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Background Treatment guidelines for prediabetes primarily focus on glycemic control and lifestyle management. Few evidence-based cardiovascular and kidney risk-reduction strategies are available in this population. Objectives This study sought to characterize cardiovascular and kidney outcomes across the glycemic spectrum. Methods Among participants in the UK Biobank without prevalent type 1 diabetes, cardiovascular disease, or kidney disease, Cox models tested the association of glycemic exposures (type 2 diabetes [T2D], prediabetes, normoglycemia) with outcomes (atherosclerotic cardiovascular disease [ASCVD], chronic kidney disease [CKD], and heart failure), adjusting for demographic, lifestyle, and cardiometabolic risk factors. Results Among 336,709 individuals (mean age: 56.3 years, 55.4% female), 46,911 (13.9%) had prediabetes and 12,717 (3.8%) had T2D. Over median follow-up of 11.1 years, 6,476 (13.8%) individuals with prediabetes developed ≥1 incident outcome, of whom only 802 (12.4%) developed T2D prior to an incident diagnosis. Prediabetes and T2D were independently associated with ASCVD (prediabetes: adjusted HR [aHR]: 1.11; 95% CI: 1.08-1.15; P Conclusions Prediabetes and T2D were associated with ASCVD, CKD, and heart failure, but a substantial gradient of risk was observed across HbA1c levels below the threshold for diabetes. These findings highlight the need to design risk-reduction strategies across the glycemic spectrum.

Background Small studies have correlated hypertension with pneumonia risk; whether this is recapitulated in larger prospective studies, and represents a causal association, is unclear. Methods We estimated the risk for prevalent hypertension with incident respiratory diseases over mean follow-up of 8 years among 377,143 British participants in the UK Biobank. Mendelian randomization of blood pressure on pneumonia was implemented using 75 independent, genome-wide significant variants associated with systolic and diastolic blood pressures among 299,024 individuals not in the UK Biobank. Secondary analyses with pulmonary function tests were performed. Findings In total, 107,310 participants (30%) had hypertension at UK Biobank enrollment, and 9,969 (3%) developed pneumonia during follow-up. Prevalent hypertension was independently associated with increased risk for incident pneumonia (HR: 1.36; 95% CI: 1.29–1.43; p < 0.001), as well as other incident respiratory diseases. Genetic predisposition to a 5 mm Hg increase in blood pressure was associated with increased risk for incident pneumonia for systolic blood pressure (HR: 1.08; 95% CI: 1.04–1.13; p < 0.001) and diastolic blood pressure (HR: 1.11; 95% CI: 1.03–1.20; p = 0.005). Additionally, consistent with epidemiologic associations, increased blood pressure genetic risk was significantly associated with reduced performance on pulmonary function tests (p < 0.001). Conclusions These results suggest that elevated blood pressure increases risk for pneumonia. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia. Funding S.M.Z. (1F30HL149180-01), M.H. (T32HL094301-07), and P.N. (R01HL1427, R01HL148565, and R01HL148050) are supported by the National Institutes of Health. J.P. is supported by the John S. LaDue Memorial Fellowship., Graphical Abstract, Highlights We linked high BP and incident pneumonia in the UK Biobank using epidemiology and genetics Hypertension was associated with increased risk for incident pneumonia Genetically elevated BP increased risk for incident pneumonia Hypertension and genetically elevated BP also reduced pulmonary function, Context and Significance Epidemiologic analyses have correlated hypertension with pneumonia risk. Whether this represents a direct consequence of hypertension or the influence of co-morbid risk factors such as age, diabetes mellitus, or smoking is unclear. Here, across 377,143 individuals from the UK Biobank, we show that hypertension is independently associated with significantly increased risk for incident pneumonia. Additionally, using Mendelian randomization, we show that a genetic predisposition to elevated blood pressure across 75 independent genetic variants is associated with increased risk for incident pneumonia and reduced pulmonary function test performance. These results suggest that elevated blood pressure may be a causal risk factor for pneumonia. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia., Through epidemiological and genetic association analyses in the UK Biobank (N = 377,143), Zekavat et al. link high blood pressure with increased risk for incident pneumonia and reduced performance on pulmonary function tests. These results suggest that maintaining adequate blood pressure control may reduce risk for pneumonia and improve pulmonary function.

Protein truncating variants (PTVs) are likely to modify gene function and have been linked to hundreds of Mendelian disorders. However, the impact of PTVs on complex traits has been limited by the available sample size of whole-exome sequencing studies (WES). Here we assemble WES data from 100,304 individuals to quantify the impact of rare PTVs on 13 quantitative traits and 10 diseases. We focus on those PTVs that occur in PTV-intolerant (PI) genes, as these are more likely to be pathogenic. Carriers of at least one PI-PTV were found to have an increased risk of autism, schizophrenia, bipolar disorder, intellectual disability and ADHD (P-value (p) range: 5x10-3-9x10-12). In controls, without these disorders, we found that this burden associated with increased risk of mental, behavioral and neurodevelopmental disorders as captured by electronic health record information. Furthermore, carriers of PI-PTVs tended to be shorter (p=2x10-5), have fewer years of education (p=2x10-4) and be younger (p=2x10-7); the latter observation possibly reflecting reduced survival or study participation. While other gene-sets derived from in vivo experiments did not show any associations with PTV-burden, gene sets implicated in GWAS of cardiovascular-related traits and inflammatory bowel disease showed a significant PTV-burden with corresponding traits, mainly driven by established genes involved in familial forms of these disorders. We leveraged population health registries from 14,117 individuals to study the phenome-wide impact of PI-PTVs and identified an increase in the number of hospital visits among PI-PTV carriers. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

We developed an in silico mathematical model of retinal cholesterol (Ch) dynamics (RCD) to quantify the physiological rate of Ch turnover in the rod outer segment (ROS), the lipoprotein transport mechanisms by which Ch enters and leaves the outer retina, and the rates of drusen growth and macrophage-mediated clearance in dry age-related macular degeneration. Based on existing experimental data and mechanistic hypotheses, we estimated the Ch turnover rate in the ROS to be 1–6 pg/mm2/min, dependent on the rate of Ch recycling in the outer retina, and found comparable rates for LDL receptor-mediated endocytosis of Ch by the retinal pigment epithelium (RPE), ABCA1-mediated Ch transport from the RPE to the outer retina, ABCA1-mediated Ch efflux from the RPE to the choroid, and the secretion of 70 nm ApoB-Ch particles from the RPE. The drusen growth rate is predicted to increase from 0.7 to 4.2 μm/year in proportion to the flux of ApoB-Ch particles. The rapid regression of drusen may be explained by macrophage-mediated clearance if the macrophage density reaches ∼3,500 cells/mm2. The RCD model quantifies retinal Ch dynamics and suggests that retinal Ch turnover and recycling, ApoB-Ch particle efflux, and macrophage-mediated clearance may explain the dynamics of drusen growth and regression.

Background: Small studies have correlated hypertension with pneumonia risk; whether this is recapitulated in larger prospective studies, and represents a causal association, is unclear. Methods and Results: We estimated the risk of prevalent hypertension with incident respiratory diseases over mean 8 follow-up years among 377,143 British participants in the UK Biobank. Mendelian randomization of blood pressure on pneumonia was implemented using 75 independent, genome-wide significant variants associated with systolic and diastolic blood pressures among 299,024 individuals not in the UK Biobank. Secondary analyses with pulmonary function tests were performed.107,310 (30%) participants had hypertension at UK Biobank enrollment, and 9,969 (3%) developed a pneumonia during follow-up. Prevalent hypertension was independently associated with increased risk for incident pneumonia (HR: 1.36; 95% CI: 1.29 to 1.43; P

Early menopause has been associated with risk of heart failure. Further, aging is associated with smaller left ventricular end-diastolic volume (LVEDV). The relationship of age at menopause with LV remodeling is unknown. Women in the UK Biobank who were postmenopausal, completed cardiac magnetic