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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.
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.
The aims of this study were to identify areas of wind erosion and dust deposition and to quantify the effects of different grazing intensities on soil redistribution rates in grasslands based on the Cs-137 technique. Because the method uses a reference inventory as threshold for erosion or deposition, the classification of any other site as source or sink for dust depends on the accurate selection of this reference site.
Measurements of Cs-137 inventories and depth distributions were carried out at pasture sites with predominant species of Stipa grandis and Leymus chinensis which are grazed with different intensities. Additional measurements were made at arable land, plant-covered sand dunes and alluvial plains. Wind-induced soil erosion and dust deposition rates were calculated from Cs-137 inventories by means of the "Profile-Distribution" and the "Mass Balance II" models.
The selection of the reference site was based on fluid dynamical and process-determining parameters. The chosen site should meet the following four conditions: (i) located at a summit position with obviously low deposition rates, (ii) sufficient vegetation cover to prevent wind erosion, (iii) plane to exclude water erosion and (iv) in the wind/dust shadow of a higher elevation. The measured reference inventory of Cs-137 was 1967(+/- 102) Bqm(-2) located at a summit position of moderately grazed Leymus chinensis steppe. The Cs-137 inventories at other sites ranged from 1330 Bqm(-2) at heavily grazed sites to 5119 Bqm(-2) at river deposits, representing annual average soil losses of up to 130 tkm(-2) and deposits of up to 540 tkm(-2), respectively. The calculated annual averages of dust depositions at ungrazed Leymus chinensis sites were related to the dust storm frequencies of the last 50 years resulting in a description of the temporal variability of annual dust depositions from about 154 tkm(-2) in the 1960s to 26 tkm(-2) at recent times. Based on this quantification already 80% of the total dust depositions can be related to the 20 years between the 1960s and the end of the 1970s and only 20% to the time between 1980 and 2001.
Cs-137 technique is a promising method to assess the effect of grazing intensity and land use types on the spatial variability of wind-induced soil and dust redistribution processes in semi-arid grasslands. However, considerable efforts are needed to identify a reliable reference site, because erosion and deposition induced by wind may occur at the same places. The combination of the dust deposition rates derived from Cs-137 profile data with the dust storm frequencies is helpful for a better reconstruction of the temporal variability of dust deposition and wind erosion in this region. The calculated recent deposition rates of about 20 tkm(-2) are in good agreement with data of other authors.
Aims/hypothesis Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy. Methods Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy.
In order to identify the areas in the Xilingele grassland which are sensitive to wind erosion, a computational fluid dynamics model (CFD-WEM) was used to simulate the wind fields over a region of 37 km(2) which contains different topography and land use types. Previous studies revealed the important influences of topography and land use on wind erosion in the Xilingele grassland. Topography influences wind fields at large scale, and land use influences wind fields near the ground. Two steps were designed to implement the CFD wind simulation, and they were respectively to simulate the influence of topography and surface roughness on the wind. Digital elevation model (DEM) and surface roughness length were the key inputs for the CFD simulation. The wind simulation by CFD-WEM was validated by a wind data set which was measured simultaneously at six positions in the field. Three scenarios with different wind velocities were designed based on observed dust storm events, and wind fields were simulated according to these scenarios to predict the sensitive areas to wind erosion. General assumptions that cropland is the most sensitive area to wind erosion and heavily and moderately grazed grasslands are both sensitive etc. can be refined by the modelling of CFD-WEM. Aided by the results of this study, the land use planning and protection measures against wind erosion can be more efficient. Based on the case study in the Xilingele grassland, a method of regional wind erosion assessment aided by CFD wind simulation is summarized. The essence of this method is a combination of CFD wind simulation and determination of threshold wind velocity for wind erosion. Because of the physically-based simulation and the flexibility of the method, it can be generalised to other regions.
Background: Scrub typhus is a potentially fatal infectious disease caused by Orientia tsutsugamushi. There is little attention given to hepatic impairment in the adults with scrub typhus. This study investigated the incidence and the prognostic implications of hepatic impairment in patients with scrub typhus.
Methods: We retrospectively reviewed a total of 143 adult patients with scrub typhus who were admitted between January 1999 and December 2010 in Guangdong province, China. The patients were divided into three groups, e.g., normal, mild, and moderate to severe groups based on the elevated serum ALT and/or total bilirubin levels. Furthermore, clinical characteristics and prognosis of the patient groups were compared.
Results: 109 patients (76.2%) had abnormal liver function. Among the patients with hepatic impairment 45 cases (31.4%), 54 cases (37.8%), and 10 cases (7.0%) had mild, moderate, and severe hepatic damage, respectively. The moderate to severe hepatic impairment group had higher levels of serum creatinine compared with that of normal hepatic function. The incidence of new onset of renal dysfunction - defined as peak serum creatinine >= 176 mu mol/L during hospital stay with no evidence of renal disease prior hospitalization - was 0% in the mild hepatic impairment group, 8.9% in the moderate hepatic impairment group, and 21.9% in the severe hepatic impairment group, (p = 0.005 for trend). Additionally, the patients with hepatic impairment (n = 109) had higher incidences of episodes of thrombocytopenia (45.9% vs. 8.82%, p < 0.001), hypoalbuminemia (50.5% vs. 11.8%, p < 0.001), new onset of renal dysfunction (16.5% vs. 0.0%, p = 0.011), and electrocardiogram abnormality (28.4% vs. 8.82%, p = 0.019) than the patients without hepatic impairment.
Conclusions: The degree of hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction.
Beckground: Evaluate the efficacy and safety of telbivudine during the 2nd and 3rd trimester of pregnancy in intrauterine transmission of hepatitis B virus (HBV). Based on the principle of Cochrane systematic reviews, a database was constructed from Medline, EMBASE, Cochrane Library, the US National Science Digital Library (NSDL), the China Biological Medicine Database (CBM-disc), and contact with Chinese experts in the field from November 2006 to February 2013.
Results: Either the Mantel-Haenszel or Inverse Variance fixed-effects model or Mantel-Haenszel or Inverse Variance random-effects model was applied for all analyses indicated by odds ratio (OR) and 95% confidence interval (CI). The meta-analysis based on new onset of HBsAg seropositivity of infants at 6 - 12 months postpartum revealed that the control group had an intrauterine transmission rate of 8.25 - 42.31%. This rate was reduced to 0 - 14.29% in the telbivudine treatment group (OR 0.09, 95% CI 0.04 - 0.22, including seven trials, p < 0.001). The rates of intrauterine transmission based on new onset of HBV DNA seropositivity of infants at 6 - 12 months postpartum were 8.25 - 19.23% in the control group and 0 - 3.57% in the treatment group (OR 0.07, 95% CI 0.02 - 0.22, p < 0.001, including only five trials, since two trials had no data on HBV DNA in infants). With the exception of CK elevations, adverse effect frequencies were similar in both groups.
Conclusions: Telbivudine is an effective and safe drug for preventing intrauterine transmission of HBV.
Intensive grazing leads to land degradation and desertification of grassland ecosystems followed by serious environmental and social problems. The Xilingol steppe grassland in Inner Mongolia, China, which has been a sink area for dust for centuries, is strongly affected by the negative effects of overgrazing and wind erosion. The aim of this study is the provision of a wind erosion risk map with a spatial high resolution of 25 m to identify actual source and sink areas. In an integrative approach, field measurements of vegetation features and surface roughness length z0 were combined with Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) image data for a land use classification. To determine the characteristics of the different land use classes, a field observation (ground truth) was performed in April 2009. The correlation of vegetation height and z0 (R2 = 0.8, n = 55) provided the basis for a separation of three main classes, grassland, non-vegetation and other. The integration of the soil-adjusted vegetation index (SAVI) and the spectral information from the atmospheric corrected ASTER bands 1, 2 and 3 (visible to near-infrared) led to a classification of the overall accuracy (OA) of 0.79 with a kappa () statistic of 0.74, respectively. Additionally, a digital elevation model (DEM) was used to identify topographical effects in relation to the main wind direction, which enabled a qualitative estimation of potential dust deposition areas. The generated maps result in a significantly higher description of the spatial variability in the Xilingol steppe grassland reflecting the different land use intensities on the current state of the grassland less, moderately and highly degraded. The wind erosion risk map enables the identification of characteristic mineral dust sources, sinks and transition zones.
To provide physically based wind modelling for wind erosion research at regional scale, a 3D computational fluid dynamics (CFD) wind model was developed. The model was programmed in C language based on the Navier-Stokes equations, and it is freely available as open source. Integrated with the spatial analysis and modelling tool (SAMT), the wind model has convenient input preparation and powerful output visualization. To validate the wind model, a series of experiments was conducted in a wind tunnel. A blocking inflow experiment was designed to test the performance of the model on simulation of basic fluid processes. A round obstacle experiment was designed to check if the model could simulate the influences of the obstacle on wind field. Results show that measured and simulated wind fields have high correlations, and the wind model can simulate both the basic processes of the wind and the influences of the obstacle on the wind field. These results show the high reliability of the wind model. A digital elevation model (DEM) of an area (3800 m long and 1700 m wide) in the Xilingele grassland in Inner Mongolia (autonomous region, China) was applied to the model, and a 3D wind field has been successfully generated. The clear implementation of the model and the adequate validation by wind tunnel experiments laid a solid foundation for the prediction and assessment of wind erosion at regional scale.
Background/Aims: Diabetes is well-known to influence endothelial function. Endothelial function and blood flow regulation might be different in diabetic and non-diabetic pregnancy. However, the impact of umbilical blood flow regulation in gestational diabetes on fetal development is unknown so far. Methods: In a prospective birth cohort study, we analyzed the association of the umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) and fetal size measures (biparietal diameter, head circumference, abdominal circumference, femur length and birth weight) in 519 non-gestational diabetes mellitus pregnancies (controls) and 226 gestational diabetes mellitus pregnancies in middle (day 160.32 +/- 16.29 of gestation) and late (day 268.12 +/- 13.04 of gestation) pregnancy. Results: Multiple regression analysis considering confounding factors (gestational day of ultrasound examination, offspring sex, maternal body mess index before pregnancy, maternal age at delivery, maternal body weight at delivery and maternal hypertension) showed that umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) were associated with fetal head circumference and femur length in middle gestational diabetes mellitus pregnancy but not in non-gestational diabetes mellitus pregnancy. Head circumference, biparietal diameter, abdominal circumference and femur length in mid gestation were smaller in fetus of gestational diabetes mellitus pregnancy versus non-gestational diabetes mellitus pregnancy. In contrast to non-gestational diabetes mellitus pregnancy in late gestation, umbilical artery Doppler indices in gestational diabetes mellitus pregnancy were not associated with ultrasound measures of fetal growth. Birth weight was slightly increased in gestational diabetes mellitus pregnancy as compared to non-gestational diabetes mellitus pregnancy. Conclusions: The impact of umbilical blood flow on fetal growth is time dependent in human gestational diabetes mellitus and non-gestational diabetes mellitus pregnancy. In gestational diabetes mellitus pregnancy umbilical blood flow is critical for organ development in much earlier stages of pregnancy as compared to non-gestational diabetes mellitus pregnancy. The physiological and molecular pathways why there is a catch up growth in later times of gestational diabetes mellitus pregnancy resulting in larger gestational diabetes mellitus babies at birth needs to be addressed in further studies.