Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

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

Scales of fluid-rock interaction and carbon mobility in the deeply underplated and HP-Metamorphosed Schistes Lustrés, Western Alps

International audienceThe Schistes Lustrés metasedimentary complex, exposed in the Italian and French Alps, is a regionally extensive unit of blueschist to eclogite facies marble, calc-schist and metapelite providing a record of sediment underplating and fluid-rock interaction at 40-65 km of a paleo-subduction zone. Limestones, carbonate-rich mudstones, and black shales in SE France and central Switzerland, herein used as a proxy for the unmetamorphosed Schistes Lustrés, bear a striking resemblance to sediments currently subducting into the E. Sunda margin. The Schistes Lustrés, with estimated P-T conditions ranging from ∼1 GPa and 350 °C to ∼2.3 GPa and 550 °C, have on a regional scale had their average carbonate δ18OVSMOW lowered to +20.4‰, relative to the average of +28.5‰ of their likely protoliths. This decrease in δ18O can be most easily explained by varying combinations of: (1) closed-system equilibration of carbonate O with O in silicate minerals in the same rocks (i.e., at the μm to cm scale); and (2) interaction between carbonates and H2O-rich fluids released during prograde metamorphic devolatilization of the metapelitic rocks in the section (at up to km scales). Regional-scale decrease in carbonate δ18O in the Schistes Lustrés could have occurred without the need for infiltration by fluids generated outside of the Schistes Lustrés complex. More dramatic reductions in δ18O (as low as +8‰; average = +15.5‰) at/near major tectonic contacts, inferred to be fossil transient subduction interfaces, likely reflect deformation-enhanced infiltration by fluids derived in mafic or ultramafic rocks at greater depths. Pressure solution and concomitant cleavage formation in the Schistes Lustrés presumably were associated with some carbonate removal, and higher-grade rocks show some evidence for decarbonation. However, within the Schistes Lustrés, C is deposited as carbonate in locally abundant veins and it has proven difficult to identify clear evidence of wholesale carbonate removal from the complex (i.e., at scales of kms to 10s of kms). This study demonstrates that large fractions of subducted sedimentary carbonate sections could persist to depths approaching those beneath volcanic fronts, if they are not accreted or underplated and depending on the extents to which they are infiltrated by H2O-rich fluids capable of driving both decarbonation reactions and carbonate dissolution. Sediments such as these could supply C for additions to arc source regions or, with further subduction, convey C into the deeper mantle. The C removal and deposition reported by others for sites of particularly high fluid flux, along large fault systems, in zones of high fracture/vein density, and in metasomatized contacts with mafic/ultramafic rocks, contrast with the relative retention and lower degrees of mobilization of C observed within km-scale packets of Schistes Lustrés away from zones of enhanced deformation and behaving as relatively closed systems. The fragmented and potentially lithologically biased nature of HP/UHP metamorphic suites greatly complicates attempts to derive fluid and C fluxes scalable to modern subduction margins

Carbon mobility and exchange in a plate-interface subduction mélange: a case study of meta-ophiolitic rocks in Champorcher Valley, Italian Alps

Ultramafic and carbonate-rich rocks juxtaposed in an oceanic sedimentary mélange that experienced Alpine subduction (Champorcher, Aosta Valley, Italy) show evidence of metasomatic alteration at their contacts. The reactions that occurred at these contacts afford an assessment of the sources and compositions of fluids associated with the alteration, the degree and scale at which these reactions mobilized carbon. At these contacts, carbonate-rich rocks display calcite replacement by diopside and tremolite along foliations and pressure-dissolution planes as the result of decarbonation and/or carbonate dissolution. The associated ultramafic bodies record serpentine replacement by carbonates and formation of metamorphic veins hosting carbonate and carbonate + diopside + chlorite. These two sets of observations point to coeval, coupled decarbonation and carbonation reactions resulting in C mobility along the subduction interface (at about 60 km depth) but conceivably without considerable net loss and large-scale transport.The δ18OV-SMOW values of all the samples analyzed in this study are lower than expected for oceanic protoliths (for marine limestone, carbonate with values of +28 to +30‰; for seafloor ophicarbonate somewhat lower), suggesting pervasive interaction of these rocks with externally derived fluids, as has been observed throughout the region (for calcschists such as the Schistes Lustrés, lowering values to +20 ± 2‰). The calcschist unit at Champorcher has δ18O (+21.9 to +23.6‰) falling into this regionally developed range; however, the other rocks at this locality (carbonate mélange/broken formation, metasomatic rinds, and veins) tend to have lower values (to as low as +13.5‰). These lower values appear to require interaction with a fluid with δ18O lower than that affecting the calcschist on a regional scale and more consistent with derivation from a mafic/ultramafic (ophiolitic) source. Some metamorphic veins showing carbonate δ18O values 1 to 2‰ lower than their hosts and the occurrence of metamorphic veins and metasomatic horizons with anomalously high 87Sr/86Sr point to circulation of isotopically distinct external fluids enriched in radiogenic Sr within the Champorcher suite, perhaps involving a source in devolatilizing terrigenous rocks.Juxtaposition of rocks at scales observed in these mélange units could enhance the mobilization of C via decarbonation reactions if this deformation is accompanied by the infiltration by H2O-rich fluids capable of driving the reaction process. Information regarding the metasomatism within this hybrid carbonate-ultramafic unit bears on the question of C mobilization along subduction interfaces and whether the magnitude of any loss or gain at the scales investigated could significantly influence whole-margin C cycling

Mantle peridotite and associated metasomatic rocks in the Orocopia Schist subduction channel (latest Cretaceous) at Cemetery Ridge, southwest Arizona

This geologic map and report document peridotite—harzburgite, olivine orthopyroxenite, and serpentinite after dunite—entrained in a latest Cretaceous (“Laramide”) low-angle subduction channel, the Orocopia Schist, exposed at Cemetery Ridge, southwest Arizona. Oceanic peridotite, serpentinized by seawater, is strikingly out of place in this region of Paleoproterozoic to Jurassic continental crust.Documents in the AZGS Documents Repository collection are made available by the Arizona Geological Survey (AZGS) and the University Libraries at the University of Arizona. For more information about items in this collection, please contact [email protected]

Cycling of CO2 and N2 Along the Hikurangi Subduction Margin, New Zealand: An Integrated Geological, Theoretical, and Isotopic Approach

Abstract We present a quantitative assessment of the input and output of CO2 and N2 along the Hikurangi margin based on the chemical and stable isotope composition of sediments and basalts (from IODP 375), previously accreted metasedimentary rocks, and volcanic/hydrothermal gases (together with noble gas data for the latter). We compare these results with 3‐D thermo‐petrologic models for four lithologic structures, representing different plateau inputs. The model results indicate that 59%–85% of initially subducted C and 5%–12% of N is lost from the slab during metamorphism, with both volatiles being dominantly sourced from altered oceanic crust with some contribution from subducted sediment at the forearc‐arc transition (75–90 km depth). The δ13CVPDB and CO2/3He values for the arc gases range from −8.3 to −1.4‰ and 2 × 109 to 2.7 × 1011, indicating contributions from slab carbonate, organic C, and mantle C of 67%, 30%, and 3%, respectively. The δ15Nair and N2/36Ar values of arc gases are −1.0 to +2.3‰ and 1.54 × 104 to 1.9 × 105, indicating slab and mantle contributions of 74% and 26%. The δ13C signature of gases requires addition of organic C by tectonic erosion and/or shallow crustal assimilation. These calculations yield whole‐margin fluxes of 5.4–7.0 Tg/yr for CO2 and 0.0022–0.0057 Tg/yr for N2, corresponding to ∼2.2% and 1%–30% of the global CO2 and N2 flux from subaerial volcanoes worldwide (assuming no loss during transit). This unique assessment of volatile cycling could prove useful in refining regional and global estimates of volatile recycling efficiency