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

Contemporary Incidence and Prevalence of Rheumatic Fever and Rheumatic Heart Disease in Australia Using Linked Data: The Case for Policy Change

Background In 2018, the World Health Organization prioritized control of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), including disease surveillance. We developed strategies for estimating contemporary ARF/RHD incidence and prevalence in Australia (2015-2017) by age group, sex, and region for Indigenous and non-Indigenous Australians based on innovative, direct methods. Methods and Results This population-based study used linked administrative data from 5 Australian jurisdictions. A cohort of ARF (age <45 years) and RHD cases (<55 years) were sourced from jurisdictional ARF/RHD registers, surgical registries, and inpatient data. We developed robust methods for epidemiologic case ascertainment for ARF/RHD. We calculated age-specific and age-standardized incidence and prevalence. Age-standardized rate and prevalence ratios compared disease burden between demographic subgroups. Of 1425 ARF episodes, 72.1% were first-ever, 88.8% in Indigenous people and 78.6% were aged <25 years. The age-standardized ARF first-ever rates were 71.9 and 0.60/100 000 for Indigenous and non-Indigenous populations, respectively (age-standardized rate ratio=124.1; 95% CI, 105.2-146.3). The 2017 Global Burden of Disease RHD prevalent counts for Australia (<55 years) underestimate the burden (1518 versus 6156 Australia-wide extrapolated from our study). The Indigenous age-standardized RHD prevalence (666.3/100 000) was 61.4 times higher (95% CI, 59.3-63.5) than non-Indigenous (10.9/100 000). Female RHD prevalence was double that in males. Regions in northern Australia had the highest rates. Conclusions This study provides the most accurate estimates to date of Australian ARF and RHD rates. The high Indigenous burden necessitates urgent government action. Findings suggest RHD may be underestimated in many high-resource settings. The linked data methods outlined here have potential for global applicability.Judith M. Katzenellenbogen, Daniela Bond-Smith, Rebecca J. Seth, Karen Dempsey, Jeffrey Cannon, Ingrid Stacey, Vicki Wade, Nicholas de Klerk, Melanie Greenland, Frank M. Sanfilippo, Alex Brown, Jonathan R. Carapetis, Rosemary Wyber, Lee Nedkoff, Joe Hung, Dawn Bessarab, Anna P. Ralp

Nanoparticles featuring amino acid-functionalized side chains as DNA receptors

A family of nanoparticles has been fabricated featuring cationic amino acid-based side chains. This controlled surface modification provides a tool to investigate the effect of various non-covalent interactions at the nanoparticle-DNA interface. The binding affinities of these nanoparticles towards DNA were determined using fluorescence, exhibiting more than threefold modulation in binding a 37-mer DNA strand. The secondary structure of the DNA strand was distorted upon nanoparticle binding, with the extent of distortion dependent on the structure of amino acid side chain