Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Identification of cardiovascular genes in omentum from morbidly obese patients with type 2 diabetes

Background: The metabolic syndrome describes the association between obesity and co-morbidities including insulin resistance, hypertension, dyslipidemia, and cardiovascular (CV) disease. Adipokines produced from omentum contribute to the risk of CV disease and increase the inflammatory state. This study examines the gene expression differences in the omental tissue of morbidly obese diabetic and non-diabetic patients. Methods: Twenty morbidly obese patients undergoing bariatric surgery were included. Ten patients were diabetic and 10 were non-diabetic. Omental samples were collected intraoperatively and snap frozen. Total RNA was extracted using the Trizol reagent and purified with the RNeasy kit (Qiagen). Microarray experiments were performed using the Affymetrix Gene 1.0 ST array and data was analyzed with the Partek 6.3 program using an unpaired t-test (P\u3e0.05). The gene expression profiles of the diabetic group were compared with the non-diabetic group. Using the Ingenuity program, the gene list generated from the microarray analysis was evaluated and real-time quantitative PCR (qPCR) was used to validate the array data. Results: Compared with the non-diabetic group, the diabetic obese patients showed 79 upregulated genes and 4 downregulated genes with \u3c1.4-fold difference in expression. Ingenuity analysis showed numerous dysregulated genes associated with CV disease including leptin, Von Willebrand factor, P-selectin, angiopoietin-1 (ANGPT1), phospholipase A2 (group VII), and periostin osteoblast specific factor. Microarray results for the earlier mentioned genes were confirmed with qPCR. The results were analyzed with respect to the presence or absence of hyperlipidemia, hypertension, and coronary artery disease. In patients with hyperlipidemia, ANGPT1 and P-selectin were upregulated 1.9-and 2.9-fold, respectively.Conclusions:This microarray analysis of omental tissue from morbidly obese diabetic patients documents a host of upregulated genes related to CV disease. This study provides further evidence that diabetic status predisposes obese patients to a higher risk of developing CV disease. © 2010 Macmillan Publishers Limited All rights reserved

Effects of entomopathogenic fungus Metarhizium anisopliae on non-target ants associated with Odontotermes spp. (Isoptera: Termitidae) termite mounds in Kenya

doi:10.1017/S1742758416000114Termites are an important component of savannah ecosystems throughout Africa. Despite their importance in the ecosystem, they can be serious pests of structures, houses, rangelands, tropical forestry, and agriculture. For many decades, chemical insecticides have remained popular for termite management worldwide. However, with the growing environmental concerns over pesticides, biological control using entomopathogenic fungi such as Metarhizium anisopliae (Metschnikoff) Sorokin has become an often-considered alternative. Metarhizium anisopliaeis an ubiquitous, naturally occurring pathogen, which has been reported infecting over 200 insect species; therefore, there is concern that use of M. anisopliae may affect non-target organisms. The effects of M. anisopliae isolate ICIPE 30 were experimentally tested on the ants which associate with Odontotermes spp. termite mounds. Laboratory bioassays were carried out to assess the effects of direct exposure to M. anisopliae on Crematogaster mimosae and Camponotus spp. In addition, ant diversity was monitored over 18 months from termite mounds treated with M. anisopliae in situ near the Mpala Research Centre in Laikipia District of central Kenya. Results obtained revealed no effects of direct exposure to M. anisopliae isolate ICIPE 30 on the mortality of C. mimosae (F1 = 7.29, P = 0.0072) or Camponotus spp. (F1 = 13.01, P = 0.0004) in the laboratory. No significant difference in Shannon indices of ant diversity from treated and untreated mounds (F1 = 0.016, P = 0.8989) was found. It is evident that M. anisopliae has no negative effects on ants that are associated with Odontotermes spp. termite