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).     

Identifying Fishes through DNA Barcodes and Microarrays

Background

International fish trade reached an import value of 62.8 billion Euro in 2006, of which 44.6% are covered by the European Union. Species identification is a key problem throughout the life cycle of fishes: from eggs and larvae to adults in fisheries research and control, as well as processed fish products in consumer protection.

Methodology/Principal Findings

This study aims to evaluate the applicability of the three mitochondrial genes 16S rRNA (16S), cytochrome b (cyt b), and cytochrome oxidase subunit I (COI) for the identification of 50 European marine fish species by combining techniques of “DNA barcoding” and microarrays. In a DNA barcoding approach, neighbour Joining (NJ) phylogenetic trees of 369 16S, 212 cyt b, and 447 COI sequences indicated that cyt b and COI are suitable for unambiguous identification, whereas 16S failed to discriminate closely related flatfish and gurnard species. In course of probe design for DNA microarray development, each of the markers yielded a high number of potentially species-specific probes in silico, although many of them were rejected based on microarray hybridisation experiments. None of the markers provided probes to discriminate the sibling flatfish and gurnard species. However, since 16S-probes were less negatively influenced by the “position of label” effect and showed the lowest rejection rate and the highest mean signal intensity, 16S is more suitable for DNA microarray probe design than cty b and COI. The large portion of rejected COI-probes after hybridisation experiments (>90%) renders the DNA barcoding marker as rather unsuitable for this high-throughput technology.

Conclusions/Significance

Based on these data, a DNA microarray containing 64 functional oligonucleotide probes for the identification of 30 out of the 50 fish species investigated was developed. It represents the next step towards an automated and easy-to-handle method to identify fish, ichthyoplankton, and fish products.     

Long-term monitoring of insulin-like growth factor I in adult growth hormone deficiency: a critical appraisal

Serum insulin-like growth factor I (IGF-I) levels predominantly reflect the hepatic effect of growth hormone (GH). Compared with serum GH levels, which reflect pulsatile GH secretion, serum IGF-I levels exhibit no major diurnal variation and thus provide a better estimate of integrated GH secretion in an individual patient. Measurement of serum IGF-I levels allows reliable identification of states of GH excess. In contrast, in a large proportion of adults with severe GH deficiency, serum IGF-I levels are within the normal range. Serum IGF-I levels increase markedly in response to GH administration and are often used as a surrogate variable for overall responsiveness to such treatment. Current data, however, suggest a poor relationship between changes in or levels of IGF-I and efficacy variables such as body composition, muscle function and well-being. The use of serum IGF-I as a guide during dose titration in the initial phase of treatment and during long-term monitoring of GH replacement therapy in adults, and its use as a safety marker or predictor of future morbidity and mortality are discussed here.     

Filtering Impacts of an Introduced Bivalve (Dreissena polymorpha) in a Shallow Lake: Application of a Hydrodynamic Model

Nonindigenous species may exert strong effects on ecosystem structure and function. The zebra mussel (Dreissena polymorpha) has been attributed with profound changes in invaded ecosystems across eastern North America. We explored vertical profiles of water flow velocity and chlorophyll a concentration in western Lake Erie, over rocky substrates encrusted with Dreissena, to assess the extent to which mussels influence coupling between benthic and pelagic regions of the lake. Flow velocity was always low at surveyed sites (less than or equal to 2.9 cm s^-1) and declined in direct proximity to the lakebed. Mean chlorophyll a concentration was also low (less than 5μg L^-1) at all sites and depths. Chlorophyll a concentration was positively correlated with distance above lakebed and was lowest (0.3μg L^-1) directly adjacent to the lakebed. Spatial patterns of zooplankton grazers could not explain observed vertical gradients in chlorophyll concentration. Hydrodynamic modeling revealed that filtering effects of Dreissena in a nonstratified, shallow basin depend mainly on upstream chlorophyll concentration, intensity of turbulent diffusion, feeding efficiency of the mussel colony, and the distance downstream from the leading edge of the mussel colony. In contrast to widespread perceptions that molluscs reduce phytoplankton concentration only adjacent to the lakebed, modeling scenarios indicated that depletion occurs throughout the water column. Depletion was, however, inversely proportional to distance above the lakebed. Simulation results are consistent with field-based observations made in shallow water habitats populated by large Dreissena populations in the Great Lakes and elsewhere. Results from this study indicate that zebra mussels strongly enhance coupling between pelagic and benthic regions in shallow lakes. Enhanced coupling between these regions explains, in part, high population densities of Dreissena and of many benthic invertebrates in ecosystems invaded by zebra mussels. Received 14 July 1998; accepted 25 March 1999.     

Do Arctic waders use adaptive wind drift?

We analysed five data sets of flight directions of migrating arctic waders in relation to winds, recorded by tracking radar and optical range finder, in order to find out if these birds compensate for wind drift, or allow themselves to be drifted by winds. Our purpose was to investigate whether arctic waders use adaptive wind drift strategies or not. The data sets were collected in Siberia (two sets) and Canada during post-breeding (autumn) migration, and in Mauritania and South Sweden during pre-breeding (spring) migration. Both significant drift and compensation effects were found in three of the data sets, Canada, Mauritania and South Sweden. Almost no compensation was found in birds departing in easterly directions from the Siberian tundra (complete drift), while no drift effect was found in birds departing in westerly directions (complete compensation). There were indications that at least some populations of waders may use an adaptive drift strategy consisting of drift at high altitude and/or in high wind speed combined with compensation at low altitude and/or in lower wind speeds, but support for this idea was rather weak and not consistent. Our results were instead more in accordance with the adaptive drift theory that predicts initial drift during the migratory journey, followed by compensation during later stages as the birds are approaching their destinations. Such a strategy implies that arctic waders, at least adult birds, have the capacity of true navigation. A comparison with earlier studies of migrating arctic waders from different parts of the world show that all results so far may be interpreted in accordance with this general adaptive drift strategy. An element of non-adaptive drift can, however, not be completely ruled out.     

Icelandic lampreys (<Emphasis Type="Italic">Petromyzon marinus</Emphasis>): where do they come from?

The recent discovery of sea lamprey wounds on salmonids in Icelandic rivers prompted an investigation on the origin of sea lampreys in Icelandic waters. Using a mitochondrial DNA fragment, the origin of the lampreys examined was assigned to the European stock and not to the North American one.     

The SNP Consortium website: past,present and future

The SNP Consortium website (http://snp.cshl.org) has undergone many changes since its initial conception three years ago. The database back end has been changed from the venerable ACeDB to the more scalable MySQL engine. Users can access the data via gene or single nucleotide polymorphism (SNP) keyword searches and browse or dump SNP data to textfiles. A graphical genome browsing interface shows SNPs mapped onto the genome assembly in the context of externally available gene predictions and other features. SNP allele frequency and genotype data are available via FTP-download and on individual SNP report web pages. SNP linkage maps are available for download and for browsing in a comparative map viewer. All software components of the data coordinating center (DCC) website (http://snp.cshl.org) are open source.     

Isolation and characterization of a mixotrophic sulfur-oxidizing Thermus scotoductus

Thermophilic, faculatatively mixotrophic sulfur-oxidizing bacteria were isolated from a sulfide-rich, neutral hot spring in Iceland. The strain, IT-7254, used thiosulfate and elemental sulfur as electron donors, oxygen and nitrate as electron acceptors, and acetate and other organic compounds as carbon sources. After a few days of growth in the presence of thiosulfate, this strain formed sulfur globules. Comparison of intracellular enzymes and heme proteins of heterotrophically and mixotrophically grown cells showed some differences. The new isolate belonged to Thermus scotoductus because the small subunit (SSU) rRNA gene sequence analysis showed 98.6% sequence similarity and 84% DNA:DNA reassociation to Thermus scotoductus NMX2 A. 1. It is also close to Thermus antranikianii HN3-7, with 98.3% and 79% SSU rRNA sequence similarity and DNA:DNA reassociation, respectively. It was also found that both Thermus NMX2 A.1 and T. antranikianii HN3-7 were able to oxidize thiosulfate but that the T. scotoductus type strain SE-1 was not. This is the first report of Thermus strains that are capable of mixotrophic growth with sulfur oxidation.     

Transepithelial potential in the Magadi tilapia, a fish living in extreme alkalinity

We investigated the transepithelial potential (TEP) and its responses to changes in the external medium in Alcolapia grahami, a small cichlid fish living in Lake Magadi, Kenya. Magadi water is extremely alkaline (pH = 9.92) and otherwise unusual: titratable alkalinity (290 mequiv L(-1), i.e. HCO(3) (-) and CO(3) (2-)) rather than Cl(-) (112 mmol L(-1)) represents the major anion matching Na(+) = 356 mmol L(-1), with very low concentrations of Ca(2+) and Mg(2+) (<1 mmol L(-1)). Immediately after fish capture, TEP was +4 mV (inside positive), but stabilized at +7 mV at 10-30 h post-capture when experiments were performed in Magadi water. Transfer to 250% Magadi water increased the TEP to +9.5 mV, and transfer to fresh water and deionized water decreased the TEP to -13 and -28 mV, respectively, effects which were not due to changes in pH or osmolality. The very negative TEP in deionized water was attenuated in a linear fashion by log elevations in [Ca(2+)]. Extreme cold (1 vs. 28°C) reduced the positive TEP in Magadi water by 60%, suggesting blockade of an electrogenic component, but did not alter the negative TEP in dilute solution. When fish were transferred to 350 mmol L(-1) solutions of NaHCO(3), NaCl, NaNO(3), or choline Cl, only the 350 mmol L(-1) NaHCO(3) solution sustained the TEP unchanged at +7 mV; in all others, the TEP fell. Furthermore, after transfer to 50, 10, and 2% dilutions of 350 mmol L(-1) NaHCO(3), the TEPs remained identical to those in comparable dilutions of Magadi water, whereas this did not occur with comparable dilutions of 350 mmol L(-1) NaCl-i.e. the fish behaves electrically as if living in an NaHCO(3) solution equimolar to Magadi water. We conclude that the TEP is largely a Na(+) diffusion potential attenuated by some permeability to anions. In Magadi water, the net electrochemical forces driving Na(+) inwards (+9.9 mV) and Cl(-) outwards (+3.4 mV) are small relative to the strong gradient driving HCO(3) (-) inwards (-82.7 mV). Estimated permeability ratios are P (Cl)/P (Na) = 0.51-0.68 and [Formula: see text] = 0.10-0.33. The low permeability to HCO(3) (-) is unusual, and reflects a unique adaptation to life in extreme alkalinity. Cl(-) is distributed close to Nernst equilibrium in Magadi water, so there is no need for lower P (Cl). The higher P (Na) likely facilitates Na(+) efflux through the paracellular pathway. The positive electrogenic component is probably due to active HCO(3) (-) excretion.