Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified ...associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression information identified 94 effector genes for 109 metabolites and 48 metabolite ratios. Using Mendelian randomization (MR), we identified 22 metabolites and 20 metabolite ratios having estimated causal effect on 12 traits and diseases, including orotate for estimated bone mineral density, α-hydroxyisovalerate for body mass index and ergothioneine for inflammatory bowel disease and asthma. We further measured the orotate level in a separate cohort and demonstrated that, consistent with MR, orotate levels were positively associated with incident hip fractures. This study provides a valuable resource describing the genetic architecture of metabolites and delivers insights into their roles in common diseases, thereby offering opportunities for therapeutic targets.
Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively ...little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from β-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.
The deterioration of the inner blood-retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss ...of sight. We provide evidence from both human and animal studies for the critical role of the classical neuronal guidance cue, semaphorin 3A, in instigating pathological vascular permeability in diabetic retinas via its cognate receptor neuropilin-1. We reveal that semaphorin 3A is induced in early hyperglycemic phases of diabetes within the neuronal retina and precipitates initial breakdown of endothelial barrier function. We demonstrate, by a series of orthogonal approaches, that neutralization of semaphorin 3A efficiently prevents diabetes-induced retinal vascular leakage in a stage of the disease when vascular endothelial growth factor neutralization is inefficient. These observations were corroborated in TgCre-Esr1/Nrp1flox/flox conditional knockout mice. Our findings identify a therapeutic target for macular edema and provide further evidence for neurovascular crosstalk in the pathogenesis of DR.
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•The guidance cue semaphorin 3A is induced in the early phases of diabetes in the retina•Semaphorin 3A instigates pathological vascular permeability in diabetes via NRP-1•Neutralization of semaphorin 3A prevents retinal vascular leakage in diabetes
Idiopathic pulmonary fibrosis (IPF) is a progressive form of fibrosing interstitial pneumonia with poor survival. This study provides insight into the epidemiology, cost, and disease course of IPF in ...Germany.
A cohort of incident patients with IPF (n = 1737) was identified from German claims data (2014-2019). Incidence and prevalence rates were calculated and adjusted for age differences compared with the overall German population. All-cause and IPF-related healthcare resource utilization as well as associated costs were evaluated per observed person-year (PY) following the initial IPF diagnosis. Finally, Kaplan-Meier analyses were performed to assess time from initial diagnosis to disease deterioration (using three proxy measures: non-elective hospitalization, IPF-related hospitalization, long-term oxygen therapy LTOT); antifibrotic therapy initiation; and all-cause death.
The cumulative incidence of IPF was estimated at 10.7 per 100,000 individuals in 2016, 10.9 in 2017, 10.5 in 2018, and 9.6 in 2019. The point prevalence rates per 100,000 individuals for the respective years were 21.7, 23.5, 24.1, and 24.1. On average, ≥ 14 physician visits and nearly two hospitalizations per PY were observed after the initial IPF diagnosis. Of total all-cause direct costs (€15,721/PY), 55.7% (€8754/PY) were due to hospitalizations and 29.1% (€4572/PY) were due to medication. Medication accounted for 49.4% (€1470/PY) and hospitalizations for 34.8% (€1034/PY) of total IPF-related direct costs (€2973/PY). Within 2 years of the initial IPF diagnosis (23.6 months), 25% of patients died. Within 5 years of diagnosis, 53.1% of patients had initiated LTOT; only 11.6% were treated with antifibrotic agents. The median time from the initial diagnosis to the first non-elective hospitalization was 5.5 months.
The incidence and prevalence of IPF in Germany are at the higher end of the range reported in the literature. The main driver for all-cause cost was hospitalization. IPF-related costs were mainly driven by medication, with antifibrotic agents accounting for around one-third of the total medication costs even if not frequently prescribed. Most patients with IPF do not receive pharmacological treatment, highlighting the existing unmet medical need for effective and well-tolerated therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in the working-age population. Impaired blood-retinal barrier function leads to macular edema that is ...closely associated with the deterioration of central vision. We previously demonstrated that the neuronal guidance cue netrin-1 activates a program of reparative angiogenesis in microglia within the ischemic retina. Here, we provide evidence in both vitreous humor of diabetic patients and in retina of a murine model of diabetes that netrin-1 is metabolized into a bioactive fragment corresponding to domains VI and V of the full-length molecule. In contrast to the protective effects of full-length netrin-1 on retinal microvasculature, the VI-V fragment promoted vascular permeability through the uncoordinated 5B (UNC5B) receptor. The collagenase matrix metalloprotease 9 (MMP-9), which is increased in patients with diabetic macular edema, was capable of cleaving netrin-1 into the VI-V fragment. Thus, MMP-9 may release netrin-1 fragments from the extracellular matrix and facilitate diffusion. Nonspecific inhibition of collagenases or selective inhibition of MMP-9 decreased pathological vascular permeability in a murine model of diabetic retinal edema. This study reveals that netrin-1 degradation products are capable of modulating vascular permeability, suggesting that these fragments are of potential therapeutic interest for the treatment of DR.
AbstractObjectiveTo determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures.DesignMendelian randomisation ...study.SettingCohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics).ParticipantsA genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed.ResultsA standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm2, 95% confidence interval −0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects.ConclusionsGenetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.
Abstract
Background/Aims
The safety profile of filgotinib (FIL), a second-generation oral Janus kinase (JAK) 1 preferential inhibitor approved in Europe, Japan, and the UK for treatment of rheumatoid ...arthritis (RA) has been reported. In patients (pts) with active RA aged ≥50y with ≥1 cardiovascular (CV) risk factor, treated with the pan-JAK inhibitor tofacitinib, data from an interventional post-marketing study (NCT02092467) suggested a higher risk of major adverse cardiovascular events (MACE) and malignancies compared with TNF inhibitors. No data are available from a similar prospective study with FIL. This post hoc exploratory analysis aimed to describe the incidence of MACE and malignancies in a subgroup of pts with RA from the FINCH and DARWIN clinical trials, receiving FIL 200 mg (FIL200) and FIL 100 mg (FIL100).
Methods
Exploratory analysis of adverse events of special interest are reported using integrated FIL RA data from phase 2 (NCT01668641, NCT01894516), phase 3 (NCT02889796, NCT02873936, NCT02886728), and the long-term extension (LTE) studies DARWIN 3 (NCT02065700) and FINCH 4 (NCT03025308), in a pt population at higher risk of CV events similar to ORAL-SURVEILLANCE,1 namely, aged ≥50y with ≥1 CV risk factor (history of dyslipidemia, diabetes or CV disease; hypertension, ischemic vascular conditions, peripheral vascular disease, extra-articular manifestations of RA; or current smokers). All pts met ACR criteria for functional class I-III. Censored exposure-adjusted incidence rates (EAIRs)/100 pt-years of exposure for MACE, venous thromboembolism (VTE), malignancies excluding nonmelanoma skin cancer (NMSC), NMSC, (serious) infections, and deaths were determined. Data were as of Jan 11, 2022 (DARWIN 3) and Jan 31, 2022 (FINCH 4). Analyses were performed on an ad hoc interim analysis data set without additional cleaning.
Results
The higher-risk population included 1484 pts: mean age 62.1y (536 36.1% aged ≥65y), 291 (22.5%) current smokers, and 904 (60.9%) received background MTX; baseline (BL) MTX use was higher in the FIL100 vs FIL200 group (66.6% vs 54.6%); other BL demographics were balanced. Numerically higher EAIRs for malignancies (excluding NMSC), NMSC, serious infections, and deaths were observed for pts receiving FIL200 vs FIL100; 95% confidence intervals overlapped. For MACE and VTE, incidence is considered similar for both doses. The risk of experiencing MACE, malignancies excluding NMSC, and NMSC over time with FIL100 or FIL200 will be described.
Conclusion
In this RA population at higher risk of CV events, the incidence of MACE and VTE was similar for both doses. A numerically higher incidence of malignancies (excluding NMSC), NMSC, serious infections, and deaths was observed in the high- vs low-dose group. Limitations included population selection bias, low event numbers, and the post hoc nature of the analysis. The ongoing LTE and real-world studies in RA will continue to investigate the safety of FIL in these populations.
Disclosure
M.H. Buch: Honoraria; MHB has recieved funding (Paid to her host institution) fromAbbVie, Galapagos, Gilead, Pfizer, Eli Lilly, Merck-Serono, Roche, UCB. G.R. Burmester: Honoraria; AbbVie, Galapagos, Lilly, MSD, Pfizer, Roche, UCB, Janssen, Gilead Sciences, Inc. X. Mariette: Honoraria; AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, Pfizer. C. Charles-Schoeman: Honoraria; AbbVie, Bristol Myers Squibb (BMS), Pfizer, Regeneron-Sanofi, Gilead. V. Rajendran: Other; Employee of Galapagos NV. P. Stiers: Other; Employee of Galapagos NV. A. Cerani: Other; Employee of Galapagos NV. P. Van Hoek: Other; Employee of Galapagos NV. K. Van Beneden: Other; Employee of Galapagos NV. Y. Tanaka: Honoraria; Lilly, AbbVie, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Pfizer, Mitsubishi Tanabe, GlaxoSmithKline, Asahi Kasei, Takeda, Astellas, Janssen, Novartis, Sanofi, UCB, YL Biologics, MSD, Ono, T. H. Schulze-Koops: Honoraria; AbbVie, Galapagos, Lilly, Pfizer. R. Westhovens: Honoraria; Celltrion, Galapagos, Gilead. E. Favalli: Honoraria; AbbVie, BMS, Celltrion, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB.
Immunological activity in the CNS is largely dependent on an innate immune response and is heightened in diseases, such as diabetic retinopathy, multiple sclerosis, amyotrophic lateral sclerosis, and ...Alzheimer's disease. The molecular dynamics governing immune cell recruitment to sites of injury and disease in the CNS during sterile inflammation remain poorly defined. Here, we identified a subset of mononuclear phagocytes (MPs) that responds to local chemotactic cues that are conserved among central neurons, vessels, and immune cells. Patients suffering from late-stage proliferative diabetic retinopathy (PDR) had elevated vitreous semaphorin 3A (SEMA3A). Using a murine model, we found that SEMA3A acts as a potent attractant for neuropilin-1-positive (NRP-1-positive) MPs. These proangiogenic MPs were selectively recruited to sites of pathological neovascularization in response to locally produced SEMA3A as well as VEGF. NRP-1-positive MPs were essential for disease progression, as NRP-1-deficient MPs failed to enter the retina in a murine model of oxygen-induced retinopathy (OIR), a proxy for PDR. OIR mice with NRP-1-deficient MPs exhibited decreased vascular degeneration and diminished pathological preretinal neovascularization. Intravitreal administration of a NRP-1-derived trap effectively mimicked the therapeutic benefits observed in mice lacking NRP-1-expressing MPs. Our findings indicate that NRP-1 is an obligate receptor for MP chemotaxis, bridging neural ischemia to an innate immune response in neovascular retinal disease.
Biological markers or “biomarkers” have profoundly influenced medical research and clinical care. Depending on their association with specific disease pathophysiology, biomarkers can serve to ...determine the risk of developing a disease, screen for subclinical disease and diagnose overt disease. Such biomarkers may also identify drug targets, if the biomarker is causally associated with the disease.Current approaches employed for the discovery and validation of biochemical biomarkers of disease involve the design of expensive and time-consuming studies that use precious tissue samples from humans and animal models. Further, explorative biomarker research generally employs only classic observational designs such as case-control and cohort studies, which can suffer from bias introduced by confounding and/or reverse causation, hindering a causal interpretation when exploring etiologic biomarkers. The identification of etiologically-involved biochemical biomarkers is therefore lengthy, costly, technically challenging and, thus slow overall, ultimately limiting the number of biomarkers that translate into clinical care. Novel strategies are hence needed upstream of these costly steps for two main reasons: (1) a more effective identification of candidate biomarkers of disease and (2) a more robust evaluation of candidate biomarkers via complementary and independent lines of evidence that are subject to different key sources of bias. Metabolites—such as sugars, lipids and amino acids—are a large class of biochemical biomarkers that can be measured en masse through emerging metabolomics platforms and could thus help to identify new functional biomarkers. In turn, since the genetic determinants of several metabolites have been identified, this information can be applied to understand the role of metabolites in disease causation and to help inform the design of classic observational studies, which in combination could offer a robust approach to evaluate them. In this doctoral thesis, I explored a class of candidate small molecule blood biomarkers called metabolites, which are intrinsically involved in the human organism’s normal function and, thus their change can reflect disease pathophysiology. Given that metabolite distribution and availability is dictated by enzymes and other proteins coded in the human genome, blood metabolite levels—like many diseases—have a genetically heritable component that has been studied and reported through genome-wide association studies (GWAS). Here, I offered candidate etiologic biomarkers of three diseases—breast cancer, idiopathic pulmonary fibrosis and lung cancer risk—through a novel approach that started by identifying shared genetic determinants of both blood metabolite levels and disease risk using available GWAS summary statistics for both traits. Then the genetic variants jointly associated with metabolite blood levels and disease risk were used as instruments in a type of instrumental variable analysis called Mendelian randomization (MR) that uses genetic variants as instruments using, in this case, the genetically determined component of candidate metabolites to test and estimate their causal effect on disease risk, while—in principle—avoiding confounding by life course factors as experience by classic observational associations.In contrast to the putative application of MR to test hypotheses sourced from classic observational and other designs, the approach presented in this thesis used MR as a hypothesis-generating tool. Metabolites identified via genetics and MR later served to inform the design of separate casecontrol studies to estimate the effect of the identified candidate metabolites from an independent approach in line with the tenets of triangulation.
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