome parameter, biochemical phenotype, and inflammation and identify violations of MR assumptions.FindingsObservational analyses demonstrated that measures of central adiposity (waist-to-hip ratio (WHR) and waist circumference (WC)) are more strongly associated with incident KSD than measures of general adiposity (body mass index (BMI)). Three novel KSD-GWAS loci were identified (SLC2A12, TRPV5, and SLC28A1); no sex-specific loci were detected. MR analyses established that higher central adiposity is causally linked to both KSD and higher adjusted serum calcium concentrations independent of BMI (one standard deviation higher WHR: OR for KSD=1·43, p=4·1×10−6; ß for serum calcium concentration=0·11mmol/L, p=2·7×10−7). Mediation analyses indicated that 12% of the effect of WHR on KSD is due its role in elevating serum calcium concentration. Our MR studies indicated that other components of the metabolic syndrome, serum uric acid levels, and biomarkers of inflammation are unlikely to be implicated in the causation of KSD.InterpretationOur study indicates that visceral adipose depots elevate serum calcium concentration and cause an increased risk of KSD. Therapies targeting central adipose deposition may affect calcium homeostasis and have utility for the prevention of KSD.

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− 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.

Background Fluid intake and diet are thought to influence kidney stone risk. However, prospective studies have been limited to small samples sizes and/or restricted measures. Objective To investigate whether fluid intake and dietary factors are associated with the risk of developing a first kidney stone. Design, setting, and participants Participants were selected from UK Biobank, a population-based prospective cohort study. Outcome measurements and statistical analysis Cox proportional hazards models were used to investigate the association between fluid intake and dietary factors and the risk of a first incident kidney stone, ascertained from hospital inpatient records. Results and limitations After exclusion, 439 072 participants were available for the analysis, of whom 2057 had hospital admission with an incident kidney stone over a mean of 6.1 yr of follow-up. For every additional drink (200 ml) consumed per day of total fluid, the risk of kidney stones declined by 13% (hazard ratio [HR] = 0.87, 95% confidence interval [CI] 0.85–0.89). Similar patterns of associations were observed for tea, coffee, and alcohol, although no association was observed for water intake. Fruit and fibre intake was also associated with a lower risk (HR per 100 g increase of fruits per day = 0.88, 95% CI 0.83–0.93, and HR per 10 g fibre per day = 0.82, 95% CI 0.77–0.87), whereas meat and salt intake was associated with a higher risk (HR per 50 g increase in meat per week = 1.17, 95% CI 1.05–1.29, and HR for always vs never/rarely added salt to food = 1.33, 95% CI 1.12–1.58). Vegetable, fish, and cheese intake was not associated with kidney stone risk. Conclusions The finding that high intake of total fluid, fruit, and fibre was associated with a lower risk of hospitalisation for a first kidney stone suggests that modifiable dietary factors could be targeted to prevent kidney stone development. Patient summary We found that higher intake of total fluid, specifically tea, coffee, and alcohol (but not water), and consumption of fruit and foods high in fibre are linked with a reduced likelihood of developing kidney stones.

Previous studies on the association of adiposity with endometrial cancer risk have mostly used body mass index (BMI) as the main exposure of interest. Whether more precise measures of body fat, such as body fat percentage and fat mass estimated by bioimpedance analyses, are better indicators of risk than BMI is unknown. The role of central adiposity and fat-free mass in endometrial cancer development remains unclear. We used Cox regression models to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI) for the associations of various measures of body size/composition with the risk of endometrial cancer among 135 110 postmenopausal women enrolled in UK Biobank. During a mean follow up of 6.8 years, 706 endometrial cancers were diagnosed, with a mean age at diagnosis of 65.5 years. The HRs (95% CIs) for endometrial cancer per 1 SD increase in BMI, body fat percentage and fat mass were broadly comparable, being 1.71 (1.61-1.82), 1.92 (1.75-2.11) and 1.73 (1.63-1.85), respectively. There was an indication of positive association between central adiposity, as reflected by waist circumference (HRper 1-SD increase = 1.08, 95% CI: 1.00-1.17) and waist to hip ratio (HRper 1-SD increase = 1.13, 95% CI: 1.01-1.26), and endometrial cancer risk after accounting for BMI. Fat-free mass was not an independent predictor of risk in this cohort. These findings suggest that body fat percentage and fat mass are not better indicators of endometrial cancer risk than BMI. Further studies are needed to establish whether central adiposity contributes to risk beyond overall adiposity.