Structural correlations between brain magnetic resonance image-derived phenotypes and retinal neuroanatomy.

BACKGROUND AND PURPOSE: The eye is a well-established model of brain structure and function, yet region-specific structural correlations between the retina and the brain remain underexplored. Therefore, we aim to explore and describe the relationships between the retinal layer thicknesses and brain magnetic resonance image (MRI)-derived phenotypes in UK Biobank. METHODS: Participants with both quality-controlled optical coherence tomography (OCT) and brain MRI were included in this study. Retinal sublayer thicknesses and total macular thickness were derived from OCT scans. Brain image-derived phenotypes (IDPs) of 153 cortical and subcortical regions were processed from MRI scans. We utilized multivariable linear regression models to examine the association between retinal thickness and brain regional volumes. All analyses were corrected for multiple testing and adjusted for confounders. RESULTS: Data from 6446 participants were included in this study. We identified significant associations between volumetric brain MRI measures of subregions in the occipital lobe (intracalcarine cortex), parietal lobe (postcentral gyrus), cerebellum (lobules VI, VIIb, VIIIa, VIIIb, and IX), and deep brain structures (thalamus, hippocampus, caudate, putamen, pallidum, and accumbens) and the thickness of the innermost retinal sublayers and total macular thickness (all p < 3.3 × 10-5). We did not observe statistically significant associations between brain IDPs and the thickness of the outer retinal sublayers. CONCLUSIONS: Thinner inner and total retinal thicknesses are associated with smaller volumes of specific brain regions. Notably, these relationships extend beyond anatomically established retina-brain connections.

The Association of Physical Activity with Glaucoma and Related Traits in the UK Biobank.

PURPOSE: To examine the association of physical activity (PA) with glaucoma and related traits, to assess whether genetic predisposition to glaucoma modified these associations, and to probe causal relationships using Mendelian randomization (MR). DESIGN: Cross-sectional observational and gene-environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia. PARTICIPANTS: UK Biobank participants with data on self-reported or accelerometer-derived PA and intraocular pressure (IOP; n = 94 206 and n = 27 777, respectively), macular inner retinal OCT measurements (n = 36 274 and n = 9991, respectively), and glaucoma status (n = 86 803 and n = 23 556, respectively). METHODS: We evaluated multivariable-adjusted associations of self-reported (International Physical Activity Questionnaire) and accelerometer-derived PA with IOP and macular inner retinal OCT parameters using linear regression and with glaucoma status using logistic regression. For all outcomes, we examined gene-PA interactions using a polygenic risk score (PRS) that combined the effects of 2673 genetic variants associated with glaucoma. MAIN OUTCOME MEASURES: Intraocular pressure, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and glaucoma status. RESULTS: In multivariable-adjusted regression models, we found no association of PA level or time spent in PA with glaucoma status. Higher overall levels and greater time spent in higher levels of both self-reported and accelerometer-derived PA were associated positively with thicker mGCIPL (P < 0.001 for trend for each). Compared with the lowest quartile of PA, participants in the highest quartiles of accelerometer-derived moderate- and vigorous-intensity PA showed a thicker mGCIPL by +0.57 µm (P < 0.001) and +0.42 µm (P = 0.005). No association was found with mRNFL thickness. High overall level of self-reported PA was associated with a modestly higher IOP of +0.08 mmHg (P = 0.01), but this was not replicated in the accelerometry data. No associations were modified by a glaucoma PRS, and MR analyses did not support a causal relationship between PA and any glaucoma-related outcome. CONCLUSIONS: Higher overall PA level and greater time spent in moderate and vigorous PA were not associated with glaucoma status but were associated with thicker mGCIPL. Associations with IOP were modest and inconsistent. Despite the well-documented acute reduction in IOP after PA, we found no evidence that high levels of habitual PA are associated with glaucoma status or IOP in the general population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of Systemic Medication Use with Glaucoma and Intraocular Pressure: The European Eye Epidemiology Consortium.

PURPOSE: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. DESIGN: Meta-analysis of 11 population-based cohort studies of the European Eye Epidemiology Consortium. PARTICIPANTS: The glaucoma analyses included 143 240 participants and the IOP analyses included 47 177 participants. METHODS: We examined associations of 4 categories of systemic medications-antihypertensive medications (ß-blockers, diuretics, calcium channel blockers [CCBs], α-agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers), lipid-lowering medications, antidepressants, and antidiabetic medications-with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Results of multivariable regression analyses of each study were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in participants with diabetes only. MAIN OUTCOME MEASURES: Glaucoma prevalence and IOP. RESULTS: In the meta-analyses of our maximally adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08 to 1.39). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR, 1.96; 95% CI, 1.23 to 3.12). No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with glaucoma. Use of systemic ß-blockers was associated with a lower IOP (ß coefficient, -0.33 mmHg; 95% CI, -0.57 to -0.08 mmHg). Monotherapy of both selective systemic ß-blockers (ß coefficient, -0.45 mmHg; 95% CI -0.74 to -0.16 mmHg) and nonselective systemic ß-blockers (ß coefficient, -0.54 mmHg; 95% CI, -0.94 to -0.15 mmHg) was associated with lower IOP. A suggestive association was found between use of high-ceiling diuretics and lower IOP (ß coefficient, -0.30 mmHg; 95% CI, -0.47 to -0.14 mmHg) but not when used as monotherapy. No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with IOP. CONCLUSIONS: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic ß-blocker use. Both findings potentially are important, given that patients with glaucoma frequently use systemic antihypertensive medications. Determining causality of the CCB association should be a research priority. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Association between Serum Lipids and Intraocular Pressure in 2 Large United Kingdom Cohorts.

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

Alcohol, Intraocular Pressure, and Open-Angle Glaucoma: A Systematic Review and Meta-analysis.

TOPIC: This systematic review and meta-analysis summarizes the existing evidence for the association of alcohol use with intraocular pressure (IOP) and open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding and quantifying these associations may aid clinical guidelines or treatment strategies and shed light on disease pathogenesis. The role of alcohol, a modifiable factor, in determining IOP and OAG risk also may be of interest from an individual or public health perspective. METHODS: The study protocol was preregistered in the Open Science Framework Registries (https://osf.io/z7yeg). Eligible articles (as of May 14, 2021) from 3 databases (PubMed, Embase, Scopus) were independently screened and quality assessed by 2 reviewers. All case-control, cross-sectional, and cohort studies reporting a quantitative effect estimate and 95% confidence interval (CI) for the association between alcohol use and either IOP or OAG were included. The evidence for the associations with both IOP and OAG was qualitatively summarized. Effect estimates for the association with OAG were pooled using random effects meta-analysis. Studies not meeting formal inclusion criteria for systematic review, but with pertinent results, were also appraised and discussed. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: Thirty-four studies were included in the systematic review. Evidence from 10 studies reporting an association with IOP suggests that habitual alcohol use is associated with higher IOP and prevalence of ocular hypertension (IOP > 21 mmHg), although absolute effect sizes were small. Eleven of 26 studies, comprising 173 058 participants, that tested for an association with OAG met inclusion criteria for meta-analysis. Pooled effect estimates indicated a positive association between any use of alcohol and OAG (1.18; 95% confidence interval [CI], 1.02-1.36; P = 0.03; I2 = 40.5%), with similar estimates for both prevalent and incident OAG. The overall GRADE certainty of evidence was very low. CONCLUSIONS: Although this meta-analysis suggests a harmful association between alcohol use and OAG, our results should be interpreted cautiously given the weakness and heterogeneity of the underlying evidence base, the small absolute effect size, and the borderline statistical significance. Nonetheless, these findings may be clinically relevant, and future research should focus on improving the quality of evidence.

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

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.

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

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.

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

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.

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.

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.

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

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.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

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

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.

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.

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.

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.

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, ptrend = 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.

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

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/m2 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.

Carotenoid dietary intakes and plasma concentrations are associated with heel bone ultrasound attenuation and osteoporotic fracture risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort.

Carotenoids are found in abundance in fruit and vegetables, and may be involved in the positive association of these foods with bone health. This study aimed to explore the associations of dietary carotenoid intakes and plasma concentrations with bone density status and osteoporotic fracture risk in a European population. Cross-sectional analyses (n 14 803) of bone density status, using calcaneal broadband ultrasound attenuation (BUA) and longitudinal analyses (n 25 439) of fracture cases were conducted on data from the prospective European Prospective Investigation into Cancer and Nutrition-Norfolk cohort of middle-aged and older men and women. Health and lifestyle questionnaires were completed, and dietary nutrient intakes were derived from 7-d food diaries. Multiple regression demonstrated significant positive trends in BUA for women across quintiles of dietary α-carotene intake (P=0·029), ß-carotene intake (P=0·003), ß-cryptoxanthin intake (P=0·031), combined lutein and zeaxanthin intake (P=0·010) and lycopene intake (P=0·005). No significant trends across plasma carotenoid concentration quintiles were apparent (n 4570). The Prentice-weighted Cox regression showed no trends in fracture risk across dietary carotenoid intake quintiles (mean follow-up time 12·5 years), except for a lower risk for wrist fracture in women with higher lutein and zeaxanthin intake (P=0·022); nevertheless, inter-quintile differences in fracture risk were found for both sexes. Analysis of plasma carotenoid data (mean follow-up time 11·9 years) showed lower hip fracture risk in men across higher plasma α-carotene (P=0·026) and ß-carotene (P=0·027) quintiles. This study provides novel evidence that dietary carotenoid intake is relevant to bone health in men and women, demonstrating that associations with bone density status and fracture risk exist for dietary intake of specific carotenoids and their plasma concentrations.

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Fatigue is associated with excess mortality in the general population: results from the EPIC-Norfolk study.

BACKGROUND: Significant fatigue is a frequent reason for seeking medical advice in the general population. Patients, however, commonly feel their complaint is ignored. This situation may be because clinicians perceive fatigue to be benign, unrelated to traditional biomedical outcomes such as premature mortality. The present study aimed to investigate whether an association between significant fatigue and mortality actually exists, and, if so, to identify potential mechanisms of this association. METHODS: A population-based cohort of 18,101 men and women aged 40-79 years who completed a measure of fatigue (Short Form 36 vitality domain, SF36-VT) in addition to providing information on possible confounding factors (age, sex, body mass index, marital status, smoking, education level, alcohol consumption, social class, depression, bodily pain, diabetes, use of ß blockers, physical activity and diet) and mechanisms (haemoglobin, C-reactive protein and thyroid function) were followed up prospectively for up to 20 years. Mortality from all causes, cancer and cardiovascular disease was ascertained using death certification linkage with the UK Office of National Statistics. RESULTS: During 300,322 person years of follow-up (mean 16.6 years), 4397 deaths occurred. After adjusting for confounders, the hazard ratio (HR) for all-cause mortality was 1.40 (95 % confidence interval [CI] 1.25-1.56) for those reporting the highest fatigue (bottom SF36-VT quartile) compared with those reporting the lowest fatigue (top SF36-VT quartile). This significant association was specifically observed for those deaths related to cardiovascular disease (HR 1.45, 95 % CI 1.18-1.78) but not cancer (HR 1.09, 95 % CI 0.90-1.32). Of the considered mechanisms, thyroid function was most notable for attenuating this association. The risk of all-cause mortality, however, remained significant even after considering all putative confounders and mechanisms (HR 1.26, 95 % CI 1.10-1.45). CONCLUSIONS: High levels of fatigue are associated with excess mortality in the general population. This commonly dismissed symptom demands greater evaluation and should not automatically be considered benign.

Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.