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Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

ObjectivTo assess the associations between gout, brain structure, and neurodegenerative disease incidence.MethodsUsing observational and Mendelian randomization analyses we investigated causal relationships between gout and brain health. Exposures included gout diagnosis (from self-report, linked health records and death records) and genetically proxied gout and serum urate. Outcomes were neuroimaging markers of brain structure and neurodegenerative disease incidence (ascertained through self-report, health records and death reports). Cox proportional hazards models were used to examine time to neurodegenerative disease diagnosis.Results11,735 UK Biobank participants (mean age 55.5±8.0 years and 50.5% female) had a diagnosis of gout (n=1165 in MRI subset). Dementia was ascertained in 3126 individuals over a mean follow-up time of 12.4±1.9 years. Gout patients had smaller global and regional brain volumes and higher brain iron markers. Genetic associations mirrored observational associations. Genetically proxied gout associated with lower global grey matter volume (beta= -0.05[-0.08 to -0.01]). Participants with gout had higher incidence of all-cause dementia (hazard ratio (HR)=1.60, 95% confidence interval (CI) [1.38-1.85]), Parkinson’s disease (HR=1.43[1.15 to 1.79]), and probable essential tremor (HR=6.75[5.69 to 8.00]). Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis (HR=7.40[4.95 to 11.07]).ConclusionsThese findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases.Key pointsWhat is already known on this topic?Studies of neurodegenerative disease risk in gout are contradictory.Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain.What this study adds?In this prospective cohort study gout was associated with smaller brain volumes and higher incidence of multiple neurodegenerative diseases.Mendelian randomization analyses suggested gout is causally related to brain structure.How might this study affect research, practice or policy?Our findings emphasise the importance for clinicians of assessing for motor and cognitive impairments amongst gout patients, particularly in early years after diagnosis.

Background and Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a cysteine-altering mutation in one of the thirty-four epidermal growth factor-like repeat (EGFR) domains of the NOTCH3 protein. CADASIL has a variable phenotypic presentation and NOTCH3 mutations in EGFRs 1-6 have been found correlated with greater disease severity. We examined clinical and radiological features and performed bioinformatic annotation of mutations in a large CADASIL cohort to further understand these associations. Methods We examined the association of NOTCH3 variant position on stroke onset and other clinical features among patients with CADASIL from the United Kingdom. We also explored how in-silico predicted protein aggregation differed by variant position and the extent to which this affected stroke risk. Results We identified 76 different cysteine-altering NOTCH3 variants in our cohort of 485 patients (mean age: 50.1 years; % male: 57.5). After controlling for cardiovascular risk factors, variants in EGFRs 1-6 were associated with earlier onset of stroke (hazard ratio [HR]: 2.05, 95% CI: 1.43-2.94) and encephalopathy (HR: 2.70, 95% CI: 1.15-6.37), than variants in EGFRs 7-34. Although the risk of stroke was higher in the patients with predicted protein aggregation (HR: 1.50, 95% CI: 1.05-2.14), this association was no longer significant after controlling for variant site. Further analysis suggested lower stroke risk was observed for variants in EGFRs 10-17 compared to variants in the other EGFR domains. Discussion NOTCH3 variant position is a predictor of stroke and encephalopathy in CADASIL independent of cardiovascular risk factors. Lower stroke risk was found for variants in EGFRs 10-17. Molecular factors that influence CADASIL disease severity remain to be determined.

SARS-CoV-2 can cause acute respiratory distress and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fcγ receptors. Vaccine recipient plasma does not promote antibody-enhanced monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.

Funder: BHF Centre of Research Excellence, Oxford, Funder: China Scholarship Council, Funder: Li Ka Shing Foundation, BACKGROUND: Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits. METHODS AND FINDINGS: Observational associations between brain iron markers and alcohol consumption (n = 20,729 UK Biobank participants) were compared with associations with genetically predicted alcohol intake and alcohol use disorder from 2-sample mendelian randomization (MR). Alcohol intake was self-reported via a touchscreen questionnaire at baseline (2006 to 2010). Participants with complete data were included. Multiorgan susceptibility-weighted magnetic resonance imaging (9.60 ± 1.10 years after baseline) was used to ascertain iron content of each brain region (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Main outcomes were susceptibility (χ) and T2*, measures used as indices of iron deposition. Brain regions of interest included putamen, caudate, hippocampi, thalami, and substantia nigra. Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the scan and in online follow-up (5.82 ± 0.86 years after baseline). Executive function was assessed with the trail-making test, fluid intelligence with puzzle tasks, and reaction time by a task based on the "Snap" card game. Mean age was 54.8 ± 7.4 years and 48.6% were female. Weekly alcohol consumption was 17.7 ± 15.9 units and never drinkers comprised 2.7% of the sample. Alcohol consumption was associated with markers of higher iron (χ) in putamen (β = 0.08 standard deviation (SD) [95% confidence interval (CI) 0.06 to 0.09], p < 0.001), caudate (β = 0.05 [0.04 to 0.07], p < 0.001), and substantia nigra (β = 0.03 [0.02 to 0.05], p < 0.001) and lower iron in the thalami (β = -0.06 [-0.07 to -0.04], p < 0.001). Quintile-based analyses found these associations in those consuming >7 units (56 g) alcohol weekly. MR analyses provided weak evidence these relationships are causal. Genetically predicted alcoholic drinks weekly positively associated with putamen and hippocampus susceptibility; however, these associations did not survive multiple testing corrections. Weak evidence for a causal relationship between genetically predicted alcohol use disorder and higher putamen susceptibility was observed; however, this was not robust to multiple comparisons correction. Genetically predicted alcohol use disorder was associated with serum iron and transferrin saturation. Elevated liver iron was observed at just >11 units (88 g) alcohol weekly c.f.

Background and aims Observational studies have reported an association between periodontitis and cardiovascular disease but whether this association is causal is uncertain. We therefore used Mendelian randomization to test whether periodontitis is causally associated with stroke, coronary artery disease, or subclinical atherosclerosis. Methods A two-sample Mendelian randomization analysis was carried out using five single nucleotide polymorphisms previously associated with periodontitis in genome-wide association studies. Summary data were drawn from MEGASTROKE and combined with de novo analyses of UK Biobank for stroke and its major subtypes (up to 44,221 cases, 739,957 controls) and CARDIoGRAMplusC4D and UK Biobank for coronary artery disease (122,733 cases, 424,528 controls). We used existing data on carotid intima-media thickness in UK Biobank as a marker of subclinical atherosclerosis (N = 22,179). Causal estimates were obtained using inverse-variance weighted Mendelian randomization. Sensitivity analyses were performed using weighted median and MR-Egger approaches. Results No association was found between periodontitis and any stroke (odds ratio [OR] per doubling in the odds of periodontitis 0.99, 95% confidence interval [CI] 0.97 to 1.02), ischaemic stroke (OR 1.00, 95% CI 0.97 to 1.03) or its major subtypes (p > 0.4), or coronary artery disease (OR 1.01, 95% CI 0.99 to 1.03). Similarly, we found no association for periodontitis and subclinical atherosclerosis (β −0.002, 95% CI -0.004 to 0.001). These results were consistent across a series of sensitivity analyses. Conclusions These findings provide no robust evidence for a causal relationship between periodontitis and stroke or coronary artery disease. This suggests that associations reported in observational studies may represent confounding., Graphical abstract Image 1, Highlights • Periodontitis and cardiovascular disease correlate in observational studies. • Mendelian randomization does not support a causal association. • Results do not support treatment of periodontitis to reduce atherosclerotic disease.

Funder: British Heart Foundation, Funder: VA Boston Healthcare System, Funder: Dana-Farber Cancer Institute, Funder: VA Cooperative Studies Program, Funder: National Institutes of Health, Funder: Harvard Medical School, Effective, low-cost therapeutics are needed to prevent and treat COVID-19. Severe COVID-19 disease is linked to excessive inflammation. Disulfiram is an approved oral drug used to treat alcohol use disorder that is a potent anti-inflammatory agent and an inhibitor of the viral proteases. We investigated the potential effects of disulfiram on SARS-CoV-2 infection and disease severity in an observational study using a large database of clinical records from the national US Veterans Affairs healthcare system. A multivariable Cox regression adjusted for demographic information and diagnosis of alcohol use disorder revealed a reduced risk of SARS-CoV-2 infection with disulfiram use at a hazard ratio of 0.66 (34% lower risk, 95% confidence interval 24-43%). There were no COVID-19 related deaths among the 188 SARS-CoV-2 positive patients treated with disulfiram, in contrast to 5-6 statistically expected deaths based on the untreated population (P = 0.03). Our epidemiological results suggest that disulfiram may contribute to the reduced incidence and severity of COVID-19. These results support carefully planned clinical trials to assess the potential therapeutic effects of disulfiram in COVID-19.

Background Light-to-moderate alcohol consumption has been reported to be cardio-protective among apparently healthy individuals; however, it is unclear whether this association is also present in those with disease. To examine the association between alcohol consumption and prognosis in individuals with pre-existing cardiovascular disease (CVD), we conducted a series of meta-analyses of new findings from three large-scale cohorts and existing published studies. Methods We assessed alcohol consumption in relation to all-cause mortality, cardiovascular mortality, and subsequent cardiovascular events via de novo analyses of 14,386 patients with a previous myocardial infarction, angina, or stroke in the UK Biobank Study (median follow-up 8.7 years, interquartile range [IQR] 8.0–9.5), involving 1640 deaths and 2950 subsequent events, and 2802 patients and 1257 deaths in 15 waves of the Health Survey for England 1994–2008 and three waves of the Scottish Health Survey 1995, 1998, and 2003 (median follow-up 9.5 years, IQR 5.7–13.0). This was augmented with findings from 12 published studies identified through a systematic review, providing data on 31,235 patients, 5095 deaths, and 1414 subsequent events. To determine the best-fitting dose-response association between alcohol and each outcome in the combined sample of 48,423 patients, models were constructed using fractional polynomial regression, adjusting at least for age, sex, and smoking status. Results Alcohol consumption was associated with all assessed outcomes in a J-shaped manner relative to current non-drinkers, with a risk reduction that peaked at 7 g/day (relative risk 0.79, 95% confidence interval 0.73–0.85) for all-cause mortality, 8 g/day (0.73, 0.64–0.83) for cardiovascular mortality and 6 g/day (0.50, 0.26–0.96) for cardiovascular events, and remained significant up to 62, 50, and 15 g/day, respectively. No statistically significant elevated risks were found at higher levels of drinking. In the few studies that excluded former drinkers from the non-drinking reference group, reductions in risk among light-to-moderate drinkers were attenuated. Conclusions For secondary prevention of CVD, current drinkers may not need to stop drinking. However, they should be informed that the lowest risk of mortality and having another cardiovascular event is likely to be associated with lower levels of drinking, that is up to approximately 105g (or equivalent to 13 UK units, with one unit equal to half a pint of beer/lager/cider, half a glass of wine, or one measure of spirits) a week.

Funding: This work, including collection and genotyping of the UK Young Lacunar Stroke DNA Study 2 (DNA Lacunar 2), was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

Background Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD. Methods and findings Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703–0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009–0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40–75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to, Luanluan Sun and colleagues investigate whether adding polygenic risk scores to conventional risk factors of cardiovascular disease helps predict disease risk., Author summary Why was this study done? Application of polygenic risk scores (PRSs) has opened opportunities to enhance risk stratification and prevention for common diseases. The clinical utility of PRSs in cardiovascular disease (CVD) risk prediction is, however, uncertain. Previous analyses have generally focused only on coronary heart disease (CHD) rather than the composite outcome of CHD and stroke, and have often lacked modelling of clinical implications of initiating guideline-recommended interventions (e.g., statin therapy). What did the researchers do and find? We quantified the incremental predictive gain with PRSs on top of conventional risk factors using data on 306,654 individuals from UK Biobank. We modelled the population health implications of initiating statin therapy as recommended by current guidelines using data from 2.1 million individuals from the Clinical Practice Research Datalink. Addition of information on PRSs to a conventional risk prediction model increased the C-index (a measure of risk discrimination) and improved risk classification of cases and non-cases. We estimated that targeted assessment of PRSs among people at intermediate (i.e., 5% to

OBJECTIVE: To compare four haemoglobin measurement methods in whole blood donors. BACKGROUND: To safeguard donors, blood services measure haemoglobin concentration in advance of each donation. NHS Blood and Transplant's (NHSBT) customary method have been capillary gravimetry (copper sulphate), followed by venous spectrophotometry (HemoCue) for donors failing gravimetry. However, NHSBT's customary method results in 10% of donors being inappropriately bled (ie, with haemoglobin values below the regulatory threshold). METHODS: We compared the following four methods in 21 840 blood donors (aged ≥18 years) recruited from 10 NHSBT centres in England, with the Sysmex XN-2000 haematology analyser, the reference standard: (1) NHSBT's customary method; (2) "post donation" approach, that is, estimating current haemoglobin concentration from that measured by a haematology analyser at a donor's most recent prior donation; (3) "portable haemoglobinometry" (using capillary HemoCue); (4) non-invasive spectrometry (using MBR Haemospect or Orsense NMB200). We assessed sensitivity; specificity; proportion who would have been inappropriately bled, or rejected from donation ("deferred") incorrectly; and test preference. RESULTS: Compared with the reference standard, the methods ranged in test sensitivity from 17.0% (MBR Haemospect) to 79.0% (portable haemoglobinometry) in men, and from 19.0% (MBR Haemospect) to 82.8% (portable haemoglobinometry) in women. For specificity, the methods ranged from 87.2% (MBR Haemospect) to 99.9% (NHSBT's customary method) in men, and from 74.1% (Orsense NMB200) to 99.8% (NHSBT's customary method) in women. The proportion of donors who would have been inappropriately bled ranged from 2.2% in men for portable haemoglobinometry to 18.9% in women for MBR Haemospect. The proportion of donors who would have been deferred incorrectly with haemoglobin concentration above the minimum threshold ranged from 0.1% in men for NHSBT's customary method to 20.3% in women for OrSense. Most donors preferred non-invasive spectrometry. CONCLUSION: In the largest study reporting head-to-head comparisons of four methods to measure haemoglobin prior to blood donation, our results support replacement of NHSBT's customary method with portable haemoglobinometry.

Funder: Scottish Government; doi: https://doi.org/10.13039/100012095, Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N=246,139), total iron binding capacity (N=135,430), iron (N=163,511) and transferrin saturation (N=131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

Aims To investigate associations of life‐time hazardous and binge drinking with biomarkers of cardiometabolic health, liver function, cardiovascular disease (CVD) and mortality. Design Prospective cohort study with median follow‐up time to CVD incidence of 4.5 years. Setting London, UK: civil servants within the Whitehall II Study. Participants A total of 4820 drinkers aged 59–83 years with biological measurements during the 2011–12 survey. Measurements Hazardous drinking was defined as having an AUDIT‐C score ≥ 5 calculated at each decade of life, forming the following groups: never hazardous drinker, former early (stopping before age 50), former later (stopping after age 50), current hazardous drinker and consistent hazardous drinker (hazardous drinker at each decade of life). Findings More than half the sample had been hazardous drinkers at some point during their life‐time, comprising former early (

Contains fulltext : 282532.pdf (Publisher’s version ) (Open Access) BACKGROUND: DTI is sensitive to white matter (WM) microstructural damage and has been suggested as a surrogate marker for phase 2 clinical trials in cerebral small vessel disease (SVD). The study's objective is to establish the best way to analyse the diffusion-weighted imaging data in SVD for this purpose. The ideal method would be sensitive to change and predict dementia conversion, but also straightforward to implement and ideally automated. As part of the OPTIMAL collaboration, we evaluated five different DTI analysis strategies across six different cohorts with differing SVD severity. METHODS: Those 5 strategies were: (1) conventional mean diffusivity WM histogram measure (MD median), (2) a principal component-derived measure based on conventional WM histogram measures (PC1), (3) peak width skeletonized mean diffusivity (PSMD), (4) diffusion tensor image segmentation θ (DSEG θ) and (5) a WM measure of global network efficiency (Geff). The association between each measure and cognitive function was tested using a linear regression model adjusted by clinical markers. Changes in the imaging measures over time were determined. In three cohort studies, repeated imaging data together with data on incident dementia were available. The association between the baseline measure, change measure and incident dementia conversion was examined using Cox proportional-hazard regression or logistic regression models. Sample size estimates for a hypothetical clinical trial were furthermore computed for each DTI analysis strategy. RESULTS: There was a consistent cross-sectional association between the imaging measures and impaired cognitive function across all cohorts. All baseline measures predicted dementia conversion in severe SVD. In mild SVD, PC1, PSMD and Geff predicted dementia conversion. In MCI, all markers except Geff predicted dementia conversion. Baseline DTI was significantly different in patients converting to vascular dementia than to Alzheimer' s disease. Significant change in all measures was associated with dementia conversion in severe but not in mild SVD. The automatic and semi-automatic measures PSMD and DSEG θ required the lowest minimum sample sizes for a hypothetical clinical trial in single-centre sporadic SVD cohorts. CONCLUSION: DTI parameters obtained from all analysis methods predicted dementia, and there was no clear winner amongst the different analysis strategies. The fully automated analysis provided by PSMD offers advantages particularly for large datasets.

Highlights • Prolonged heavy drinkers had higher levels of NT-proBNP, an important cardiac biomarker for heart failure, than moderate drinkers. • This suggests a pathway through which prolonged heavy alcohol consumption may increase risk of this cardiovascular disease. • Heavy drinkers could be screened for NT-proBNP levels to identify those at high risk earlier in the clinical stages of heart failure and targeted for risk reduction strategies., Heavy alcohol consumption is associated with an increased risk of heart failure. We sought to investigate whether levels of NT-proBNP differ by alcohol consumption profiles, both current drinking as well as cumulative exposure to drinking over several decades in a general population sample. Methods Data on 2054 participants (49% male) were taken from the UK Medical Research Council National Survey for Health and Development, a longitudinal cohort study based on a nationally representative sample of births in 1946. Categories of long-term alcohol consumption were created based on consumption over 25 years of observations and compared with levels of NT-proBNP measured at mean age 63. Results We found that those who drank heavily (both currently and long-term) had higher levels of NT-proBNP than moderate drinkers, after adjusting for major confounders (age, sex, socio-economic position and smoking). As NT-proBNP has attracted attention as a biomarker for heart failure, this suggests a critical pathway through which heavy drinking may increase risk of this cardiovascular disease. When we looked at heavy drinkers who varied their intake over the decades, it was only the recently heavy group that had higher levels of NT-proBNP. Further work is needed to demonstrate whether effects are reversible upon cessation of heavy drinking, but this finding highlights the need to have repeated data to unpack dynamics over time. Conclusion Our findings suggest heavy drinkers could be screened for NT-proBNP levels in order to identify those at high risk earlier in the clinical stages of heart failure and targeted for risk reduction strategies.

OBJECTIVE: With there being an apparent impact of experience of out-of-home care in childhood on chronic disease and mortality, we examined how such adversity might be embodied such that it has a measurable impact on human biology, so mediating this relationship. METHODS: We used data from the UK National Child Development Study in which exposure to public care was prospectively gathered on three occasions up to age 16. Study members also participated in a social survey at age 42 and a clinical examination at age 44/45 when cardiovascular, inflammatory, neuroendocrine, and respiratory risk markers for mortality were collected, 19 of which were included as endpoints in the present analyses. RESULTS: Of the 8012 participants in the biomedical survey, 4% (n = 322) had been in care at some point in childhood and/or adolescence. We found the expected marked differences in the early life characteristics of poverty, health, and disability in children with experience of public care relative to their unexposed counterparts. After controlling for these confounding factors, however, care in childhood was essentially unrelated to biomarkers in middle-age. We also found no consistent links between these biomarkers and the duration, timing, or type of care. CONCLUSIONS: Our results suggest that the biomarkers captured in the present study are unlikely to mediate the link between public care in childhood and later chronic disease or mortality. Processes involving mental health, socioeconomic position, and health behaviors would seem to be a potential alternative pathway warranting investigation.

Identifying biological correlates of late life cognitive function is important if we are to ascertain biomarkers for, and develop treatments to help reduce, age-related cognitive decline. Here, we investigated the associations between plasma levels of 90 neurology-related proteins (Olink® Proteomics) and general fluid cognitive ability in the Lothian Birth Cohort 1936 (LBC1936, N = 798), Lothian Birth Cohort 1921 (LBC1921, N = 165), and the INTERVAL BioResource (N = 4451). In the LBC1936, 22 of the proteins were significantly associated with general fluid cognitive ability (β between −0.11 and −0.17). MRI-assessed total brain volume partially mediated the association between 10 of these proteins and general fluid cognitive ability. In an age-matched subsample of INTERVAL, effect sizes for the 22 proteins, although smaller, were all in the same direction as in LBC1936. Plasma levels of a number of neurology-related proteins are associated with general fluid cognitive ability in later life, mediated by brain volume in some cases., Late-life cognitive dysfunction is common, but the biological substrates are largely unknown. Here, the authors examined a panel of 90 neurology-related protein biomarkers and show that plasma levels of 22 of these proteins are associated with general fluid cognitive ability in later life.

Socioeconomic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. In a sample of 286,301 participants from UK Biobank, we identify 30 (29 previously unreported) independent-loci associated with income. Using a method to meta-analyze data from genetically-correlated traits, we identify an additional 120 income-associated loci. These loci show clear evidence of functionality, with transcriptional differences identified across multiple cortical tissues, and links to GABAergic and serotonergic neurotransmission. By combining our genome wide association study on income with data from eQTL studies and chromatin interactions, 24 genes are prioritized for follow up, 18 of which were previously associated with intelligence. We identify intelligence as one of the likely causal, partly-heritable phenotypes that might bridge the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. These results indicate that, in modern era Great Britain, genetic effects contribute towards some of the observed socioeconomic inequalities., Household income is used as a marker of socioeconomic position, a trait that is associated with better physical and mental health. Here, Hill et al. report a genome-wide association study for household income in the UK and explore its relationship with intelligence in post-GWAS analyses including Mendelian randomization.

BACKGROUND: Evidence from randomized trials has shown that therapies that lower LDL (low-density lipoprotein)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty about their effects on other cardiovascular outcomes. We therefore performed a systematic investigation of causal relationships between circulating lipids and cardiovascular outcomes using a Mendelian randomization approach. METHODS: In the primary analysis, we performed 2-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188 577 participants, and genetic associations with cardiovascular outcomes from 367 703 participants in UK Biobank. RESULTS: For LDL-cholesterol, in addition to the expected positive associations with CAD risk (odds ratio [OR] per 1 SD increase, 1.45 [95% CI, 1.35-1.57]) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically predicted LDL-cholesterol with abdominal aortic aneurysm (OR, 1.75 [95% CI, 1.40-2.17]) and aortic valve stenosis (OR, 1.46 [95% CI, 1.25-1.70]). Genetically predicted triglyceride levels were positively associated with CAD (OR, 1.25 [95% CI, 1.12-1.40]), aortic valve stenosis (OR, 1.29 [95% CI, 1.04-1.61]), and hypertension (OR, 1.17 [95% CI, 1.07-1.27]), but inversely associated with venous thromboembolism (OR, 0.79 [95% CI, 0.67-0.93]) and hemorrhagic stroke (OR, 0.78 [95% CI, 0.62-0.98]). We also found positive associations of genetically predicted LDL-cholesterol and triglycerides with heart failure that appeared to be mediated by CAD. CONCLUSIONS: Lowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis but may increase thromboembolic risk.

Owing to the often prohibitively high costs of medical examinations, or an absence of infrastructure for linkage of study members to morbidity registries, much aetiological research in the field of cardiovascular research relies on death records. Because they are regarded as being more distal to risk factor assessment than morbidity endpoints, mortality data are generally maligned in this context for seemingly providing less clear insights into aetiology. The relative utility of mortality versus morbidity registries is, however, untested. In a pooling of data from three large cohort studies whose participants had been linked to both death and morbidity registries for coronary heart disease, we related a range of established and emerging risk factors to these two methods of ascertainment. A mean duration of study member surveillance of 10.1 years (mortality) and 9.9 years (morbidity) for a maximum of 20,956 study members (11,868 women) in the analytical sample yielded 289 deaths from coronary heart disease and 770 hospitalisations for this condition. The direction of the age- and sex-adjusted association was the same for 21 of the 24 risk factor– morbidity/mortality combinations. The only marked discordance in effect estimates, such that different conclusions about the association could be drawn, was for social support, total cholesterol, and fruit/vegetable consumption whereby null effects were evident for selected outcomes. In conclusion, variation in disease definition typically did not have an impact on the direction of the association of an array of risk factors for coronary heart disease.

Background: Empirical evidence has demonstrated adverse associations between parental nonstandard work schedules (i.e., evenings, nights, or weekends) and child developmental outcomes. However, there are mixed findings concerning the relationship between parental nonstandard employment and children's body mass index (BMI), and few studies have incorporated information on paternal work schedules. Objective: This paper investigated BMI trajectories from early to middle childhood (ages 3-11) by parental work schedules at 9 months of age, using nationally representative cohort data from the United Kingdom. This study is the first to examine the link between nonstandard work schedules and children's BMI in the United Kingdom. Methods: We used data from the Millennium Cohort Study (2001‒2013, n = 13,021) to estimate trajectories in BMI, using data from ages 3, 5, 7, and 11 years. Joint parental work schedules and a range of biological, socioeconomic, and psychosocial covariates were assessed in the initial interviews at 9 months. Results: Compared to children in two-parent families where parents worked standard shifts, we found steeper BMI growth trajectories for children in two-parent families where both parents worked nonstandard shifts and children in single-parent families whose mothers worked a standard shift. Fathers' shift work, compared to standard shifts, was independently associated with significant increases in BMI. Conclusions: Future public health initiatives focused on reducing the risk of rapid BMI gain in childhood can potentially consider the disruptions to family processes resulting from working nonstandard hours. Contribution: Children in families in which both parents work nonstandard schedules had steeper BMI growth trajectories across the first decade of life. Fathers' nonstandard shifts were independently associated with increases in BMI.

Key Points Question What is the relative utility for etiological research of using underlying cause of mortality from death certificates compared with using any field? Findings In 2 large cohort studies with 696 528 participants combined, associations of known risk factors with an array of death outcomes were essentially the same, irrespective of the location of the death data on the certificate. Meaning Our findings have implications for risk factor–end point computations in studies of rarer outcomes and those with smaller sample sizes., This cohort study, using data from the UK Biobank and health surveys in England and Scotland, compares the relative utility of cause of death data extracted from the underlying cause field vs any location on the death certificate., Importance In etiological research, investigators using death certificate data have traditionally extracted underlying cause of mortality alone. With multimorbidity being increasingly common, more than one condition is often compatible with the manner of death. Using contributory cause plus underlying cause would also have some analytical advantages, but their combined utility is largely untested. Objective To compare the relative utility of cause of death data extracted from the underlying cause field vs any location on the death certificate (underlying and contributing combined). Design, Setting, and Participants This study compares the association of 3 known risk factors (cigarette smoking, low educational attainment, and hypertension) with health outcomes based on where cause of death data appears on the death certificate in 2 prospective cohort study collaborations (UK Biobank [N = 502 655] and the Health Survey for England [15 studies] and the Scottish Health Surveys [3 studies] [HSE-SHS; N = 193 873]). Data were collected in UK Biobank from March 2006 to October 2010 and in HSE-SHS from January 1994 to December 2008. Data analysis began in June 2018 and concluded in June 2019. Main Outcomes and Measures Death from cardiovascular disease, cancer, dementia, and injury. For each risk factor–mortality end point combination, a ratio of hazard ratios (RHR) was computed by dividing the effect estimate for the underlying cause by the effect estimate for any mention. Results In UK Biobank, there were 14 421 deaths (2.9%) during a mean (SD) of 6.99 (1.03) years of follow up; in HSE-SHS, there were 21 314 deaths (11.0%) during a mean (SD) of 9.61 (4.44) years of mortality surveillance. Established associations of risk factors with death outcomes were essentially the same irrespective of placement of cause on the death certificate. Results from each study were mutually supportive. For having ever smoked cigarettes (vs never having smoked) in the UK Biobank, the RHR for cardiovascular disease was 0.98 (95% CI, 0.87-1.10; P value for difference = .69); for cancer, the RHR was 0.99 (95% CI, 0.93-1.05; P value for difference = .69). In the HSE-SHS, the RHR for cardiovascular disease was 0.94 (95% CI, 0.87-1.01; P value for difference = .09); for cancer, it was 1.01 (95% CI, 0.94-1.10; P value for difference = .75). Conclusions and Relevance Risk factor–end point associations were not sensitive to the placement of data on the death certificate. This has implications for the examination of the association of risk factors with causes of death where there may be too few events to compute reliable effect estimates based on the underlying field alone.

Objective To evaluate the longitudinal relationship between repeated measures of alcohol consumption and risk of developing fatty liver. Patients and methods This study includes 5407 men and women from a British population-based cohort, the Whitehall II study of civil servants, who self-reported alcohol consumption by questionnaire over approximately 30 years (1985–1989 through to 2012–2013). Drinking typologies during midlife were linked to measures of fatty liver (the fatty liver index, FLI) when participants were in older age (age range 60–84 years) and adjusted for age, socio-economic position, ethnicity, and smoking. Results Those who consistently drank heavily had two-fold higher odds of increased FLI compared to stable low-risk moderate drinkers after adjustment for covariates (men: OR = 2.04, 95%CI = 1.53–2.74; women: OR = 2.24, 95%CI = 1.08–4.55). Former drinkers also had an increased FLI compared to low-risk drinkers (men: OR = 2.09, 95%CI = 1.55–2.85; women: OR = 1.68, 95%CI = 1.08–2.67). There were non-significant differences in FLI between non-drinkers and stable low-risk drinkers. Among women, there was no increased risk for current heavy drinkers in cross sectional analyses. Conclusion Drinking habits among adults during midlife affect the development of fatty liver, and sustained heavy drinking is associated with an increased FLI compared to stable low-risk drinkers. After the exclusion of former drinkers, there was no difference between non-drinkers and low-risk drinkers, which does not support a protective effect on fatty liver from low-risk drinking. Cross-sectional analyses among women did not find an increased risk of heavy drinking compared to low-risk drinkers, thus highlighting the need to take a longitudinal approach.

Key Points Question To what extent are established cardiovascular risk factors associated with risk of venous thromboembolism (VTE)? Findings In this analysis of individual participant data from the Emerging Risk Factors Collaboration and the UK Biobank including 1.1 million participants, among a panel of several established cardiovascular risk factors, older age, smoking, and greater adiposity were consistently associated with higher VTE risk. Meaning There is overlap in at least some of the major population determinants of important venous and arterial thrombotic diseases., This analysis of data from the Emerging Risk Factors Collaboration and the UK Biobank estimates the associations of major cardiovascular risk factors with venous thromboembolism., Importance It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. Design, Setting, and Participants This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. Exposures A panel of several established cardiovascular risk factors. Main Outcomes and Measures Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). Results Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. Conclusions and Relevance Older age, smoking, and adiposity were consistently associated with higher VTE risk.

BACKGROUND AND AIMS: Retrospective measures of alcohol intake are becoming increasingly popular; however, the reliability of such measures remains uncertain. This study assessed the reliability of a retrospective decade-based life-course alcohol consumption questionnaire, based on the standardized Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) administered in older age in a well-characterized cohort study. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: A retrospective alcohol life-grid was administered to 5980 participants (72% male, mean age 70 years) in the Whitehall II study covering frequency of drinking, number of drinks in a typical drinking day and frequency of consuming six or more drinks in a single drinking occasion in the teens (16-19 years) through to the 80s. A subsample of 385 individuals completed a repeat survey to determine test-retest reliability. Retrospective measures were also compared with prospectively ascertained information and used to predict objectively measured systolic blood pressure to test their predictive validity. FINDINGS: Across all decades of life, test-retest reliability was generally good (κ range = 0.62-0.78 for frequency, 0.55-0.62 for usual number of drinks and 0.57-0.65 for frequency of consuming six or more drinks in a single occasion). The concordance between prospective and retrospective measures was consistently moderate to high. The life-grid method performed better than a single question in identifying life-time abstainers. Retrospective measures were also related to systolic blood pressure in the manner anticipated. CONCLUSION: A retrospective decade-based AUDIT-C grid administered in older age provides a relatively reliable measure of alcohol consumption across the life-course.

Background The long-term impact of alcohol intake in midlife on developing depression is not clear. We aimed to investigate drinking pattern during midlife as a risk factor for developing depression during 28 years of follow-up. Methods We used data from a well characterised prospective cohort study (the Whitehall II study) of 7478 men and women (70% male) aged 35 to 55 years, and free from depression in 1985–1988, followed up regularly until 2013. Drinking pattern was defined in terms of usual and maximum amounts consumed within a single drinking session, total weekly volume of alcohol consumed and drinking frequency. Depression was assessed using the General Health Questionnaire Depression Subscale at multiple follow-up occasions (up to eight times in total). Associations between different drinking pattern components during midlife and depression were estimated using flexible parametric survival models. Results After adjustment for confounding factors only abstaining from alcohol during midlife was associated with an increased risk of developing depression during long-term observation. However, this association became non-significant after adjusting for baseline self-reported health. Conclusions In this community dwelling population, drinking pattern during midlife was not associated with an increased risk of developing depression.

Background For the same quantity of cigarettes smoked, relative to more affluent people, socioeconomically disadvantaged people have higher levels of smoking biomarkers. This may be ascribed to inhaling cigarette smoke more deeply and more frequently and/or choosing higher tar-containing brands. We investigated whether this increased tobacco load, as captured using cotinine measurements, is associated with a greater risk of mortality in lower social groups. Methods We used Cox proportional hazards models stratified by socioeconomic position to calculate hazard ratios in a pooled sample of 15 English and Scottish prospective cohort studies (N = 81,476). Results During a mean (SD) follow-up of 10.3 (4.4) years, 8234 deaths occurred. Risk of total mortality (hazard ratio; 95% confidence interval) for smokers relative to never-smokers in the high (2.5; 2.1, 3.1), intermediate (2.1; 1.8, 2.4), and low (2.0; 1.9, 2.2) educational groups did not differ markedly (P for interaction=0.61). Similar findings emerged when using cause-specific outcomes and occupational social class and housing tenure as socioeconomic indices. Conclusion Contrary to our hypothesis, we found no indication that chronic disease mortality associated with smoking was higher in disadvantaged people.

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVD). Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. Design, setting and participants: A pooled analysis of individual-participant-data from the Emerging Risk Factors Collaboration (ERFC; 162,036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and UK Biobank (UKB; 401,219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline. Exposure: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Centre for Epidemiological Studies Depression scale (CES-D; range 0-60; ≥16 indicates possible depressive disorder). UKB recorded the Patient Health Questionnaire-2 (PHQ-2; range 0-6; ≥3 indicates possible depressive disorder). Main Outcomes and Measures: Primary outcomes were incident fatal/nonfatal coronary heart disease (CHD), stroke and CVD (composite of CHD and stroke). Hazard ratios (HRs) per 1-SD higher log-CES-D or PHQ-2 adjusted for age, sex, smoking and diabetes were reported. Results: Among 162,036 participants from the ERFC, 73% were female, mean (SD) age at baseline was 63 (9) years, and 5,078 CHD and 3,932 stroke events were recorded (median follow-up, 9.5-years). Associations with CHD, stroke and CVD were log-linear. HRs (95%CI) per 1SD higher depression score for CHD, stroke and CVD respectively were 1.07 (1.03-1.11), 1.05 (1.01-1.10), and 1.06 (1.04-1.08). This reflects, 36 versus 29 CHD events, 28 versus 25 stroke events, and 63 versus 54 CVD events per 1000 individuals over 10 years in the highest versus lowest quintile of CES-D (geometric mean CES-D score, 19 versus 1). Among 401,219 participants from the UKB, 55% were female, mean baseline age was 56 (8) years, and 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1-years). HRs per 1SD higher depression score for CHD, stroke and CVD respectively were 1.11 (1.08-1.14), 1.10 (1.06-1.14) and 1.10 (1.08-1.13). This reflects, 21 versus 14 CHD events, 15 versus 10 stroke events, and 36 versus 25 CVD events per 1000 individuals over 10 years in those with PHQ2 ≥4 versus 0. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. Conclusions and Relevance: In a pooled analysis of 563,255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels below the threshold indicative of a depressive disorder. However, the magnitude of associations was modest., Lisa Pennells, Stephen Kaptoge and Sarah Spackman are funded by a British Heart Foundation Programme Grant (RG/18/13/33946). Steven Bell was funded by the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Tom Bolton is funded by the National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Angela Wood is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). John Danesh holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award.* *The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

BACKGROUND: Physical functioning (PF) is an essential domain of older persons' health and quality of life. Health behaviors are the main modifiable determinants of PF. Cross-sectionally, alcohol consumption appears to be linked to better PF, but longitudinal evidence is mixed and very little is known about alcohol consumption and longitudinal PF trajectories. METHODS: We conducted longitudinal analyses of 28,783 men and women aged 45-69 years from Novosibirsk (Russia), Krakow (Poland), and seven towns of the Czech Republic. At baseline, alcohol consumption was measured by a graduated frequency questionnaire and problem drinking was evaluated using the CAGE questionnaire. PF was assessed using the Physical Functioning Subscale of the SF-36 instrument at baseline and three subsequent occasions. Growth curve modeling was used to estimate the associations between alcohol consumption and PF trajectories over 10-year follow-up. RESULTS: PF scores declined during follow-up in all three cohorts. Faster decline in PF over time was found in Russian female frequent drinkers, Polish female moderate drinkers, and Polish male regular heavy drinkers, in comparison with regular and/or light-to-moderate drinkers. Nondrinking was associated with a faster decline compared with light drinking only in Russian men. Problem drinking and past drinking were not related to the decline rate of PF. CONCLUSIONS: This large longitudinal study in Central and Eastern European populations with relatively high alcohol intake does not strongly support the existence of a protective effect of alcohol on PF trajectories; if anything, it suggests that alcohol consumption is associated with greater deterioration in PF over time.

Internationally, laws on the provision of alcohol commonly exempt that provided by parents and/or consumed in private premises. Whether these exemptions mitigate alcohol-related harms, as has been posited, is unclear. We used data from 10,968 individuals (5216 women) from the 1970 British Birth Cohort Study. Exposures, self-reported at 16-years of age, were consumption of alcohol with specific people (including parents, siblings and friends) and acquisition from different places (including their own home). The outcomes, self-reported at 30-years of age, were high alcohol consumption (>14 units of alcohol in the last week), and screening positive for a possible alcohol problem using the cutting down, being annoyed by criticism, feeling guilty, and eye-openers (CAGE) questionnaire. At 30-years of age, 32.1% of study members consumed >14 units in the last week and 14.3% screened positive on the CAGE questionnaire. Neither consuming alcohol with parents nor the acquisition of alcohol from home was associated with later high consumption or alcohol problems. There was a suggestion, however, that drinking with other teenagers was related to an increased risk of both outcomes (consumption: 1.32 (1.16, 1.51); alcohol problems: 1.27 (1.01, 1.58), as was acquisition from an off-license (consumption: 1.23 (0.99, 1.51); alcohol problems: 1.49 (1.17, 1.90). This study strengthens the evidence that alcohol consumption with parents, or acquisition from home, does not protect against later alcohol-related harms., Highlights • Alcohol laws commonly exempt that provided by parents and/or consumed in private premises. • Drinking with parents did not protect against later alcohol problems. • Getting alcohol from home did not protect against later alcohol problems. • This study adds to evidence questioning exemptions allowing underage drinking.

SB is supported by grants from the European Research Council and the UK Medical Research Council/Alcohol Research UK.

It has recently been advanced that animal companionship confers protection against leading causes of death, such as cardiovascular disease, potentially via the weight control associated with the ownership of pets whose care requires physical exertion. By means of other mechanisms, there are also reasons to anticipate that pet ownership may have an impact on other important health outcomes such as suicide, another major cause of premature mortality particularly in people under 50 years of age. Thus, human–animal interaction appears to have a favourable impact on selected risk factors for suicide, including interpersonal interactions, mood, anxiety, positive attention from others, and stimulation of social behaviour. The benefits of animal contact also seem to extend to biomarkers of psychosocial stress, such as lower levels of cortisol, heart rate, and blood pressure. Despite this circumstantial evidence, to the best of our knowledge, there has been no prospective examination of the link, if any, between animal companionship and suicide.

Elevated blood pressure is a leading cause of cardiovascular disease and related disability world-wide.1 It is a largely preventable condition influenced by a range of lifestyle behaviours, including but not limited to, level of physical activity, poor diet and alcohol consumption. In this issue of the Journal of the American Heart Association, two articles make important incremental contributions in extending the evidence base of the latter.

Objective To examine the prospective relation between animal companionship and biomarkers of ageing in older people. Design Analyses of data from the English Longitudinal Study of Ageing, an ongoing, open, prospective cohort study initiated in 2002-03. Setting Nationally representative study from England. Participants 8785 adults (55% women) with a mean age of 67 years (SD 9) at pet ownership assessment in 2010-11 (wave 5). Main outcome measure Established biomarkers of ageing in the domains of physical, immunological, and psychological function, as assessed in 2012-13 (wave 6). Results One third of study members reported pet ownership: 1619 (18%) owned a dog, 1077 (12%) a cat, and 274 (3%) another animal. After adjustment for a range of covariates, there was no evidence of a clear association of any type of pet ownership with walking speed, lung function, chair rise time, grip strength, leg raises, balance, three markers of systemic inflammation, memory, or depressive symptoms. Conclusion In this population of older adults, the companionship of creatures great and small seems to essentially confer no relation with standard ageing phenotypes.psychological biomarkers of ageing.

Objective To examine the prospective relation between animal companionship and biomarkers of ageing in older people. Design Analyses of data from the English Longitudinal Study of Ageing, an ongoing, open, prospective cohort study initiated in 2002-03. Setting Nationally representative study from England. Participants 8785 adults (55% women) with a mean age of 67 years (SD 9) at pet ownership assessment in 2010-11 (wave 5). Main outcome measure Established biomarkers of ageing in the domains of physical, immunological, and psychological function, as assessed in 2012-13 (wave 6). Results One third of study members reported pet ownership: 1619 (18%) owned a dog, 1077 (12%) a cat, and 274 (3%) another animal. After adjustment for a range of covariates, there was no evidence of a clear association of any type of pet ownership with walking speed, lung function, chair rise time, grip strength, leg raises, balance, three markers of systemic inflammation, memory, or depressive symptoms. Conclusion In this population of older adults, the companionship of creatures great and small seems to essentially confer no relation with standard ageing phenotypes.

International audience; BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Pedestrian crossings in the UK and US require people to walk at 1.2 m/s to cross the road in time; however a large proportion of older people do not walk this fast, potentially discouraging walking or putting older people at risk of injury. We use longitudinal data to investigate changes in walking speed, and ability to cross the road in time, at older ages. 31,015 walking speed measurements were taken from 10,249 men and women aged 60+ years in waves 1–7 of the English Longitudinal Study of Ageing (2002–2014). Growth curve analyses were used to model how walking speed changes with increasing age, and predicted probabilities of being able to cross the road in time were estimated. 10% of measured walking speeds were fast enough to cross the road in time. Walking speed declined with age (−5.7×10$^{−3}$m/s/yr (95% CI −7.6×10$^{−3}$, −3.9×10$^{−3}$)), and the decline accelerated with increasing age (−0.3 ×10$^{−3}$m/s/yr (−0.4 ×10$^{−3}$, −0.3 ×10$^{−3}$)). Female, less wealthy and less healthy older people had slower walking speeds. For instance, predicted probability of crossing the road in time at age 60 was 14.8% (10.1, 18.5) and 2.7% (1.5, 3.8) for the richest and poorest men and 8.4% (6.0, 1.1) and 1.5% (0.9, 2.2) for the richest and poorest women, and at age 80 they were 7.1% (3.6, 10.5) and 1.0% (0.3, 1.7) for the richest and poorest men and 3.7% (1.6, 5.9) and 0.5% (0.1, 0.9) for the richest and poorest women. Most older people do not walk fast enough to cross the road in time. Even the majority of the wealthiest and healthiest people aged 60 years and older do not walk fast enough to cross pedestrian crossings in the allocated time. Crossing times should be increased to allow for older peoples’ slower walking speeds or other policies considered to improve walkability, and to help avoid injuries and social isolation.

BACKGROUND: Emerging evidence suggests that arterial stiffness, an important marker of cardiovascular health, is associated with alcohol consumption. However, the role of longer-term consumption patterns in the progression of arterial stiffness over time remains unclear. A longitudinal cohort design was used to evaluate the association between alcohol consumption over 25 years and subsequent changes in arterial stiffness. METHODS AND RESULTS: Data (N=3869; 73% male) were drawn from the Whitehall II cohort study of British civil servants, in which participants completed repeat pulse wave velocity assessments of arterial stiffness across a 4- to 5-year interval. Repeated alcohol intake measurements were used to categorize participants into alcohol consumer types, accounting for longitudinal variability in consumption. Sex-stratified linear mixed-effects modeling was used to investigate whether drinker types differed in their relationship to pulse wave velocity and its progression over time. Males with consistent long-term heavy intake >112 g of ethanol/week had significantly higher baseline pulse wave velocity (b=0.26 m/s; P=0.045) than those who drank consistently moderately (1-112 g of ethanol/week). Male former drinkers showed significantly greater increases in arterial stiffness longitudinally compared to consistently moderate drinkers (b=0.11 m/s; P=0.009). All associations were nonsignificant for females after adjustment for body mass index, heart rate, mean arterial pressure, diabetes mellitus, high-density lipoprotein, and triglycerides. CONCLUSIONS: This work demonstrates that consistently heavy alcohol consumption is associated with higher cardiovascular risk, especially among males, and also provides new insights into the potential impact of changes in drinking levels over time. It discusses the additional insights possible when capturing longitudinal consumption patterns in lieu of reliance on recent intake alone. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02663791.

$\textbf{Objectives }$ To investigate the association between alcohol consumption and cardiovascular disease at higher resolution by examining the initial lifetime presentation of 12 cardiac, cerebrovascular, abdominal, or peripheral vascular diseases among five categories of consumption. $\textbf{Design}$ Population based cohort study of linked electronic health records covering primary care, hospital admissions, and mortality in 1997-2010 (median follow-up six years). $\textbf{Setting }$ CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). $\textbf{Participants }$ 1 937 360 adults (51% women), aged ≥30 who were free from cardiovascular disease at baseline. $\textbf{Main outcome measures}$ 12 common symptomatic manifestations of cardiovascular disease, including chronic stable angina, unstable angina, acute myocardial infarction, unheralded coronary heart disease death, heart failure, sudden coronary death/cardiac arrest, transient ischaemic attack, ischaemic stroke, intracerebral and subarachnoid haemorrhage, peripheral arterial disease, and abdominal aortic aneurysm. $\textbf{Results }$ 114 859 individuals received an incident cardiovascular diagnosis during follow-up. Non-drinking was associated with an increased risk of unstable angina (hazard ratio 1.33, 95% confidence interval 1.21 to 1.45), myocardial infarction (1.32, 1.24 to1.41), unheralded coronary death (1.56, 1.38 to 1.76), heart failure (1.24, 1.11 to 1.38), ischaemic stroke (1.12, 1.01 to 1.24), peripheral arterial disease (1.22, 1.13 to 1.32), and abdominal aortic aneurysm (1.32, 1.17 to 1.49) compared with moderate drinking (consumption within contemporaneous UK weekly/daily guidelines of 21/3 and 14/2 units for men and women, respectively). Heavy drinking (exceeding guidelines) conferred an increased risk of presenting with unheralded coronary death (1.21, 1.08 to 1.35), heart failure (1.22, 1.08 to 1.37), cardiac arrest (1.50, 1.26 to 1.77), transient ischaemic attack (1.11, 1.02 to 1.37), ischaemic stroke (1.33, 1.09 to 1.63), intracerebral haemorrhage (1.37, 1.16 to 1.62), and peripheral arterial disease (1.35; 1.23 to 1.48), but a lower risk of myocardial infarction (0.88, 0.79 to 1.00) or stable angina (0.93, 0.86 to 1.00). $\textbf{Conclusions }$ Heterogeneous associations exist between level of alcohol consumption and the initial presentation of cardiovascular diseases. This has implications for counselling patients, public health communication, and clinical research, suggesting a more nuanced approach to the role of alcohol in prevention of cardiovascular disease is necessary. $\textbf{Registration }$ clinicaltrails.gov (NCT01864031).

Selection biases may have led to beneficial effects of moderate drinking being over estimated; however, they are unlikely to entirely explain the J-shaped curve. Even if all beneficial effects were eliminated, our ranking of alcohol as a public health burden would not change, nor our efforts to limit its harm.

BACKGROUND/OBJECTIVES: Combining work and family responsibilities has previously been associated with improved health in mid-life, yet little is known about how these associations change over time (both biographical and historical) and whether this extends to body mass index (BMI) trajectories for British men and women. The purpose of this study was to investigate relationships between work-family life courses and BMI trajectories across adulthood (16-42 years) for men and women in three British birth cohorts. SUBJECTS/METHODS: Multiply imputed data from three nationally representative British birth cohorts were used-the MRC National Survey of Health and Development (NSHD; 1946 birth cohort, n=3012), the National Child Development Study (NCDS; 1958 birth cohort, n=9614) and the British Cohort Study (BCS; 1970 birth cohort, n=8140). A typology of work-family life course types was developed using multi-channel sequence analysis, linking annual information on work, partnerships and parenthood from 16 to 42 years. Work-family life courses were related to BMI trajectories using multi-level growth models. Analyses adjusted for indicators of prior health, birthweight, child BMI, educational attainment and socioeconomic position across the life course, and were stratified by gender and cohort. RESULTS: Work-family life courses characterised by earlier transitions to parenthood and weaker long-term links to employment were associated with greater increases in BMI across adulthood. Some of these differences, particularly for work-family groups, which are becoming increasingly non-normative, became more pronounced across cohorts (for example, increases in BMI between 16 and 42 years in long-term homemaking women: NSHD: 4.35 kg m-2, 95% confidence interval (CI): 3.44, 5.26; NCDS: 5.53 kg m-2, 95% CI: 5.18, 5.88; BCS: 6.69 kg m-2, 95% CI: 6.36, 7.02). CONCLUSIONS: Becoming a parent earlier and weaker long-term ties to employment are associated with greater increases in BMI across adulthood in British men and women.

BACKGROUND: Moderate alcohol consumption is thought to confer cardiometabolic protective effects. Inflammatory pathways are hypothesized to partly underlie this association. OBJECTIVES: The aim of this study was to examine the association between typologies of alcohol consumption and markers of inflammation, and their rate of change over time. METHODS: Data were collected from 8209 participants [69% men; mean age, 50 years (SD 6.1)] of the British Whitehall II study. Alcohol consumption typologies were defined using up to three measures during an approximately 10-year period spanning from 1985 to 1994 as (i) stable nondrinkers, (ii) stable moderate drinkers (referent), (iii) stable heavy drinkers, (iv) nonstable drinkers and (v) former drinkers. C-reactive protein (CRP), interleukin (IL)-6 and IL-1 receptor antagonist (IL-1 RA) were measured up to three times in the following 12 years. RESULTS: Stable moderate drinkers had lower levels of CRP than stable nondrinkers, stable heavy drinkers, former drinkers and nonstable drinkers, but there were no differences in the rate of change in CRP over time between groups. Stable nondrinkers had higher levels of IL-6 as did stable heavy drinkers; rates of change in IL-6 over time were also increased in the latter group. Stable nondrinkers also had higher levels of IL-1 RA. These associations were robust to adjustment for confounding factors. CONCLUSION: Our novel investigation of 10-year drinking typologies shows that stable moderate alcohol consumption is associated with a long-term inflammatory marker profile that is consistent with conferring a reduced risk of developing coronary heart disease.

OBJECTIVE: To examine the association between alcohol consumption in midlife and subsequent cognitive decline. METHODS: Data are from 5,054 men and 2,099 women from the Whitehall II cohort study with a mean age of 56 years (range 44-69 years) at first cognitive assessment. Alcohol consumption was assessed 3 times in the 10 years preceding the first cognitive assessment (1997-1999). Cognitive tests were repeated in 2002-2004 and 2007-2009. The cognitive test battery included 4 tests assessing memory and executive function; a global cognitive score summarized performances across these tests. Linear mixed models were used to assess the association between alcohol consumption and cognitive decline, expressed as z scores (mean = 0, SD = 1). RESULTS: In men, there were no differences in cognitive decline among alcohol abstainers, quitters, and light or moderate alcohol drinkers (

$\textbf{Aims}$: Increases in glass sizes and wine strength over the last 25 years in the UK are likely to have led to an underestimation of alcohol intake in population studies. We explore whether this probable misclassification affects the association between average alcohol intake and risk of mortality from all causes, cardiovascular disease and cancer. $\textbf{Methods}$: Self-reported alcohol consumption in 1997–1999 among 7010 men and women in the Whitehall II cohort of British civil servants was linked to the risk of mortality until mid-2015. A conversion factor of 8 g of alcohol per wine glass (1 unit) was compared with a conversion of 16 g per wine glass (2 units). $\textbf{Results}$: When applying a higher alcohol content conversion for wine consumption, the proportion of heavy/very heavy drinkers increased from 28% to 41% for men and 15% to 28% for women. There was a significantly increased risk of very heavy drinking compared with moderate drinking for deaths from all causes and cancer before and after change in wine conversion; however, the hazard ratios were reduced when a higher wine conversion was used. $\textbf{Conclusions}$: In this population-based study, assuming higher alcohol content in wine glasses changed the estimates of mortality risk. We propose that investigator-led cohorts need to revisit conversion factors based on more accurate estimates of alcohol content in wine glasses. Prospectively, researchers need to collect more detailed information on alcohol including serving sizes and strength.

Background Epidemiological evidence indicates a protective effect of light-moderate drinking on cardiovascular disease and an increased risk for heavier drinking. Nevertheless, the effect of alcohol on atherosclerotic changes in vessel walls is disputed. Most previous studies have only looked at the cross-sectional relationship between alcohol and carotid intima media thickness (cIMT) – a surrogate marker of atherosclerosis. Single measurements of alcohol assume that alcohol exposure is stable and ignore the possible cumulative effects of harm, leading to possibly incorrect inferences. Methods Data were retrieved from two UK population based cohort studies: the Whitehall II cohort of civil servants and the MRC National Survey of Health and Development (combined sample size of 5403 men and women). Twenty year-drinking trajectories during midlife were linked to measures of cIMT when participants were in early old age, and adjusted for age, sex, socioeconomic position, ethnicity and smoking. Results Those who consistently drank heavily had an increased cIMT compared to stable moderate drinkers (pooled difference in cIMT 0.021 mm; 95 % CI 0.002 to 0.039), after adjustment for covariates. This was not detected in cross-sectional analyses. Former drinkers also had an increased cIMT compared to moderate drinkers (pooled difference in cIMT 0.021; 95 % CI 0.005 to 0.037). There were no appreciable differences in cIMT between non-drinkers and consistent moderate drinkers. Conclusion The drinking habits among adults during midlife affect the atherosclerotic process and sustained heavy drinking is associated with an increased cIMT compared to stable moderate drinkers. This finding was not seen when only using cross-sectional analyses, thus highlighting the importance of taking a life course approach. There was no evidence of a favourable atherosclerotic profile from stable moderate drinking compared to stable non-drinking. Electronic supplementary material The online version of this article (doi:10.1186/s12916-016-0656-9) contains supplementary material, which is available to authorized users.

AIMS: To examine the individual and cumulative effects of adverse childhood experiences (ACEs) on alcohol consumption in midlife and early old-age, and the role of ACEs in 10-year drinking trajectories across midlife. METHODS: Data were from the Whitehall II study, a longitudinal British civil service-based cohort study (N = 7870, 69.5% male). Multinomial logistic regression was used to examine the individual and cumulative effects of ACEs on weekly alcohol consumption. Mixed-effect multilevel modelling was used to explore the relationship between ACEs and change in alcohol consumption longitudinally. RESULTS: Participants who were exposed to parental arguments/fights in childhood were 1.24 (95% CI 1.06, 1.45) times more likely to drink at hazardous levels in midlife (mean age 56 years) after controlling for covariates and other ACEs. For each additional exposure to an ACE, the risk of hazardous drinking versus moderate drinking was increased by 1.12 (95% CI 1.03, 1.21) after adjusting for sex, age, adult socio-economic status, ethnicity and marital status. No associations between ACEs and increased risk of hazardous drinking in early old-age (mean age 66 years) were found. In longitudinal analyses, ACEs did not significantly influence 10-year drinking trajectories across midlife. CONCLUSION: The effect of exposure to parental arguments on hazardous drinking persists into midlife. Language: en

OBJECTIVE Observational studies indicate that moderate levels of alcohol consumption may reduce the risk of type 2 diabetes. In addition to providing an updated summary of the existing literature, this meta-analysis explored whether reductions in risk may be the product of misclassification bias. RESEARCH DESIGN AND METHODS A systematic search was undertaken, identifying studies that reported a temporal association between alcohol consumption and the risk of type 2 diabetes. No restrictions were placed upon the language or date of publication. Non-English publications were, where necessary, translated using online translation tools. Models were constructed using fractional polynomial regression to determine the best-fitting dose-response relationship between alcohol intake and type 2 diabetes, with a priori testing of sex and referent group interactions. RESULTS Thirty-eight studies met the selection criteria, representing 1,902,605 participants and 125,926 cases of type 2 diabetes. A conventional noncurrent drinking category was reported by 33 studies, while five reported a never-drinking category. Relative to combined abstainers, reductions in the risk of type 2 diabetes were present at all levels of alcohol intake CONCLUSIONS Reductions in risk among moderate alcohol drinkers may be confined to women and non-Asian populations. Although based on a minority of studies, there is also the possibility that reductions in risk may have been overestimated by studies using a referent group contaminated by less healthy former drinkers.