Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators

Seasonal cycling of phosphorus in the Southern Bight of the North Sea

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Manganese oxide reactivity in North Sea sediments

Bulk Mn oxide dissolution rates were determined in dilute acid (HCl, pH 3, proton-assisted dissolution) and in saturating ascorbic acid (pH 3, proton-assisted plus reductive dissolution) for North Sea sediments from three sites characterised by different energy regimes, one at the Frisian Front, one in the German Bight, and one in the Skagerrak. Profiles of extractable manganese (0.1 N hydrochloric acid, 1 N hydrochloric acid, citrate-dithionite-bicarbonate buffer and hydroxylamine hydrochloride in acetic acid) are presented for the three sites. The assemblage of sedimentary Mn oxides was described as a reactive continuum with a gamma distribution of Mn oxide reactivities. Initial reduction rates were highest for the oxidised sediment samples. The reactivity of the Mn assemblages during reductive dissolution in ascorbic acid decreased by up to ∼9 orders of magnitude. The largest heterogeneity in Mn reactivity of the oxidised sediment samples was found at the German Bight site, while the most homogeneous Mn assemblage was found at the Skagerrak site. The large range in sedimentary Mn oxide reactivity may explain the great variability in values for kinetic coefficients used to describe Mn reduction. Considering the broad spectrum of Mn oxide reactivities, overlap of the Mn reduction zone with that of Fe oxides is expected. © 2004 Elsevier B.V. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Phosphorus speciation in the Scheldt estuary and the Belgian coastal zone

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Phosphorus and nitrogen speciation, transformation and retention in the Scheldt estuary (Belgium/The Netherlands) from the freshwater tidal limits to the North Sea

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Fluxes and transformations of phosphorus species in the Scheldt estuary and its tributaries

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A Mössbauer spectroscopic study of the iron redox transition in eastern Mediterranean sediments

Fe cycling at two sites in the Mediterranean Sea (southwest of Rhodes and in the North Aegean) has been studied, combining the pore water determination of nutrients, manganese, and iron, citrate-bicarbonate-dithionite (CDB) and total sediment extractions, X-ray diffraction, and 57Fe Mössbauer spectroscopy (MBS). At the Rhodes site, double peaks in the CDB-extractable Mn and Fe profiles indicate non-steady-state diagenesis. The crystalline iron oxide hematite, identified at both sites by room temperature (RT) MBS, appears to contribute little to the overall Fe reduction. MBS at liquid helium temperature (LHT) revealed that the reactive sedimentary Fe oxide phase was nanophase goethite, not ferrihydrite as is usually assumed. The pore water data at both sites indicates that upon reductive dissolution of nanophase goethite, the upward diffusing dissolved Fe2+ is oxidized by Mn oxides, rather than by nitrate or oxygen. The observed oxidation of Fe2+ by Mn oxides may be more common than previously thought but not obvious in sediments where the nitrate penetration depth coincides with the Mn oxide peak. At the Rhodes site, the solid-phase Fe(II) increase occurred at a shallower depth than the accumulation of dissolved Fe2+ in the pore water. The deeper relict Mn oxide peak acts as an oxidation barrier for the upward diffusing dissolved Fe2+, thereby keeping the pore water Fe2+ at depth. At the North Aegean site, the solid-phase Fe(II) increase occurs at approximately the same depth as the increase in dissolved Fe2+ in the pore water. Overall, the use of RT and cryogenic MBS provided insight into the solid-phase Fe(II) gradient and allowed identification of the sedimentary Fe oxides: hematite, maghemite, and nanophase goethite. Copyright © 2005 Elsevier Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Spatial variation in phytoplankton dynamics in the Belgian coastal zone of the North Sea studied by microscopy, HPLC-CHEMTAX and underway fluorescence recordings

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