Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Immunization with a Recombinant, Pseudomonas fluorescens-Expressed, Mutant Form of Bacillus anthracis-Derived Protective Antigen Protects Rabbits from Anthrax Infection.

Protective antigen (PA), one of the components of the anthrax toxin, is the major component of human anthrax vaccine (Biothrax). Human anthrax vaccines approved in the United States and Europe consist of an alum-adsorbed or precipitated (respectively) supernatant material derived from cultures of toxigenic, non-encapsulated strains of Bacillus anthracis. Approved vaccination schedules in humans with either of these vaccines requires several booster shots and occasionally causes adverse injection site reactions. Mutant derivatives of the protective antigen that will not form the anthrax toxins have been described. We have cloned and expressed both mutant (PA SNKE167-ΔFF-315-E308D) and native PA molecules recombinantly and purified them. In this study, both the mutant and native PA molecules, formulated with alum (Alhydrogel), elicited high titers of anthrax toxin neutralizing anti-PA antibodies in New Zealand White rabbits. Both mutant and native PA vaccine preparations protected rabbits from lethal, aerosolized, B. anthracis spore challenge subsequent to two immunizations at doses of less than 1 μg

rPA antibody-specific Toxin Neutralization Assay (TNA) and ED50 values (μg/mL).

<p>(A) generated from vaccinated wild type and (B) mutant rPA (geometric mean with error bars representing the 95% confidence interval).</p

Recovery of <i>B</i>. <i>anthracis</i> from Select Tissues of vaccinated, unvaccinated control, and sham vaccinated control rabbits.

<p>Recovery of <i>B</i>. <i>anthracis</i> from Select Tissues of vaccinated, unvaccinated control, and sham vaccinated control rabbits.</p

Kaplan-Meier Survival Curve of vaccinated, unvaccinated control, and sham vaccinated control rabbits.

<p>Kaplan-Meier Survival Curve of vaccinated, unvaccinated control, and sham vaccinated control rabbits.</p

Experimental Procedures and Schedule.

<p>^aThrice daily observations performed on Days 72–74. Twice daily observations performed other days.</p><p>^bBody weight obtained at randomization, on Day 0 and weekly thereafter.</p><p>^cAnimals vaccinated via intramuscular injection on Day 0 or Days 0 and 28 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130952#pone.0130952.t001" target="_blank">Table 1</a>).</p><p>^dBlood collected and sera isolated for TNA and ELISA on Days -6, 14, 28, 42 and 65 ± 4, when moribund euthanized or at terminal euthanasia (Day 84).</p><p>^eRabbits challenged with 200 x ± 50 LD₅₀<i>B</i>. <i>anthracis</i> (Ames) spores. The published inhalation LD₅₀ for NZW rabbits is 1.1 x 10⁵ spores.</p><p>^fBlood collected for CBC and differential.</p><p>^gBlood collected and sera isolated for clinical chemistry parameters.</p><p>^hBlood collected for quantitative bacteriology.</p><p>ⁱBlood collected and sera isolated for electrochemiluminescence assay (ECL).</p><p>^jMoribund euthanized or found dead rabbits received a limited gross necropsy.</p><p>^kEuthanized or found dead rabbits received a gross necropsy and select tissues collected for bacteriology or histopathology.</p><p>Experimental Procedures and Schedule.</p

Study Summary of Fate and Immune Status Relevant to B. anthracis Challenge on Day 70.

<p>^aLower limit of quantitation < 30 μg/mL.</p><p>^bSamples which returned an incalculable ED50 (by Gen 5 software) were assigned an ED50 value of 1.</p><p>Study Summary of Fate and Immune Status Relevant to B. anthracis Challenge on Day 70.</p