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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Die verschwundene Diplomatie : Beiträge zur Außenpolitik der DDR ; Festschrift für Claus Montag
(2003)
This paper provides an overview of analytical techniques used to determine isoflavones (IFs) in foods and biological fluids with main emphasis on sample preparation methods. Factors influencing the content of IFs in food including processing and natural variability are summarized and an insight into IF databases is given. Comparisons of dietary intake of IFs in Asian and Western populations, in special subgroups like vegetarians, vegans, and infants are made and our knowledge on their absorption, distribution, metabolism, and excretion by the human body is presented. The influences of the gut microflora, age, gender, background diet, food matrix, and the chemical nature of the IFs on the metabolism of IFs are described. Potential mechanisms by which IFs may exert their actions are reviewed, and genetic polymorphism as determinants of biological response to soy IFs is discussed. The effects of IFs on a range of health outcomes including atherosclerosis, breast, intestinal, and prostate cancers, menopausal symptoms, bone health, and cognition are reviewed on the basis of the available in vitro, in vivo animal and human data.
AimAdvancement in ecological methods predicting species distributions is a crucial precondition for deriving sound management actions. Maximum entropy (MaxEnt) models are a popular tool to predict species distributions, as they are considered able to cope well with sparse, irregularly sampled data and minor location errors. Although a fundamental assumption of MaxEnt is that the entire area of interest has been systematically sampled, in practice, MaxEnt models are usually built from occurrence records that are spatially biased towards better-surveyed areas. Two common, yet not compared, strategies to cope with uneven sampling effort are spatial filtering of occurrence data and background manipulation using environmental data with the same spatial bias as occurrence data. We tested these strategies using simulated data and a recently collated dataset on Malay civet Viverra tangalunga in Borneo.
LocationBorneo, Southeast Asia.
MethodsWe collated 504 occurrence records of Malay civets from Borneo of which 291 records were from 2001 to 2011 and used them in the MaxEnt analysis (baseline scenario) together with 25 environmental input variables. We simulated datasets for two virtual species (similar to a range-restricted highland and a lowland species) using the same number of records for model building. As occurrence records were biased towards north-eastern Borneo, we investigated the efficacy of spatial filtering versus background manipulation to reduce overprediction or underprediction in specific areas.
ResultsSpatial filtering minimized omission errors (false negatives) and commission errors (false positives). We recommend that when sample size is insufficient to allow spatial filtering, manipulation of the background dataset is preferable to not correcting for sampling bias, although predictions were comparatively weak and commission errors increased.
Main ConclusionsWe conclude that a substantial improvement in the quality of model predictions can be achieved if uneven sampling effort is taken into account, thereby improving the efficacy of species conservation planning.
Micronutrient deficiencies are widespread in developing countries, particularly in remote communities such as mobile pastoralists. The nutritional and vitamin A status of this population is not well-documented in Chad. This study assessed serum retinol levels among women and children under five-year-old in nomadic and semi-nomadic pastoralist and rural-settled communities, who are similarly exposed to risk factors such as gastrointestinal parasitic infection, anaemia and emaciation. The novel method of portable fluorometry was used for the first time to measure beta-carotene and retinol levels in a pastoral nomadic area. Moderate level blood retinol deficiency (< 0.7 mu mol/L) was observed in 5% (CI 1-11) of nomadic, 29% (CI 13-45) of semi-nomadic and 22% (CI 8-35) of sedentary women. In children, 1% (CI 0.1-4), 17% (CI 9-25) and 28% (CI 18-39), respectively, had moderate level blood retinol deficiency. In nomadic communities, women and children had blood retinol levels close to normal. Deficiency of retinol was strongly linked with lifestyle (nomadic, semi-nomadic and settled) among women and lifestyle and age among children. The results support an ecological linkage between human retinol levels and livestock milk retinol. This study shows the feasibility of portable retinol and beta-carotene measurement in human blood as well as human and animal milk under remote field conditions, but the approach requires further validation.
Being born large for gestational age is associated with increased global placental DNA methylation
(2020)
Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
Being born large for gestational age is associated with increased global placental DNA methylation
(2020)
Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
Evolutionary history and conservation significance of the Javan leopard Panthera pardus melas
(2016)
The leopard Panthera pardus is widely distributed across Africa and Asia; however, there is a gap in its natural distribution in Southeast Asia, where it occurs on the mainland and on Java but not on the interjacent island of Sumatra. Several scenarios have been proposed to explain this distribution gap. Here, we complemented an existing dataset of 68 leopard mtDNA sequences from Africa and Asia with mtDNA sequences (NADH5+ ctrl, 724bp) from 19 Javan leopards, and hindcasted leopard distribution to the Pleistocene to gain further insights into the evolutionary history of the Javan leopard. Our data confirmed that Javan leopards are evolutionarily distinct from other Asian leopards, and that they have been present on Java since the Middle Pleistocene. Species distribution projections suggest that Java was likely colonized via a Malaya-Java land bridge that by-passed Sumatra, as suitable conditions for leopards during Pleistocene glacial periods were restricted to northern and western Sumatra. As fossil evidence supports the presence of leopards on Sumatra at the beginning of the Late Pleistocene, our projections are consistent with a scenario involving the extinction of leopards on Sumatra as a consequence of the Toba super volcanic eruption (similar to 74kya). The impact of this eruption was minor on Java, suggesting that leopards managed to survive here. Currently, only a few hundred leopards still live in the wild and only about 50 are managed in captivity. Therefore, this unique and distinctive subspecies requires urgent, concerted conservation efforts, integrating insitu and ex situ conservation management activities in a One Plan Approach to species conservation management.
Aims/hypothesis It was shown that maternal endothelial nitric oxide synthase (eNOS) deficiency causes fatty liver disease and numerically lower fasting glucose in female wild-type offspring, suggesting that parental genetic variants may influence the offspring's phenotype via epigenetic modifications in the offspring despite the absence of a primary genetic defect. The aim of the current study was to analyse whether paternal eNOS deficiency may cause the same phenotype as seen with maternal eNOS deficiency. Methods Heterozygous (+/-) male eNOS (Nos3) knockout mice or wild-type male mice were bred with female wild-type mice. The phenotype of wild-type offspring of heterozygous male eNOS knockout mice was compared with offspring from wild-type parents. Results Global sperm DNA methylation decreased and sperm microRNA pattern altered substantially. Fasting glucose and liver glycogen storage were increased when analysing wild-type male and female offspring of +/- eNOS fathers. Wild-type male but not female offspring of +/- eNOS fathers had increased fasting insulin and increased insulin after glucose load. Analysing candidate genes for liver fat and carbohydrate metabolism revealed that the expression of genes encoding glucocorticoid receptor (Gr; also known as Nr3c1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a; also known as Ppargc1a) was increased while DNA methylation of Gr exon 1A and Pgc1a promoter was decreased in the liver of male wild-type offspring of +/- eNOS fathers. The endocrine pancreas in wild-type offspring was not affected. <br /> Conclusions/interpretation Our study suggests that paternal genetic defects such as eNOS deficiency may alter the epigenome of the sperm without transmission of the paternal genetic defect itself. In later life wild-type male offspring of +/- eNOS fathers developed increased fasting insulin and increased insulin after glucose load. These effects are associated with increased Gr and Pgc1a gene expression due to altered methylation of these genes.
The Chew Bahir Drilling Project (CBDP) aims to test possible linkages between climate and evolution in Africa through the analysis of sediment cores that have recorded environmental changes in the Chew Bahir basin. In this statistical project we consider the Chew Bahir palaeolake to be a dynamical system consisting of interactions between its different components, such as the waterbody, the sediment beneath lake, and the organisms living within and around the lake. Recurrence is a common feature of such dynamical systems, with recurring patterns in the state of the system reflecting typical influences. Identifying and defining these influences contributes significantly to our understanding of the dynamics of the system. Different recurring changes in precipitation, evaporation, and wind speed in the Chew Bahir basin could result in similar (but not identical) conditions in the lake (e.g., depth and area of the lake, alkalinity and salinity of the lake water, species assemblages in the water body, and diagenesis in the sediments). Recurrence plots (RPs) are graphic displays of such recurring states within a system. Measures of complexity were subsequently introduced to complement the visual inspection of recurrence plots, and provide quantitative descriptions for use in recurrence quantification analysis (RQA). We present and discuss herein results from an RQA on the environmental record from six short (< 17 m) sediment cores collected during the CBDP, spanning the last 45 kyrs. The different types of variability and transitions in these records were classified to improve our understanding of the response of the biosphere to climate change, and especially the response of humans in the area.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Background Host factors such as angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine-subtype-2 (TMPRSS2) are important factors for SARS-CoV-2 infection. Clinical and pre-clinical studies demonstrated that RAAS-blocking agents can be safely used during a SARS-CoV-2 infection but it is unknown if DPP-4 inhibitors or SGLT2-blockers may promote COVID-19 by increasing the host viral entry enzymes ACE2 and TMPRSS2. Methods We investigated telmisartan, linagliptin and empagliflozin induced effects on renal and cardiac expression of ACE2, TMPRSS2 and key enzymes involved in RAAS (REN, AGTR2, AGT) under high-salt conditions in a non-diabetic experimental 5/6 nephrectomy (5/6 Nx) model. In the present study, the gene expression of Ace2, Tmprss2, Ren, Agtr2 and Agt was assessed with qRT-PCR and the protein expression of ACE2 and TMPRSS2 with immunohistochemistry in the following experimental groups: Sham + normal diet (ND) + placebo (PBO); 5/6Nx + ND + PBO; 5/6Nx + high salt-diet (HSD) + PBO; 5/6Nx + HSD + telmisartan; 5/6Nx + HSD + linagliptin; 5/6Nx + HSD + empagliflozin. Results In the kidney, the expression of Ace2 was not altered on mRNA level under disease and treatment conditions. The renal TMPRSS2 levels (mRNA and protein) were not affected, whereas the cardiac level was significantly increased in 5/6Nx rats. Intriguingly, the elevated TMPRSS2 protein expression in the heart was significantly normalized after treatment with telmisartan, linagliptin and empagliflozin. Conclusions Our study indicated that there is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker linagliptin are used. The results obtained in a preclinical, experimental non-diabetic kidney failure model need confirmation in ongoing interventional clinical trials.