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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.
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.
We present the Pristine survey, a new narrow-band photometric survey focused on the metallicity-sensitive Ca H&K lines and conducted in the Northern hemisphere with the wide-field imager MegaCam on the Canada-France-Hawaii Telescope. This paper reviews our overall survey strategy and discusses the data processing and metallicity calibration. Additionally we review the application of these data to the main aims of the survey, which are to gather a large sample of the most metal-poor stars in the Galaxy, to further characterize the faintest Milky Way satellites, and to map the (metal-poor) substructure in the Galactic halo. The current Pristine footprint comprises over 1000 deg(2) in the Galactic halo ranging from b similar to 30 degrees to similar to 78 degrees and covers many known stellar substructures. We demonstrate that, for Sloan Digital Sky Survey (SDSS) stellar objects, we can calibrate the photometry at the 0.02-mag level. The comparison with existing spectroscopic metallicities from SDSS/Sloan Extension for Galactic Understanding and Exploration (SEGUE) and Large Sky Area Multi-Object Fiber Spectroscopic Telescope shows that, when combined with SDSS broad-band g and i photometry, we can use the CaHK photometry to infer photometric metallicities with an accuracy of similar to 0.2 dex from [Fe/H] = -0.5 down to the extremely metal-poor regime ([Fe/H] < -3.0). After the removal of various contaminants, we can efficiently select metal-poor stars and build a very complete sample with high purity. The success rate of uncovering [Fe/H](SEGUE) < -3.0 stars among [Fe/H](Pristine) < -3.0 selected stars is 24 per cent, and 85 per cent of the remaining candidates are still very metal poor ([Fe/H]<-2.0). We further demonstrate that Pristine is well suited to identify the very rare and pristine Galactic stars with [Fe/H] < -4.0, which can teach us valuable lessons about the early Universe.
Background: Estimating dietary intake is important for both epidemiological and clinical studies, but often lacks accuracy. Objective: To investigate the accuracy and validity of energy intake estimated by an easy-to-use semiquantitative food record (EISQFR) compared to total energy expenditure ( TEE) estimated by doubly labelled water technique (EEDLW). Design: TEE was measured in 29 nonobese subjects using the doubly labelled water method over a period of 14 days. Within this period, subjects reported their food consumption by a newly developed semiquantitative food record for 4 consecutive days. Energy intake was calculated using the German Food Code and Nutrition Data Base BLS II.3. Results: A good correlation was observed between EISQFR and EEDLW (r = 0.685, P<0.001). The mean difference between EISQFR and EEDLW was - 1.7 +/- 2.6 MJ/ day ( - 14 +/- 21%, P = 0.002). An underestimation of EISQFR <10% was observed in nine subjects (31%), of 10 - 20% in six subjects (21%), and of >20% in nine subjects (31%). In five subjects (17%), an overestimation of EISQFR was observed. Conclusions: The easy-to-use semiquantitative food record provided good estimates of EI in free-living and nonobese adults without prior detailed verbal instructions. The presented food record has limitations regarding accuracy at the individual level
INTRODUCTION: For obtaining reliable information about physical activity in epidemiological studies, validated and easy-to-use instruments are required. Therefore, a new simplified physical activity record based on 15-min recording intervals was developed and validated. SUBJECTS: Nonobese volunteers (n = 31). MEASUREMENTS: Physical activity was recorded over a 7-day period without detailed instructions. Energy expenditure was calculated (EEsPAR) and compared to energy expenditure measured by doubly labelled water technique (EEDLW). RESULTS: A good agreement between EEsPAR (12.1 +/ 3.0) and EEDLW (11.7 +/- 3.3) with a mean difference of 0.33 +/- 1.55 MJ (r = 0.880, P < 0.001) was observed. The absolute difference between EEsPAR and EEDLW was <10% in 65% of the subjects. The difference between EEsPAR and EEDLW was independent of gender, age, body weight, and body mass index. A weak positive association between the difference and total body fat was observed (r = 0.618, P < 0.001), suggesting a slight tendency to overestimate EEsPAR with increasing total body fat. CONCLUSION: The new simplified physical activity protocol needs no detailed instructions, provides valid estimates of physical activity in nonobese free-living adults and can be used in epidemiological studies to assess total daily energy expenditure and physical activity level
A novel common variant in DCST2 is associated with length in early life and height in adulthood
(2015)
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
Using standard cell biological and biochemical methods we were able to test the ability of a degradable, thermoplastic block copolymer to support the adhesion, proliferation, and the cellular activity of primary cell cultures of the oral cavity in vitro. The delicate balance between a group of endogenous enzymes, Matrix Metalloproteinases (MMPs), and their inhibitors (Tissue Inhibitor of MMPs, TIMPs) have a decisive function in the remodeling of the extracellular matrix during processes like wound healing or the integration of biomaterials in surrounding tissues after implantation. Recently developed, biodegradable thermoplastic elastomers with shape-memory properties may be the key to develop new therapeutical options in head and neck surgery. Primary cell cultures of the oral cavity of Sprague-Dawley rats were seeded on the surface of a thermoplastic block copolymer and on a polystyrene surface as control. Conditioned media of the primary cells were analyzed for MMPs and TIMPs after different periods of cell growth. The MMP and TIMP expression was analysed by zymography and a radiometric enzyme assay. No statistically significant differences in the appearance and the kinetic of MMP-1, MMP-2, MMP-9 and TIMPs were detected between cells grown on the polymer surface compared to the control. An appropriate understanding of the molecular processes that regulate cellular growth and integration of a biomaterial in surrounding tissue is the requirement for an optimal adaptation of biodegradable, polymeric biomaterials to the physiological, anatomical, and surgical conditions in vivo to develop new therapeutic options in otolaryngology and head and neck surgery
Reflexion ist eine Schlüsselkategorie für die professionelle Entwicklung von Lehrkräften, welche als Ausbildungsziel in den Bildungsstandards für die Lehrkräftebildung verankert ist. Eine Verstetigung universitär geprägter Forschung und Modellierung in der praxisnahen Anwendung im schulischen Kontext bietet Potentiale nachhaltiger Professionalisierung. Die Stärkung reflexionsbezogener Kompetenzen durch Empirie und Anwendung scheint eine phasenübergreifende Herausforderung der Lehrkräftebildung zu sein, die es zu bewältigen gilt. Ziele des Tagungsbandes Reflexion in der Lehrkräftebildung sind eine theoretische Schärfung des Konzeptes „Reflexive Professionalisierung“ und der Austausch über Fragen der Einbettung wirksamer reflexionsbezogener Lerngelegenheiten in die Lehrkräftebildung. Forschende und Lehrende der‚ drei Phasen (Studium, Referendariat sowie Fort- und Weiterbildung) der Lehrkräftebildung stellen Lehrkonzepte und Forschungsprojekte zum Thema Reflexion in der Lehrkräftebildung vor und diskutieren diese. Gemeinsam mit Teilnehmenden aller Phasen und von verschiedenen Standorten der Lehrkräftebildung werden zukünftige Herausforderungen identifiziert und Lösungsansätze herausgearbeitet.