Publications by authors named "Robert N Luben"

171 Publications

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Breast Cancer Res 2021 Aug 18;23(1):86. Epub 2021 Aug 18.

Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.

Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).

Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.

Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
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http://dx.doi.org/10.1186/s13058-021-01450-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371820PMC
August 2021

Long Term Prognostic Impact of Sex-specific Longitudinal Changes in Blood Pressure. The EPIC-Norfolk Prospective Population Cohort Study.

Eur J Prev Cardiol 2021 Jul 5. Epub 2021 Jul 5.

Aberdeen Diabetes and Cardiovascular Centre, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Room 4:013, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK.

Aims: We aimed to determine the sex differences in longitudinal systolic and diastolic blood pressure (SBP and DBP) trajectories in mid-life and delineate the associations between these and mortality (all-cause, cardiovascular, and non-cardiovascular) and incident cardiovascular disease (CVD) in old age.

Methods And Results: Participants were selected from the European Prospective Investigation into Cancer, Norfolk (EPIC-Norfolk) cohort study. Sex-specific trajectories were determined using group-based trajectory models using three clinic BP measurements acquired between 1993 and 2012 (mean exposure ∼12.9 years). Multivariable Cox regressions determined the associations between trajectories and incident outcomes over the follow-up (median follow-up 9.4 years). A total of 2897 men (M) and 3819 women (F) were included. At baseline, women were younger (F-55.5, M-57.1), had a worse cardiometabolic profile and were less likely to receive primary CVD prevention including antihypertensive treatment (F-36.0%, M-42.0%). Over the exposure period, women had lower SBP trajectories while men exhibited more pronounced SBP decreases over this period. Over the follow-up period, women had lower mortality (F-11.9%, M-20.5%) and CVD incidence (F-19.8%, M-29.6%). Compared to optimal SBP (≤120 mmHg) and DBP (≤70 mmHg) trajectories, hypertensive trajectories were associated with increased mortality and incident CVD in both men and women during follow-up at univariable level. These associations were nevertheless not maintained upon extensive confounder adjustment including antihypertensive therapies.

Conclusion: We report sex disparities in CVD prevention which may relate to worse cardiometabolic profiles and less pronounced longitudinal SBP decreases in women. Effective anti-hypertensivetherapy may offset the adverse outcomes associated with prolonged exposure to high blood pressure.
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http://dx.doi.org/10.1093/eurjpc/zwab104DOI Listing
July 2021

Association between serum secretory phospholipase A2 and risk of ischaemic stroke.

Eur J Neurol 2021 Jul 3. Epub 2021 Jul 3.

Ageing Clinical and Experimental Research, Institute of Applied Health Sciences, Aberdeen, UK.

Background And Purpose: Previous literature has demonstrated an association between high serum levels of type II secretory phospholipase A2 (sPLA2) concentration and an increased risk of coronary artery disease. However, such association has not been established in terms of ischaemic stroke risk. The aim was to evaluate the association between both sPLA2 concentration and activity as continuous variables with risk of future ischaemic stroke.

Methods: A nested case-control study was conducted using data from the European Prospective Investigation into Cancer-Norfolk study. Cases (n = 145) in the current study were participants who developed ischaemic stroke during follow-up, with controls (n = 290) matched in a 2:1 ratio based on age and sex. Statistical analyses were performed using SPSS (version 25.0) software. Logistic regression was used to determine odds ratios (OR) and corresponding 95% confidence intervals (95% CIs) for ischaemic stroke.

Results: After adjusting for a wide array of cardiovascular confounders, sPLA2 activity was found to be associated with an increased risk of ischaemic stroke using both multiple imputations with chained equations and complete case analysis: OR 1.20 (95% CI 1.01-1.43) and OR 1.23 (95% CI 1.01-1.49), respectively. However, sPLA2 concentration was not found to be associated with increased risk of ischaemic stroke.

Conclusions: The activity of sPLA2, but not sPLA2 concentration, is associated with an increased risk of future ischaemic stroke. This finding may be significant in risk group stratification, allowing targeted prophylactic treatment, or the development of novel therapeutic agents.
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http://dx.doi.org/10.1111/ene.15004DOI Listing
July 2021

The relationship between alcohol intake and falls hospitalization: Results from the EPIC-Norfolk.

Geriatr Gerontol Int 2021 Aug 22;21(8):657-663. Epub 2021 Jun 22.

Ageing Clinical & Experimental Research (ACER) Team, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.

Aim: To evaluate the relationship between habitual alcohol consumption and the risk of falls hospitalization.

Methods: The EPIC-Norfolk is a prospective population-based cohort study in Norfolk, UK. In total, 25 637 community dwelling adults aged 40-79 years were recruited. Units of alcohol consumed per week were measured using a validated Food Frequency Questionnaire. The main outcome was the first hospital admission following a fall.

Results: Over a median follow-up period of 11.5 years (299 211 total person years), the cumulative incidence function (95% confidence interval) of hospitalized falls at 121-180 months for non-users, light (>0 to ≤7 units/week), moderate (>7 to ≤28 units/week) and heavy (>28 units/week) were 11.08 (9.94-12.35), 7.53 (7.02-8.08), 5.91 (5.29-6.59) and 8.20 (6.35-10.56), respectively. Moderate alcohol consumption was independently associated with a reduced risk of falls hospitalization after adjustment for most major confounders (hazard ratio = 0.88; 95% confidence interval 0.79-0.99). The relationship between light alcohol consumption and falls hospitalization was attenuated by gender differences. Alcohol intake higher than the recommended threshold of 28 units/week was associated with an increased risk of falls hospitalization (hazard ratio 1.40 [1.14-1.73]).

Conclusions: Moderate alcohol consumption appears to be associated with a reduced risk of falls hospitalization, and intake above the recommended limit is associated with an increased risk. This provides incentive to limit alcohol consumption within the recommended range and has important implications for public health policies for aging populations. Geriatr Gerontol Int 2021; 21: 657-663.
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http://dx.doi.org/10.1111/ggi.14219DOI Listing
August 2021

Alcohol Consumption and Incident Cataract Surgery in Two Large UK Cohorts.

Ophthalmology 2021 Jun 8;128(6):837-847. Epub 2021 Feb 8.

NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust & UCL Institute of Ophthalmology, London, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

Purpose: To examine the association of alcohol consumption and type of alcoholic beverage with incident cataract surgery in 2 large cohorts.

Design: Longitudinal, observational study.

Participants: We included 469 387 participants of UK Biobank with a mean age of 56 years and 23 162 participants of European Prospective Investigation of Cancer (EPIC)-Norfolk with a mean age of 59 years.

Methods: Self-reported alcohol consumption at baseline was ascertained by a touchscreen questionnaire in UK Biobank and a food-frequency questionnaire in EPIC-Norfolk. Cases were defined as participants undergoing cataract surgery in either eye as ascertained via data linkage to National Health Service procedure statistics. We excluded participants with cataract surgery up to 1 year after the baseline assessment visit or those with self-reported cataract at baseline. Cox proportional hazards models were used to examine the associations of alcohol consumption with incident cataract surgery, adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index (BMI), smoking, and diabetes status.

Main Outcome Measures: Incident cataract surgery.

Results: There were 19 011 (mean cohort follow-up of 95 months) and 4573 (mean cohort follow-up of 193 months) incident cases of cataract surgery in UK Biobank and EPIC-Norfolk, respectively. Compared with nondrinkers, drinkers were less likely to undergo cataract surgery in UK Biobank (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.93) and EPIC-Norfolk (HR, 0.90; 95% CI, 0.84-0.97) after adjusting for covariables. Among alcohol consumers, greater alcohol consumption was associated with a reduced risk of undergoing cataract surgery in EPIC-Norfolk (P < 0.001), whereas a U-shaped association was observed in the UK Biobank. Compared with nondrinkers, subgroup analysis by type of alcohol beverage showed the strongest protective association with wine consumption; the risk of incident cataract surgery was 23% and 14% lower among those in the highest category of wine consumption in EPIC-Norfolk and UK Biobank, respectively.

Conclusions: Our findings suggest a lower risk of undergoing cataract surgery with low to moderate alcohol consumption. The association was particularly apparent with wine consumption. We cannot exclude the possibility of residual confounding, and further studies are required to determine whether this association is causal in nature.
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http://dx.doi.org/10.1016/j.ophtha.2021.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162662PMC
June 2021

Positive Associations of Dietary Intake and Plasma Concentrations of Vitamin E with Skeletal Muscle Mass, Heel Bone Ultrasound Attenuation and Fracture Risk in the EPIC-Norfolk Cohort.

Antioxidants (Basel) 2021 Jan 22;10(2). Epub 2021 Jan 22.

Department of Epidemiology and Public Health, Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich NR4 7TJ, UK.

The prevalence of sarcopenia, frailty and fractures is increasing. Prevention options are limited, but dietary factors including vitamin E have the potential to confer some protection. This study investigated cross-sectional associations between dietary and plasma concentrations of vitamin E with indices of skeletal muscle mass (SMM) ( = 14,179 and 4283, respectively) and bone density ( = 14,694 and 4457, respectively) and longitudinal fracture risk ( = 25,223 and 7291, respectively) in European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk participants, aged 39-79 years at baseline. Participants completed a health and lifestyle questionnaire, a 7-day diet diary (7dDD) and had anthropometric measurements taken. Fat-free mass (as a SMM proxy) was measured using bioimpedance and bone density was measured using calcaneal broadband ultrasound attenuation (BUA) and incident fractures over 18.5 years of follow-up. Associations between indices of SMM, BUA and fracture risk were investigated by quintiles of dietary vitamin E intake or plasma concentrations. Positive trends in SMM indices and BUA were apparent across dietary quintiles for both sexes, with interquintile differences of 0.88%-1.91% ( < 0.001), and protective trends for total and hip fracture risk. Circulating plasma α- and γ-tocopherol results matched the overall dietary findings. Dietary vitamin E may be important for musculoskeletal health but further investigation is required to fully understand the relationships of plasma tocopherols.
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http://dx.doi.org/10.3390/antiox10020159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911901PMC
January 2021

Calcium intake, calcium supplementation and cardiovascular disease and mortality in the British population: EPIC-norfolk prospective cohort study and meta-analysis.

Eur J Epidemiol 2021 Jul 31;36(7):669-683. Epub 2020 Dec 31.

Ageing Clinical and Experimental Research (ACER) Team, University of Aberdeen, Aberdeen, UK.

The role of dietary calcium in cardiovascular disease prevention is unclear. We aimed to determine the association between calcium intake and incident cardiovascular disease and mortality. Data were extracted from the European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk). Multivariable Cox regressions analysed associations between calcium intake (dietary and supplemental) and cardiovascular disease (myocardial infarction, stroke, heart failure, aortic stenosis, peripheral vascular disease) and mortality (cardiovascular and all-cause). The results of this study were pooled with those from published prospective cohort studies in a meta-analsyis, stratifying by average calcium intake using a 700 mg/day threshold. A total of 17,968 participants aged 40-79 years were followed up for a median of 20.36 years (20.32-20.38). Compared to the first quintile of calcium intake (< 770 mg/day), intakes between 771 and 926 mg/day (second quintile) and 1074-1254 mg/day (fourth quintile) were associated with reduced all-cause mortality (HR 0.91 (0.83-0.99) and 0.85 (0.77-0.93), respectively) and cardiovascular mortality [HR 0.95 (0.87-1.04) and 0.93 (0.83-1.04)]. Compared to the first quintile of calcium intake, second, third, fourth, but not fifth quintiles were associated with fewer incident strokes: respective HR 0.84 (0.72-0.97), 0.83 (0.71-0.97), 0.78 (0.66-0.92) and 0.95 (0.78-1.15). The meta-analysis results suggest that high levels of calcium intake were associated with decreased all-cause mortality, but not cardiovascular mortality, regardless of average calcium intake. Calcium supplementation was associated with cardiovascular and all-cause mortality amongst women, but not men. Moderate dietary calcium intake may protect against cardiovascular and all-cause mortality and incident stroke. Calcium supplementation may reduce mortality in women.
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http://dx.doi.org/10.1007/s10654-020-00710-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403619PMC
July 2021

Long-term effects of gestational diabetes on bone mineral density and fracture risk: Analysis of the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) population-based study.

Maturitas 2021 Feb 18;144:68-73. Epub 2020 Nov 18.

School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, Scotland, UK. Electronic address:

Objectives: Gestational diabetes mellitus (GDM) is a common pregnancy complication. This study aims to investigate the association between a history of GDM and bone mineral density (BMD), fractures, and falls in later life.

Study Design: We used data from the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) where BMD at calcaneum was measured at second health check (1997-2000) using broadband ultrasound attenuation (BUA) and velocity of sound (VOS) in 7,515 women. Fractures and falls were documented from hospital admissions data via linkage with ENCORE (East Norfolk Commission Record) and history of GDM from health questionnaires at baseline. We examined the relationship between GDM and BUA/VOS using linear regression. Cox regression was used to estimate hazard ratios (HRs) for incident fractures and falls, controlling for age, BMI, smoking status, physical activity, area deprivation, self-reported stroke, use of diuretics, calcium and vitamin D supplements, social class and education, statin and total blood cholesterol, prevalent diabetes, hormone therapy and menopausal status.

Results: History of GDM (n = 183) was not statistically significantly associated with BUA/VOS in fully adjusted linear regression models with unstandardised beta coefficients (standard error): -0.37 (1.40) and -5.41 (3.48). GDM was significantly (p < 0.05) associated with risk of hip and all fractures, fully adjusted HRs(95 %CI) 2.46(1.54-3.92) and 1.60(1.09-2.35), respectively. Median follow-up from first live birth to date of admission was 53 and 52 years, respectively.

Conclusion: There was an association between history of GDM and risk of any fracture as well as hip fracture specifically. Further research is required to confirm this.
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http://dx.doi.org/10.1016/j.maturitas.2020.11.005DOI Listing
February 2021

Anticholinergic medication exposure predicts poor physical capability: Findings from a large prospective cohort study in England.

Maturitas 2020 Dec 25;142:55-63. Epub 2020 Jul 25.

Ageing Clinical & Experimental Research (ACER) Team, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; Department of Medicine for the Elderly, Aberdeen Royal Infirmary, Aberdeen, UK. Electronic address:

Objectives: To examine whether anticholinergic medication exposure in middle and late life is associated with physical capability.

Study Design: We used data from 8477 men and women who had enrolled in the European Prospective Investigation of Cancer-Norfolk study at baseline (1HC; 1993-1997) and who had attended its third health examination (3HC; 2004-2010). Medication history at the 1HC and 3HC was used to score participants according to the Anticholinergic Cognitive Burden (ACB) Scale at baseline and 3HC; participants were categorised as ACB = 0, ACB = 1, ACB>2.

Main Outcome Measure: At 3HC, physical capability was objectively measured by: usual walking speed, maximum grip strength, timed chair stands speed (TCSS) and standing balance. Linear and logistic regression models examined prospective and cross-sectional associations between ACB and physical capability, controlling for co-morbidity, sociodemographic and lifestyle factors.

Results: The analyses included 3386 men and 4110 women who were 56.4 (SD 7.9) and 55.0 (7.7) years old respectively at baseline and 69.4 (8.1) and 67.9 (8.0) years old at follow-up. Significant cross-sectional and prospective relationships were observed for all physical capability measures in women, except grip strength. For example, women with ACB ≥ 2 compared with ACB = 0 at baseline had 0.07 m/s (95 % CI -0.11, -0.03) slower usual walking speed, 2.61 stands/min (-4.17, -1.05) slower TCSS and higher odds of being unable to complete a tandem stand (odds ratio 2.40, 95 % CI 1.53, 3.76). These trends were observed in men but were less consistent in prospective analyses.

Conclusion: Exposure to anticholinergic medication predicts poor physical capability and is a potentially reversible risk factor.
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http://dx.doi.org/10.1016/j.maturitas.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656240PMC
December 2020

Hypertensive Disorders of Pregnancy (HDP) and the Risk of Common Cancers in Women: Evidence from the European Prospective Investigation into Cancer (EPIC)-Norfolk Prospective Population-Based Study.

Cancers (Basel) 2020 Oct 23;12(11). Epub 2020 Oct 23.

Aberdeen Centre for Women's Health Research, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen AB25 2ZL, UK.

Purpose: The purpose was to determine the association between HDP and cancer in a UK cohort.

Methods: Between 1993 and 1997, participants from the EPIC-Norfolk cohort attended baseline health-checks and completed questionnaires, where a history of HDP was collected. Incident cancer cases were identified through NHS record linkage until March 2016. Univariable and multivariable logistic regression analyses were employed to determine the association between HDP and odds of cancer, with adjustment for potential confounders including co-morbidities, sociodemographic, lifestyle and reproductive factors.

Results: 13,562 women were included after excluding prevalent cancer cases and women with no pregnancies. 2919 (21.5%) reported HDP and 2615 incident cancers occurred during mean follow up of 19 years. Median age (IQR) at baseline for incident cancer was 60.8 (±14.8) years. Among incident cancer cases, 578 (22.1%) had HDP. In multivariable analyses, HDP had odds ratio (OR) 1.06; 95% CI 0.95-1.18 for incident cancer. The ORs (95% CIs) for common site-specific cancers including breast, colorectal, lung, ovarian and endometrial cancers were 1.06 (0.88-1.28), 1.15 (0.92-1.45), 0.96 (0.68-1.35), 1.30 (0.93-1.83) and 1.16 (0.80-1.67).

Conclusion: We found no association between HDP and cancer risk. Further studies are required to confirm and account for any underlying genetic factors involved in pregnancy-related exposures and cancer risk.
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http://dx.doi.org/10.3390/cancers12113100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690818PMC
October 2020

Dietary acid-base load and its association with risk of osteoporotic fractures and low estimated skeletal muscle mass.

Eur J Clin Nutr 2020 08;74(Suppl 1):33-42

Department of Population Health and Primary Care, Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.

Background/objectives: Age-related decline in skeletal muscle mass and strength, loss of bone density, and increased risk of osteoporotic fractures are important public health issues. Systemic acid-base balance is affected by dietary intake and may be relevant to these conditions. We therefore investigated associations of dietary acid-base load with skeletal muscle mass, bone density status, and fracture risk.

Subjects/methods: We analysed the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort of >25,000 individuals, 39-79 years at baseline. Potential renal acid load (PRAL) was calculated from 7-day food diary data. As a proxy for skeletal muscle mass, we estimated fat-free mass from bioelectrical impedance analysis and scaled this for BMI (FFM). Bone density status was assessed by heel-bone broadband ultrasound attenuation (BUA), and fracture rates were obtained from health-care records. Multivariable regression was used to test musculoskeletal outcomes across sex-specific quintiles of PRAL.

Results: PRAL in quintiles was negatively associated with FFM in men (n = 6350, p < 0.001) and women (n = 7989, p < 0.001), with quintile 5 vs 1 differences of -1.5% and -3.2% (both p < 0.001). PRAL was also negatively associated with BUA in women (n = 8312, p = 0.016; quintile 5 vs 1 difference -1.5%, p = 0.024). The combined hazard of hip, wrist and spine fractures (mean ± SD follow-up 17.9 ± 4.9 years) was higher with increasing quintiles of PRAL in men (610 fractures; n = 11,511; p = 0.013) and women (1583 fractures; n = 13,927; p = 0.009), with quintile 5 vs 1 hazard ratios of 1.33 (95% CI: 1.03-1.72, p = 0.029) and 1.21 (95% CI: 1.03-1.42, p = 0.022), but associations were not consistent for all fractures sites and age groups tested.

Conclusions: This study provides strong evidence, albeit observational, for a negative association between PRAL and musculoskeletal health in middle to older age men and women, and thus supports the rationale for a less acidic dietary load.
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http://dx.doi.org/10.1038/s41430-020-0686-4DOI Listing
August 2020

Lower Dietary and Circulating Vitamin C in Middle- and Older-Aged Men and Women Are Associated with Lower Estimated Skeletal Muscle Mass.

J Nutr 2020 10;150(10):2789-2798

Department of Epidemiology and Public Health, Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, United Kingdom.

Background: Age-related loss of skeletal muscle mass contributes to poor outcomes including sarcopenia, physical disability, frailty, type 2 diabetes, and mortality. Vitamin C has physiological relevance to skeletal muscle and may protect it during aging, but few studies have investigated its importance in older populations.

Objectives: We aimed to investigate cross-sectional associations of dietary and plasma vitamin C with proxy measures of skeletal muscle mass in a large cohort of middle- and older-aged individuals.

Methods: We analyzed data from >13,000 men and women in the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, aged 42-82 y. Fat-free mass (FFM), as a proxy for skeletal muscle mass, was estimated using bioelectrical impedance analysis and expressed as a percentage of total mass (FFM%) or standardized by BMI (FFMBMI). Dietary vitamin C intakes were calculated from 7-d food diary data, and plasma vitamin C was measured in peripheral blood. Multivariable regression models, including relevant lifestyle, dietary, and biological covariates, were used to determine associations between FFM measures and quintiles of dietary vitamin C or insufficient compared with sufficient plasma vitamin C (<50 μmol/L and ≥50 μmol/L).

Results: Positive trends were found across quintiles of dietary vitamin C and FFM measures for both sexes, with interquintile differences in FFM% and FFMBMI of 1.0% and 2.3% for men and 1.9% and 2.9% for women, respectively (all P < 0.001). Similarly, FFM% and FFMBMI measures were higher in participants with sufficient than with insufficient plasma vitamin C: by 1.6% and 2.0% in men, and 3.4% and 3.9% in women, respectively (all P < 0.001). Associations were also evident in analyses stratified into <65-y and ≥65-y age groups.

Conclusions: Our findings of positive associations, of both dietary and circulating vitamin C with measures of skeletal muscle mass in middle- and older-aged men and women, suggest that dietary vitamin C intake may be useful for reducing age-related muscle loss.
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http://dx.doi.org/10.1093/jn/nxaa221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549302PMC
October 2020

Baseline anticholinergic burden from medications predicts poorer baseline and long-term health-related quality of life in 16 675 men and women of EPIC-Norfolk prospective population-based cohort study.

Pharmacoepidemiol Drug Saf 2021 02 5;30(2):135-143. Epub 2020 Aug 5.

Ageing Clinical & Experimental Research (ACER) Team, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.

Purpose: Previous studies investigating the association between anticholinergic burden (ACB) and health-related quality of life (HRQoL) showed conflicting results and focused on older adults or specific patient groups only.

Methods: Participants from the European Prospective Investigation of Cancer-Norfolk study were divided into three groups according to their ACB from medications at baseline, representing ACB scores of 0, 1 and ≥2. Outcomes of interest were the physical and mental component summary scores (PCS and MCS) of the Short Form-36, collected at 18 months from the baseline and again after a mean 13 years of follow-up. Linear regression and logistic regression for cross-sectional and longitudinal associations between ACB and HRQoL were constructed adjusting for potential confounders.

Results: A total of 16 675 participants, mean age 58.9 ± 9.1 years (55.6% female) and 7133 participants, mean age at follow-up 69.1 ± 8.7 years (56.8% female), were included in the cross-sectional and longitudinal analyses, respectively. In cross-sectional analysis, higher anticholinergic burden was associated with higher odds of being in the lowest quartile of PCS (ACB = 1; OR, 1.85[1.64, 2.09] and ACB ≥ 2:2.19[1.85, 2.58] and MCS (ACB = 1:1.47[1.30, 1.66] and ACB ≥ 2:1.68[1.42, 1.98]). In longitudinal analysis, higher anticholinergic burden was similarly associated with higher odds of being in the lowest quartile of PCS (ACB = 1:1.56[1.24, 1.95] and ACB ≥ 2:1.48[1.07, 2.03]) compared with ACB 0 group. The association with MCS scores did not reach statistical significance.

Conclusion: The use of anticholinergic medications is associated with both short and long-term poorer physical functions but association with mental functioning appears more short-term.
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http://dx.doi.org/10.1002/pds.5085DOI Listing
February 2021

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Sci Rep 2020 06 16;10(1):9688. Epub 2020 Jun 16.

Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41598-020-65665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297796PMC
June 2020

A Mediterranean Diet Is Positively Associated with Bone and Muscle Health in a Non-Mediterranean Region in 25,450 Men and Women from EPIC-Norfolk.

Nutrients 2020 Apr 21;12(4). Epub 2020 Apr 21.

Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich NR4 7UQ, UK.

Research on Mediterranean diet (MD) adherence and musculoskeletal health is limited. The current study determined if adherence to the alternative MD score (aMED) and MD score (MDS), quantified from 7-d food diaries, was associated with fracture incidence, bone density (calcaneal broadband ultrasound attenuation (BUA)) and fat free mass (expressed over BMI (FFM) using bioelectrical impedance) in 25,450 men and women recruited to the European Prospective Investigation into Cancer study in Norfolk, UK. During 17.4 years of follow up (443,178 total person years) 2195 incident fractures occurred. Higher aMED adherence was associated with 23% reduced total (Q5-Q1 HR 0.77; 95% CI 0.67, 0.88; -trend < 0.01) and 21% reduced hip (Q5-Q1 HR 0.79; 95% CI 0.65, 0.96; -trend = 0.01) fracture incidence, and significantly higher BUA (Q5-Q1 1.0 dB/MHz 95% CI 0.2, 1.9; -trend < 0.01) and FFM (Q5-Q1 0.05 kg/(kg/m) 95% CI 0.04, 0.06; -trend < 0.01), comparing extreme adherence quintiles. Higher MDS was also associated with reduced total fractures (Q5-Q1 HR 0.83; 95% CI 0.71, 0.96; -trend = 0.03) and significantly higher BUA (Q5-Q1 1.4 dB/MHz 95% CI 0.5, 2.3; -trend < 0.01) and FFM (Q5-Q1 0.03 kg/(kg/m) 95% CI 0.01, 0.04; -trend < 0.01). This evidence supports the need to develop interventions to enhance MD adherence, particularly in women, where evidence for associations was stronger.
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http://dx.doi.org/10.3390/nu12041154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231007PMC
April 2020

Use of Medications with Anticholinergic Properties and the Long-Term Risk of Hospitalization for Falls and Fractures in the EPIC-Norfolk Longitudinal Cohort Study.

Drugs Aging 2020 02;37(2):105-114

Clinical Gerontology Unit, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

The consumption of medications with anticholinergic activity has been suggested to result in the adverse effects of mental confusion, visual disturbance, and muscle weakness, which may lead to falls. Existing published evidence linking anticholinergic drugs with falls, however, remains weak. This study was conducted to evaluate the relationship between anticholinergic cognitive burden (ACB) and the long-term risk of hospitalization with falls and fractures in a large population study. The dataset comprised information from 25,639 men and women (aged 40-79 years) recruited from 1993 to 1997 from Norfolk, United Kingdom into the European Prospective Investigation into Cancer (EPIC)-Norfolk study. The time to first hospital admission with a fall with or without fracture was obtained from the National Health Service hospital information system. Cox-proportional hazards analyses were conducted to adjust for confounders and competing risks. The fall hospitalization rate was 5.8% over a median follow-up of ~ 19.4 years. The unadjusted incidence rate ratio for the use of any drugs with anticholinergic properties was 1.79 (95% CI 1.66-1.93). The hazard ratios (95% CI) for ACB scores of 1, 2-3, and ≥ 4 compared with ACB = 0 for fall hospitalization were 1.20 (1.09-1.33), 1.42 (1.25-1.60), and 1.39 (1.21-1.60) after adjustment for age, gender, medical conditions, physical activity, and blood pressure. Medications with anticholinergic activity are associated with an increased risk of subsequent hospitalization with a fall over a 19-year follow-up period. The biological mechanisms underlying the long-term risk of hospitalization with a fall or fracture following baseline ACB exposure remains unclear and requires further evaluation.
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http://dx.doi.org/10.1007/s40266-019-00731-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115837PMC
February 2020

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

25University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX USA.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.
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http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019

Changes in waist circumference and risk of all-cause and CVD mortality: results from the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) cohort study.

BMC Cardiovasc Disord 2019 10 28;19(1):238. Epub 2019 Oct 28.

European Prospective Investigation into Cancer and Nutrition, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Worts Causeway, Cambridge, UK.

Background: Measures of abdominal adiposity are strongly associated with all-cause mortality and cardiovascular disease (CVD). However, data are limited and conflicting regarding the consequences of changes in body fat distribution. The main aims of this paper are to investigate the association between changes in waist circumference (WC) and all-cause and CVD mortality and to examine these changes in relation to concurrent changes in weight.

Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study recruited 25,639 participants between 1993 and 1997, aged 39-79, a number of whom also attended a second examination (1998-2000), and were followed up to 2016 for mortality. Participants were eligible for inclusion if they had WC, weight and height measurements at both time-points; those with a self-reported history of CVD or cancer, body mass index < 18.5 kg/m2 or missing data on covariates were excluded, leaving 12,337 participants for analyses. The median (IQR) follow-up time was 16.4 (15.7, 17.2) years. Hazard Ratios (HRs) for all-cause (2866 deaths) and CVD mortality (822 deaths), by categories of WC change, were determined using Cox proportional hazards analyses.

Results: After multivariable adjustment, the HRs (95% CIs) for all-cause mortality for men and women with a WC gain (WCG) >  5 cm were 1.51 (1.29-1.75) and 1.25 (1.06-1.46) respectively. For CVD mortality in men and women with a WCG >  5 cm, the HRs were 1.84 (1.39-2.43) and 1.15 (0.85-1.55) respectively. In analyses of concurrent changes in WC and weight, the greatest risk (HRs) (95% CIs) in men occurred with weight loss and WCG: 1.80 (1.13-2.86) for all-cause and 2.22 (1.03-4.82) for CVD mortality. In women, the greatest risk for both all-cause (HR 1.50 (1.16-1.95)) and CVD mortality (HR 1.81 (1.15-2.85)) was observed in those with weight loss and maintenance of WC (WCM).

Conclusions: Objectively measured WCG > 5 cm, was associated with subsequent higher total mortality risk and higher CVD mortality risk in men. Interventions focusing on preventing increase in central adiposity rather than lowering weight per se in later life may potentially have greater health benefits.
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http://dx.doi.org/10.1186/s12872-019-1223-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819575PMC
October 2019

Plasma Vitamin C Levels: Risk Factors for Deficiency and Association with Self-Reported Functional Health in the European Prospective Investigation into Cancer-Norfolk.

Nutrients 2019 Jul 9;11(7). Epub 2019 Jul 9.

Ageing Clinical & Experimental Research Group, Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.

Background: To investigate the demographic and lifestyles factors associated with vitamin C deficiency and to examine the association between plasma vitamin C level and self-reported physical functional health.

Methods: A population-based cross-sectional study using the European Prospective Investigation into Cancer-Norfolk study. Plasma vitamin C level < 11 µmol/L indicated vitamin C deficiency. Unconditional logistic regression models assessed the association between vitamin C deficiency and potential risk factors. Associations between quartiles of vitamin C and self-reported functional health measured by the 36-item short-form questionnaire (SF-36) were assessed.

Results: After adjustment, vitamin C deficiency was associated with older age, being male, lower physical activity, smoking, more socially deprived area (Townsend index) and a lower educational attainment. Compared to the highest, those in the lowest quartile of vitamin C were more likely to score in the lowest decile of physical function (adjusted odds ratio (aOR): 1.43 (95%CI: 1.21-1.70)), bodily pain (aOR: 1.29 (95% CI: 1.07-1.56)), general health (aOR: 1.4 (95%CI: 1.18-1.66)), and vitality (aOR: 1.23 (95%CI: 1.04-1.45)) SF-36 scores.

Conclusions: Simple public health interventions should be aimed at populations with risk factors for vitamin C deficiency. Poor self-reported functional health was associated with lower plasma vitamin C levels, which may reflect symptoms of latent scurvy.
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http://dx.doi.org/10.3390/nu11071552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682997PMC
July 2019

Disentangling the genetics of lean mass.

Am J Clin Nutr 2019 02;109(2):276-287

Icelandic Heart Association Holtasmari, Kopavogur, Iceland.

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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http://dx.doi.org/10.1093/ajcn/nqy272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500901PMC
February 2019

Plasma vitamin C concentrations and risk of incident respiratory diseases and mortality in the European Prospective Investigation into Cancer-Norfolk population-based cohort study.

Eur J Clin Nutr 2019 11 31;73(11):1492-1500. Epub 2019 Jan 31.

Clinical Gerontology Unit, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Background/objectives: Cancerous and non-cancerous respiratory diseases are common and contribute significantly to global disease burden. We aim to quantify the association between plasma vitamin C concentrations as an indicator of high fruit and vegetable consumption and the risk of incident respiratory diseases and associated mortality in a general population.

Subjects/methods: Nineteen thousand three hundred and fifty-seven men and women aged 40-79 years without prevalent respiratory diseases at the baseline (1993-1997) and participating in the European Prospective Investigation into Cancer (EPIC)-Norfolk study in the United Kingdom were followed through March 2015 for both incidence and mortality from respiratory diseases.

Results: There were a total of 3914 incident events and 407 deaths due to any respiratory diseases (excluding lung cancers), 367 incident lung cancers and 280 lung cancer deaths during the follow-up (total person-years >300,000 years). Cox's proportional hazards models showed that persons in the top quartiles of baseline plasma vitamin C concentrations had a 43% lower risk of lung cancer (hazard ratio (HR) 0.57; 95% confidence interval (CI): 0.41-0.81) than did those in the bottom quartile, independently of potential confounders. The results are similar for any non-cancerous respiratory diseases (HR 0.85; 0.77-0.95), including chronic respiratory diseases (HR 0.81; 0.69-0.96) and pneumonia (HR 0.70; 0.59-0.83). The corresponding values for mortality were 0.54 (0.35-0.81), 0.81 (0.59-1.12), 0.85 (0.44-1.66) and 0.61 (0.37-1.01), respectively. Confining analyses to non-smokers showed 42% and 53% risk reduction of non-smoking-related lung cancer incidence and death.

Conclusions: Higher levels of vitamin C concentrations as a marker of high fruit and vegetable consumption reduces the risk of cancerous and non-cancerous respiratory illnesses including non-smoking-related cancer incidence and deaths.
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http://dx.doi.org/10.1038/s41430-019-0393-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340537PMC
November 2019

The Relation Between Thyroid Function and Anemia: A Pooled Analysis of Individual Participant Data.

J Clin Endocrinol Metab 2018 10;103(10):3658-3667

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.

Context: Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce.

Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.

Design: Individual participant data meta-analysis.

Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162).

Main Outcome Measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).

Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants [overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87)]. Hemoglobin levels were lower in all groups compared with participants with euthyroidism. In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for overt hypothyroidism, 1.18 (1.00 to 1.38) for subclinical hypothyroidism, 1.15 (0.94 to 1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.

Conclusion: Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.
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http://dx.doi.org/10.1210/jc.2018-00481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179176PMC
October 2018

Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies.

Eur Urol 2018 11 1;74(5):585-594. Epub 2018 Aug 1.

Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.

Background: Experimental and clinical evidence implicates testosterone in the aetiology of prostate cancer. Variation across the normal range of circulating free testosterone concentrations may not lead to changes in prostate biology, unless circulating concentrations are low. This may also apply to prostate cancer risk, but this has not been investigated in an epidemiological setting.

Objective: To examine whether men with low concentrations of circulating free testosterone have a reduced risk of prostate cancer.

Design, Setting, And Participants: Analysis of individual participant data from 20 prospective studies including 6933 prostate cancer cases, diagnosed on average 6.8 yr after blood collection, and 12 088 controls in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group.

Outcome Measurements And Statistical Analysis: Odds ratios (ORs) of incident overall prostate cancer and subtypes by stage and grade, using conditional logistic regression, based on study-specific tenths of calculated free testosterone concentration.

Results And Limitations: Men in the lowest tenth of free testosterone concentration had a lower risk of overall prostate cancer (OR=0.77, 95% confidence interval [CI] 0.69-0.86; p<0.001) compared with men with higher concentrations (2nd-10th tenths of the distribution). Heterogeneity was present by tumour grade (p=0.01), with a lower risk of low-grade disease (OR=0.76, 95% CI 0.67-0.88) and a nonsignificantly higher risk of high-grade disease (OR=1.56, 95% CI 0.95-2.57). There was no evidence of heterogeneity by tumour stage. The observational design is a limitation.

Conclusions: Men with low circulating free testosterone may have a lower risk of overall prostate cancer; this may be due to a direct biological effect, or detection bias. Further research is needed to explore the apparent differential association by tumour grade.

Patient Summary: In this study, we looked at circulating testosterone levels and risk of developing prostate cancer, finding that men with low testosterone had a lower risk of prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2018.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195673PMC
November 2018

Circulating isoflavone and lignan concentrations and prostate cancer risk: a meta-analysis of individual participant data from seven prospective studies including 2,828 cases and 5,593 controls.

Int J Cancer 2018 12 29;143(11):2677-2686. Epub 2018 Sep 29.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Phytoestrogens may influence prostate cancer development. This study aimed to examine the association between prediagnostic circulating concentrations of isoflavones (genistein, daidzein, equol) and lignans (enterolactone and enterodiol) and the risk of prostate cancer. Individual participant data were available from seven prospective studies (two studies from Japan with 241 cases and 503 controls and five studies from Europe with 2,828 cases and 5,593 controls). Because of the large difference in circulating isoflavone concentrations between Japan and Europe, analyses of the associations of isoflavone concentrations and prostate cancer risk were evaluated separately. Prostate cancer risk by study-specific fourths of circulating concentrations of each phytoestrogen was estimated using multivariable-adjusted conditional logistic regression. In men from Japan, those with high compared to low circulating equol concentrations had a lower risk of prostate cancer (multivariable-adjusted OR for upper quartile [Q4] vs. Q1 = 0.61, 95% confidence interval [CI] = 0.39-0.97), although there was no significant trend (OR per 75 percentile increase = 0.69, 95 CI = 0.46-1.05, p = 0.085); Genistein and daidzein concentrations were not significantly associated with risk (ORs for Q4 vs. Q1 = 0.70, 0.45-1.10 and 0.71, 0.45-1.12, respectively). In men from Europe, circulating concentrations of genistein, daidzein and equol were not associated with risk. Circulating lignan concentrations were not associated with the risk of prostate cancer, overall or by disease aggressiveness or time to diagnosis. There was no strong evidence that prediagnostic circulating concentrations of isoflavones or lignans are associated with prostate cancer risk, although further research is warranted in populations where isoflavone intakes are high.
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http://dx.doi.org/10.1002/ijc.31640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283047PMC
December 2018

Low thyroid function is not associated with an accelerated deterioration in renal function.

Nephrol Dial Transplant 2019 04;34(4):650-659

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia.

Background: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.

Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.

Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.

Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.
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http://dx.doi.org/10.1093/ndt/gfy071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452200PMC
April 2019

Baseline anticholinergic burden from medications predicts incident fatal and non-fatal stroke in the EPIC-Norfolk general population.

Int J Epidemiol 2018 04;47(2):625-633

Ageing Clinical & Experimental Research (ACER) Team, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.

Background: Stroke is primarily a disease of older age, with a substantial impact on global mortality and morbidity. Medications with anticholinergic effects are widely used, but no studies have been conducted to examine the relationship between anticholinergic burden (ACB) and stroke in a general population.

Method: The sample was drawn from the EPIC-Norfolk cohort. Baseline assessments were carried out during 1993-97 and participants were followed up until March 2016. Participants were divided into four groups according to their total ACB score at baseline; these groups were those with a total ACB score of 0, 1, 2-3 and >3. After exclusion, Cox proportional hazards models were constructed to determine the associations between the ACB score groups and the risk of incident stroke and stroke mortality. Sensitivity analysis and propensity score matched analyses were performed.

Results: In total 25 639 participants attended the first health check; 3917 participants were excluded, leaving 21 722 participants to be included. Participants had a mean age [standard deviation (SD)] of 58.9 (9.2) years (54.4% women). Of these, 2131 suffered incident stroke and 562 died from stroke. Mean follow-up was approximately 18 years for both outcomes. In the fully adjusted model, those with an ACB of >3 had 59% relative risk of incident stroke {hazard ratio [HR] [95% confidence interval (CI) 1.59 [1.34-1.89]} and 86% relative risk of stroke mortality [1.86 (1.37-2.53)] compared with those in ACB 0 category. Sensitivity analyses and propensity score matched analyses showed similar results.

Conclusions: Our results provide an incentive for the cautious use of medications with anticholinergic properties, to help reduce the global burden of stroke.
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http://dx.doi.org/10.1093/ije/dyx265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198932PMC
April 2018

Dimension of pain-related quality of life and self-reported mental health in men and women of the European Prospective Investigation into Cancer-Norfolk cohort: a population-based cross-sectional study.

Br J Pain 2018 Feb 15;12(1):35-46. Epub 2017 Aug 15.

Ageing Clinical and Experimental Research Team, Institute of Applied Health Sciences, The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

Both cognitive and behavioural factors are linked to the experience of pain as well as its interference with quality of life. Psychological distress has been shown to be associated to several emotional and social impairments. Although, the association between pain and mental health has been widely discussed, the understanding of life interference and outcome is not fully understood. This study examined the association of pain dimension and mental health domain in 16,051 participants of the EPIC-Norfolk cohort (mean age = 58.9 ± 9.1 years). Study outcomes were depressive or anxious behaviour and limitations due to emotional problems and impairments in social functioning (mental functional health components of the Short Form-36 (SF-36)). Logistic regression models were constructed controlling for the potentially confounding factors including socio-economic variables (occupational social class, deprivation, marital status, education), lifestyle behaviour (physical activity, smoking, alcohol, dietary) and previous medical history. Strong interference in quality of life due to pain (bottom 20% of pain dimension score of SF-36) was significantly associated with poor MH in men and women (odds ratios (ORs) (95% confidence intervals (CIs)): 1.35 (1.19, 1.54) and 1.39 (1.25, 1.55), respectively; p < 0.0001) in fully adjusted models. Moreover, strong interference due to pain was also significantly associated with poor overall MH including emotional and social functioning (ORs (95% CIs): 1.42 (1.25, 1.62) and 1.39 (1.25, 1.55) respectively; p < 0.0001) in fully adjusted models; subsidiary analysis using linear regression models demonstrated similar results for these domains. Although a strong association has been shown, further research is needed to provide information on the different site and/or causes of pain which would allow stratification. Moreover, assuming a bi-directional nature of both domains, systematic assessment and management of pain have a lot of potential to improve the MH-related quality of life in the general population and vice versa.
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http://dx.doi.org/10.1177/2049463717724566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788113PMC
February 2018

Cross-sectional associations of dietary and circulating magnesium with skeletal muscle mass in the EPIC-Norfolk cohort.

Clin Nutr 2019 02 15;38(1):317-323. Epub 2018 Feb 15.

Department of Population Health and Primary Care, Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, NR4 7TJ, UK. Electronic address:

Background: Maintenance of skeletal muscle in older age is critical to reducing frailty and the risk of falls and fractures. Nutrition has established importance for muscle health in general, but less research has looked at associations of dietary intake of specific micronutrients on skeletal muscle mass in older adults.

Aims: This study aimed to investigate the influence of dietary and circulating magnesium on skeletal muscle mass in a UK population of 14,340 middle to older-aged men and women participating in the EPIC-Norfolk cohort study.

Methods: Dietary nutrient intakes were estimated from 7-day food diaries and fat-free mass (FFM) by bioelectrical impedance analysis. Multivariable regression was used to investigate associations of FFM-based indices of muscle mass with quintiles of dietary magnesium intake or serum magnesium concentration groups. All analyses were stratified by sex, and regression models were adjusted for relevant covariates.

Results: Significant positive trends in FFM measures were evident across magnesium dietary intake quintiles for both sexes (all p < 0.001; n = 6350 men; n = 7990 women) and both <60 and ≥ 60 year olds, with all-age quintile 5 versus quintile 1 maximal differences of 4.6% in men and 6.3% in women; highly relevant compared to the estimated 1% decline per year after 40 years of age. These observations were not reflected in serum magnesium analyses, where no consistent trends were found across the skeletal muscle mass indices tested.

Conclusion: Further investigation will be required to improve our understanding of the relationship between serum magnesium concentration and skeletal muscle mass. However, this study has demonstrated strong associations between dietary magnesium intake and indices of skeletal muscle mass in a UK population of middle to older-aged adults, highlighting the likely importance of dietary magnesium for optimal muscle health in this population.
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http://dx.doi.org/10.1016/j.clnu.2018.01.014DOI Listing
February 2019

Weight change and 15 year mortality: results from the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) cohort study.

Eur J Epidemiol 2018 01 20;33(1):37-53. Epub 2017 Dec 20.

Strangeways Research Laboratory, European Prospective Investigation into Cancer and Nutrition, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, UK.

Studies have reported a higher mortality risk associated with weight loss, particularly in middle-aged and older adults, although some of these studies did find that gaining weight was also associated with an increased mortality risk. We examined changes in weight in relation to mortality in a prospective population-based cohort study of men and women, resident in Norfolk, UK. Participants were assessed at baseline (1993-1997) and at a second examination (1998-2000), as part of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, and followed up to 2015 for mortality. Participants with a self-reported history of cancer or cardiovascular disease, body mass index < 18.5 kg/m or missing data on adjustment variables, at either time-point were excluded, leaving 12,580 participants, aged 39-78 in 1993-1997, eligible for analyses. Cox proportional hazards models were used to determine Hazard Ratios (HRs) for all-cause (2603 deaths), cardiovascular (749 deaths), cancer (981 deaths), respiratory (226 deaths) and other causes of mortality (647 deaths) by categories of weight change. After multivariate adjustment, the HRs (95% CIs) for all-cause mortality for men and women who lost more than 5 kg were 1.85 (1.48-2.31) and 1.64 (1.31-2.05) respectively. Higher hazards were also found for specific causes of mortality and weight loss > 5 kg. Similar associations were observed after excluding deaths in the first 5 years of follow-up. Results for weight gain were inconclusive. We conclude that objectively measured weight loss, but not weight gain, was associated with subsequent higher mortality risk in this population-based study of middle-aged and elderly men and women. However, undiagnosed, pre-existing disease and the inability to account for weight cycling need to be remembered when interpreting these results. Unravelling the causal pathways underlying this association will require more detailed studies, including that of changes in body composition.
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http://dx.doi.org/10.1007/s10654-017-0343-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803289PMC
January 2018

Impact of physical activity on the risk of cardiovascular disease in middle-aged and older adults: EPIC Norfolk prospective population study.

Eur J Prev Cardiol 2018 01 21;25(2):200-208. Epub 2017 Nov 21.

3 Medical Research Council Epidemiology Unit, Cambridge, UK.

Background There is broad consensus that regular physical activity yields major health benefits. However, current guidelines on physical activity are mainly aimed at middle-aged adults. It is unclear whether physical activity also translates into cardiovascular health benefits in older adults. Therefore, we aimed to compare the association between different levels of physical activity and the risk of cardiovascular disease (CVD) in elderly to middle-aged individuals. Methods We analysed data from the EPIC Norfolk prospective population study. Cox proportional hazards models were used to analyse the association between physical activity levels and time to CVD events in three age categories (<55, 55-65 and >65 years). Interaction between age categories and physical activity levels was assessed. Results Analyses were based on 24,502 study participants aged 39-79 years. A total of 5240 CVD events occurred during 412,954 person-years follow-up (median follow-up was 18.0 years). Among individuals aged over 65 years, hazard ratios for CVD were 0.86 (95% confidence interval (CI) 0.78-0.96), 0.87 (95% CI 0.77-0.99) and 0.88 (95% CI 0.77-1.02) in moderately inactive, moderately active and active people, respectively, compared to inactive people. Among people aged 55-65 and less than 55 years, the associations were directionally similar, but not statistically significant. The interaction term between physical activity levels and age categories was not significant ( P = 0.38). Conclusion The inverse association between physical activity and the risk of CVD was significant in elderly and comparable with middle-aged individuals. In addition, we observed that modest levels of physical activity confer benefits in terms of CVD risk, compared to being completely inactive.
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http://dx.doi.org/10.1177/2047487317737628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757406PMC
January 2018
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