Association of Variants at UMOD with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1×10−10). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3×10−23) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0×10−17) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0×10−6), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7×10−5)

Rapid KRAS, EGFR, BRAF and PIK3CA Mutation Analysis of Fine Needle Aspirates from Non-Small-Cell Lung Cancer Using Allele-Specific qPCR

Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS-TBNA) and Trans-esophageal Ultrasound Scanning with Fine Needle Aspiration (EUS-FNA) are important, novel techniques for the diagnosis and staging of non-small cell lung cancer (NSCLC) that have been incorporated into lung cancer staging guidelines. To guide and optimize treatment decisions, especially for NSCLC patients in stage III and IV, EGFR and KRAS mutation status is often required. The concordance rate of the mutation analysis between these cytological aspirates and histological samples obtained by surgical staging is unknown. Therefore, we studied the extent to which allele-specific quantitative real-time PCR with hydrolysis probes could be reliably performed on EBUS and EUS fine needle aspirates by comparing the results with histological material from the same patient. We analyzed a series of 43 NSCLC patients for whom cytological and histological material was available. We demonstrated that these standard molecular techniques can be accurately applied on fine needle cytological aspirates from NSCLC patients. Importantly, we show that all mutations detected in the histological material of primary tumor were also identified in the cytological samples. We conclude that molecular profiling can be reliably performed on fine needle cytology aspirates from NSCLC patients

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

A user's guide to the Encyclopedia of DNA elements (ENCODE)

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome

Dimensional, age and spatial structure of middle taiga post­fire pine stands on automorphic soils (on the example of Komi Republic)

The distribution of woody plants in terms of diameter and height was studied in virgin indigenous monodominant pine communities with the last fire of 5–130 years. High lability of morphometric characters of trees and undergrowth are shown. The types of age and vertical structure of stands are revealed. Both stepwise­different­aged and conditionally different­aged stands are formed under the influence of the pyrogenic factor. Pine stands have «regular top», «regular bottom» and «symmetrical» vertical structure. The horizontal structure of stands and undergrowth was interpreted based on the analysis of point processes using the pair correlation function. Trees are distributed on area randomly. We observed weak aggregation of young trees in stands on distances of 2–6 m. Both undergrowth and self­sowing are characterized by group distribution at small distances of up to 1–2 m. The direction of the displacement of the projections of the tree crowns centers relative to the bases of their trunks is ambiguous. The shift of the crown space towards the maximum solar radiation was detected in thinned stand with high age and big size of trees. In other types of pine forests no one­sided orientation of tree crown development was revealed. The position of the tree crowns centers on the plot shows the same spatial distribution as the base of the trunks. In phytocenoses with the presence of a young generation of trees, the effect of «convergence» of crowns is manifested due to the inclination of their thin and elongated trunks under snow pressure. It leads to a denser structure of the distribution of projections of crown centers in comparison with the position of the bases of the trunks of young trees on the plots

Biological productivity of the naturally developing and disturbed by windfall lichen pine forest (Komi Republic)

The evidence characterizing the changes in the structural organization and productivity of the post-windfall middle-taiga lichen pine forest growing in the Northern Ural region are presented. It is shown that the stand after the windfall changes from a relatively uneven age with demutative phases of the dynamics of the age structure type to a conditionally uneven age. Pine undergrowth in both the background and disturbed areas is characterized as «healthy». It has been established that with an increase in the height of undergrowth, the number of individuals of the oppressed categories decreases. It was revealed that in naturally developing lichen pine forests of the same age, the morphometric indicators of trees (diameter, height), the reserves of organic matter of phytocenoses are higher than in post-windfall pine stand. A comparative analysis is made of the accumulation of the deposition of plant organic matter of naturally developing and post-windfall pine forests. Ten years after the windfall in the lichen pine forest, 91.8 t ha–1 of phytomass is concentrated, which is 1.4 times less than in the background pine forest. Ten years after the windfall, the bulk of organic matter is concentrated in large tree residues, whereas in naturally growing cenosis in growing trees, the annual production of phytomass of disturbed pine trees is 1.9 times less than in the background, makes up 1019 kg ha–1. The accumulation of phytomass production in the post-windfall lichen pine forest is equivalent to the role of woody plants and plants of ground cover, whereas in the background pine forest the main role is played by woody plants. It was revealed that after windfall there was a decrease in the participation of lichens and an increase in the participation of shrubs and mosses in the formation of ground cover. Annually, the decomposition constants of large wood residues in the windfall were 0.02 year–1

Spatial interrelations in the placement of woody plants in the middle taiga virgin spruce forests of the upper reaches of the Pechora river

Investigation was carried out in virgin spruce forests in the upper reaches of the Pechora river in middle taiga condition. It was show that spruce forests of different types are characterized by common features of the structure of stands and undergrowth. There was a large variability of trees in volume of stem and undergrowth height. Investigated stands formed a cyclical-multi-age type of age structure. The calculated data obtained using spatial statistics and analyses of point processes were presented. It was found that in spruce forests is expressed regardless of forest types, the group distribution of young individuals of woody plants, which passes into random distribution at more late stages of generation. The spatial relationships between woody plants tested using the cross-correlation function gij(r) show that the undergrowth is attracted to each other at distances of up to 1 meter. There were no spatial interrelation between the undergrowth and the trees. Trees demonstrated independent from each other placement in the area. The density of trees in the area and their phytosocial status are determining the intensity of competitive relations between woody plants in the indigenous spruce communities of the upper reaches of the Pechora River