Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Erratum: Corrigendum: Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

International Chicken Genome Sequencing Consortium. The Original Article was published on 09 December 2004. Nature432, 695–716 (2004). In Table 5 of this Article, the last four values listed in the ‘Copy number’ column were incorrect. These should be: LTR elements, 30,000; DNA transposons, 20,000; simple repeats, 140,000; and satellites, 4,000. These errors do not affect any of the conclusions in our paper. Additional information. The online version of the original article can be found at 10.1038/nature0315

Major transformations reveal Earth's deep secrets

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Eclogites in the SCLM: The subduction myth

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Detrital-zircon ages and geochemistry of sedimentary rocks in basement Mesozoic terranes and their cover rocks in New Caledonia, and provenances at the Eastern Gondwanaland margin

Geochemical and Sr-Nd isotope data for Mesozoic greywackes of New Caledonia terranes, indicate a forearc tectonic environment at the Eastern Gondwanaland margin, but they support only minor continental influences. Detrital-zircon U-Pb age patterns for the greywackes in these terranes similarly reflect an active-margin tectonic environment of Late Triassic, Late Jurassic, and in particular mid-Cretaceous, depocentres which comprise much contemporaneous volcanic detritus, but also include minor sediment inputs from Precambrian-Early Paleozoic continental clastic rocks. The contemporary volcanic sources are probably now hidden within a former hinterland to New Caledonia, such as Lord Howe Rise or Marion Plateau. The older, continental sediment sources were probably in northeastern-most Queensland, and beyond the northern extremity of the New England Orogen. Such sediments could have been supplied on long rivers, and submarine longshore current systems outboard of the orogen. Alternatively, the depocentres could have been consolidated close to the contemporary Gondwanaland margin and then tectonically transported, as suspect terranes, southwards in Early Cretaceous times to their present New Caledonia position.25 page(s

Crust-mantle evolution in NW Spitsbergen: Re-Os, U-Pb, and Hf isotope data

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The kimberlites and related rocks of the Kuruman Kimberlite Province, Kaapvaal Craton, South Africa

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Tracing the Caples Terrane through New Zealand using detrital zircon age patterns and radiogenic isotope signatures

Rb-Sr isochron ages and associated initial 87Sr/86Sr ratios of metasedimentary rocks of Caples Group in Southland and Otago, Pelorus Group in Nelson and Marlborough, and their minor North Island correlates in Northland and King Country, reveal the essential continuity of a long Caples Terrane throughout New Zealand. The Rb-Sr ages, in the range 251-117 Ma, record post-metamorphic, Early Triassic to Early Cretaceous uplift and cooling, whilst their associated range of initial 87Sr/86Sr ratios, 0.7039-0.7053, allows a discrimination from analogous datasets of neighbouring Torlesse and Waipapa Terranes. Some petrographically and geochemically anomalous Caples Terrane rocks in East Otago, and Otago Schists of the Aspiring Terrane, all with initial 87Sr/86Sr ratios >0.7055, compare best with datasets of Waipapa Terrane of the North Island. Detrital zircon U-Pb ages of greywackes from Caples Terrane metasediments have youngest zircon age components from 251 to 215 Ma, and a comparison of dataset patterns from fossiliferous examples suggests that these probably originate from contemporary volcanic sources. Caples volcanism and associated depocentres thus span much of the Triassic. However, their major zircon component, invariably in the range Early Triassic to latest Permian, is most persistent, and constitutes an enormous and enduring zircon source thought to be in the New England Orogen of eastern Australia. Minor, late Paleozoic (295-340 Ma) zircon components are restricted to (Early-Middle Triassic) Caples Terrane metasediments with older, minimum zircon age components, perhaps originating in nearby primary sources in the northeasternmost Lachlan Fold Belt and southern part of the New England Orogen. More scattered early Paleozoic-Precambrian zircons are present throughout the Caples Terrane and reflect reworking of zircons from Paleozoic metasediments and plutonic rocks within the New England Orogen (and its immediate hinterland). Caples Terrane metasediments thus represent an offshore, Triassic component of the accretionary prism terranes (Late Carboniferous to Early Cretaceous) of the Eastern Province of New Zealand. Their depocentres were more isolated from the Gondwanaland continental margin than Torlesse and Waipapa Terrane counterparts, and more influenced by substantial contemporary volcanic centres, perhaps located along the Lord Howe Rise.23 page(s