In Situ Observations of the Deformation Behavior and Fracture Mechanisms of Ti-45Al-2Nb-2Mn+0.8 vol pct TiB₂

The deformation and fracture mechanisms of a nearly lamellar Ti-45Al-2Nb-2Mn (at. pct) + 0.8 vol pct TiB₂ intermetallic, processed into an actual low-pressure turbine blade, were examined by means of in situ tensile and tensile-creep experiments performed inside a scanning electron microscope (SEM). Low elongation-to-failure and brittle fracture were observed at room temperature, while the larger elongations-to-failure at high temperature facilitated the observation of the onset and propagation of damage. It was found that the dominant damage mechanisms at high temperature depended on the applied stress level. Interlamellar cracking was observed only above 390 MPa, which suggests that there is a threshold below which this mechanism is inhibited. Failure during creep tests at 250 MPa was controlled by intercolony cracking. The in situ observations demonstrated that the colony boundaries are damage nucleation and propagation sites during tensile creep, and they seem to be the weakest link in the microstructure for the tertiary creep stage. Therefore, it is proposed that interlamellar areas are critical zones for fracture at higher stresses, whereas lower stress, high-temperature creep conditions lead to intercolony cracking and fracture.The authors are grateful to Industria de Turbo Propulsores, S.A. for supplying the intermetallic blades. Funding from the Spanish Ministry of Science and Innovation through projects MAT2009-14547-C02-01 and MAT2009-14547-C02-02 is acknowledged. The Madrid Regional Government supported this project partially through the ESTRUMAT grant P2009/MAT-1585. C.J.B. acknowledges the support from Grant SAB2009-0045 from the Spanish Ministry of Education for his sabbatical stage in Madrid.Publicad

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC. Radiolog