Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Computed tomographic assessment of coronary artery bypass grafts with fast dynamic scanning

28 coronary grafts in 12 symptomatic patients were studied at the time of graft angiography at Prince Charles Hospital. The grafts were studied using the Toshiba 900S scanner with bolus injections of contrast agent into an anticubital vein. The assessment was carried out using fast incremental and continuous acquisition scanning with stepped reconstructions in the last 5 patients. Of the 27 grafts, 16 were shown at angiography to be patent and of good calibre. 14 of these were similarly assessed at CT. 11 were either diseased or blocked at angiography, and these were graded also as small, stenosed or blocked at CT. This early study would support previous reports that CT does offer a reliable method of diagnosing good patent grafts. The study also suggests that with conventional fast dynamic scanning some information regarding graft quality can be obtained

Lessons for higher education : the university as a site of activism

Len Barton is acutely aware of the power of the academy to either enhance critical thinking or to depress it. He is a true academic, never accepting the received wisdom or perspective of any given sociological standpoint, no matter how powerful or fashionable it was at the time. He has encouraged and promoted a unique blend of professional and public sociology of education that has left a profound legacy not only in the UK but beyond. While the neo-liberal ideology had hegemonic status for most of his professional life, Len chose to engage in a counter ideological struggle; he created new intellectual spaces in the academy where people could safely dissent from the reigning intellectual orthodoxies. He operated according to the principles of Gramscian thinking by mounting a war of position, in journals, books, teaching, conferences and research, for critical intellectuals. And he encouraged other people to do likewise. This article explores the ways in which Len’s work inspired the establishment of the Equality Studies Centre and the School of Social Justice in UCD. It outlines the lessons learned from Len Barton about higher education and its potential as a site for critical analysis and action.Not applicableti,ke.kpw1/10/1