A Low-Frequency Inactivating Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Authors:
Ravindranath Duggirala, Ph.D.
Ravindranath Duggirala, Ph.D.
University of Texas Rio Grande Valley
Professor
Genetic Epidemiology and Statistical Genetics
Edinburg, TX | United States
Alisa Manning Heather M Highland Jessica Gasser Xueling Sim Taru Tukiainen Pierre Fontanillas Niels Grarup Manuel A Rivas Anubha Mahajan Adam E Locke Pablo Cingolani Tune H Pers Ana Viñuela Andrew A Brown Ying Wu Jason Flannick Christian Fuchsberger Eric R Gamazon Kyle J Gaulton Hae Kyung Im Tanya M Teslovich Thomas W Blackwell Jette Bork-Jensen Noël P Burtt Yuhui Chen Todd Green Christopher Hartl Hyun Min Kang Ashish Kumar Claes Ladenvall Clement Ma Loukas Moutsianas Richard D Pearson John R B Perry N William Rayner Neil R Robertson Laura J Scott Martijn van de Bunt Johan G Eriksson Antti Jula Seppo Koskinen Terho Lehtimäki Aarno Palotie Olli T Raitakari Suzanne B R Jacobs Jennifer Wessel Audrey Y Chu Robert A Scott Mark O Goodarzi Christine Blancher Gemma Buck David Buck Peter S Chines Stacey Gabriel Anette P Gjesing Christopher J Groves Mette Hollensted Jeroen R Huyghe Anne U Jackson Goo Jun Johanne Marie Justesen Massimo Mangino Jacquelyn Murphy Matt Neville Robert Onofrio Kerrin S Small Heather M Stringham Joseph Trakalo Eric Banks Jason Carey Mauricio O Carneiro Mark DePristo Yossi Farjoun Timothy Fennell Jacqueline I Goldstein George Grant Martin Hrabé de Angelis Jared Maguire Benjamin M Neale Ryan Poplin Shaun Purcell Thomas Schwarzmayr Khalid Shakir Joshua D Smith Tim M Strom Thomas Wieland Jaana Lindstrom Ivan Brandslund Cramer Christensen Gabriela L Surdulescu Timo A Lakka Alex S F Doney Peter Nilsson Nicholas J Wareham Claudia Langenberg Tibor V Varga Paul W Franks Olov Rolandsson Anders H Rosengren Vidya S Farook Farook Thameem Sobha Puppala Satish Kumar Donna M Lehman Christopher P Jenkinson Joanne E Curran Daniel Esten Hale Sharon P Fowler Rector Arya Ralph A DeFronzo Hanna E Abboud Ann-Christine Syvänen Pamela J Hicks Nicholette D Palmer Maggie C Y Ng Donald W Bowden Barry I Freedman Tõnu Esko Reedik Mägi Lili Milani Evelin Mihailov Andres Metspalu Narisu Narisu Leena Kinnunen Lori L Bonnycastle Amy Swift Dorota Pasko Andrew R Wood João Fadista Toni I Pollin Nir Barzilai Gil Atzmon Benjamin Glaser Barbara Thorand Konstantin Strauch Annette Peters Michael Roden Martina Müller-Nurasyid Liming Liang Jennifer Kriebel Thomas Illig Harald Grallert Christian Gieger Christa Meisinger Lars Lannfelt Solomon K Musani Michael Griswold Herman A Taylor Gregory Wilson Adolfo Correa Heikki Oksa William R Scott Uzma Afzal Sian-Tsung Tan Marie Loh John C Chambers Jobanpreet Sehmi Jaspal Singh Kooner Benjamin Lehne Yoon Shin Cho Jong-Young Lee Bok-Ghee Han Annemari Käräjämäki Qibin Qi Lu Qi Jinyan Huang Frank B Hu Olle Melander Marju Orho-Melander Jennifer E Below David Aguilar Tien Yin Wong Jianjun Liu Chiea-Chuen Khor Kee Seng Chia Wei Yen Lim Ching-Yu Cheng Edmund Chan E Shyong Tai Tin Aung Allan Linneberg Bo Isomaa Thomas Meitinger Tiinamaija Tuomi Liisa Hakaste Jasmina Kravic Marit E Jørgensen Torsten Lauritzen Panos Deloukas Kathleen E Stirrups Katharine R Owen Andrew J Farmer Timothy M Frayling Stephen P O'Rahilly Mark Walker Jonathan C Levy Dylan Hodgkiss Andrew T Hattersley Teemu Kuulasmaa Alena Stančáková Inês Barroso Dwaipayan Bharadwaj Juliana Chan Giriraj R Chandak Mark J Daly Peter J Donnelly Shah B Ebrahim Paul Elliott Tasha Fingerlin Philippe Froguel Cheng Hu Weiping Jia Ronald C W Ma Gilean McVean Taesung Park Dorairaj Prabhakaran Manjinder Sandhu James Scott Rob Sladek Nikhil Tandon Yik Ying Teo Eleftheria Zeggini Richard M Watanabe Heikki A Koistinen Y Antero Kesaniemi Matti Uusitupa Timothy D Spector Veikko Salomaa Rainer Rauramaa Colin N A Palmer Inga Prokopenko Andrew D Morris Richard N Bergman Francis S Collins Lars Lind Erik Ingelsson Jaakko Tuomilehto Fredrik Karpe Leif Groop Torben Jørgensen Torben Hansen Oluf Pedersen Johanna Kuusisto Gonçalo Abecasis Graeme I Bell John Blangero Nancy J Cox Mark Seielstad James G Wilson Josee Dupuis Samuli Ripatti Craig L Hanis Jose C Florez Karen L Mohlke James B Meigs Markku Laakso Andrew P Morris Michael Boehnke David Altshuler Mark I McCarthy Anna L Gloyn Cecilia M Lindgren

Diabetes 2017 07 24;66(7):2019-2032. Epub 2017 Mar 24.

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of .

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Source
http://dx.doi.org/10.2337/db16-1329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482074PMC
July 2017
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