低频和罕见的外显子芯片变异与空腹血糖及2型糖尿病易感性相关。
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.
作者信息
Wessel Jennifer, Chu Audrey Y, Willems Sara M, Wang Shuai, Yaghootkar Hanieh, Brody Jennifer A, Dauriz Marco, Hivert Marie-France, Raghavan Sridharan, Lipovich Leonard, Hidalgo Bertha, Fox Keolu, Huffman Jennifer E, An Ping, Lu Yingchang, Rasmussen-Torvik Laura J, Grarup Niels, Ehm Margaret G, Li Li, Baldridge Abigail S, Stančáková Alena, Abrol Ravinder, Besse Céline, Boland Anne, Bork-Jensen Jette, Fornage Myriam, Freitag Daniel F, Garcia Melissa E, Guo Xiuqing, Hara Kazuo, Isaacs Aaron, Jakobsdottir Johanna, Lange Leslie A, Layton Jill C, Li Man, Hua Zhao Jing, Meidtner Karina, Morrison Alanna C, Nalls Mike A, Peters Marjolein J, Sabater-Lleal Maria, Schurmann Claudia, Silveira Angela, Smith Albert V, Southam Lorraine, Stoiber Marcus H, Strawbridge Rona J, Taylor Kent D, Varga Tibor V, Allin Kristine H, Amin Najaf, Aponte Jennifer L, Aung Tin, Barbieri Caterina, Bihlmeyer Nathan A, Boehnke Michael, Bombieri Cristina, Bowden Donald W, Burns Sean M, Chen Yuning, Chen Yii-DerI, Cheng Ching-Yu, Correa Adolfo, Czajkowski Jacek, Dehghan Abbas, Ehret Georg B, Eiriksdottir Gudny, Escher Stefan A, Farmaki Aliki-Eleni, Frånberg Mattias, Gambaro Giovanni, Giulianini Franco, Goddard William A, Goel Anuj, Gottesman Omri, Grove Megan L, Gustafsson Stefan, Hai Yang, Hallmans Göran, Heo Jiyoung, Hoffmann Per, Ikram Mohammad K, Jensen Richard A, Jørgensen Marit E, Jørgensen Torben, Karaleftheri Maria, Khor Chiea C, Kirkpatrick Andrea, Kraja Aldi T, Kuusisto Johanna, Lange Ethan M, Lee I T, Lee Wen-Jane, Leong Aaron, Liao Jiemin, Liu Chunyu, Liu Yongmei, Lindgren Cecilia M, Linneberg Allan, Malerba Giovanni, Mamakou Vasiliki, Marouli Eirini, Maruthur Nisa M, Matchan Angela, McKean-Cowdin Roberta, McLeod Olga, Metcalf Ginger A, Mohlke Karen L, Muzny Donna M, Ntalla Ioanna, Palmer Nicholette D, Pasko Dorota, Peter Andreas, Rayner Nigel W, Renström Frida, Rice Ken, Sala Cinzia F, Sennblad Bengt, Serafetinidis Ioannis, Smith Jennifer A, Soranzo Nicole, Speliotes Elizabeth K, Stahl Eli A, Stirrups Kathleen, Tentolouris Nikos, Thanopoulou Anastasia, Torres Mina, Traglia Michela, Tsafantakis Emmanouil, Javad Sundas, Yanek Lisa R, Zengini Eleni, Becker Diane M, Bis Joshua C, Brown James B, Cupples L Adrienne, Hansen Torben, Ingelsson Erik, Karter Andrew J, Lorenzo Carlos, Mathias Rasika A, Norris Jill M, Peloso Gina M, Sheu Wayne H-H, Toniolo Daniela, Vaidya Dhananjay, Varma Rohit, Wagenknecht Lynne E, Boeing Heiner, Bottinger Erwin P, Dedoussis George, Deloukas Panos, Ferrannini Ele, Franco Oscar H, Franks Paul W, Gibbs Richard A, Gudnason Vilmundur, Hamsten Anders, Harris Tamara B, Hattersley Andrew T, Hayward Caroline, Hofman Albert, Jansson Jan-Håkan, Langenberg Claudia, Launer Lenore J, Levy Daniel, Oostra Ben A, O'Donnell Christopher J, O'Rahilly Stephen, Padmanabhan Sandosh, Pankow James S, Polasek Ozren, Province Michael A, Rich Stephen S, Ridker Paul M, Rudan Igor, Schulze Matthias B, Smith Blair H, Uitterlinden André G, Walker Mark, Watkins Hugh, Wong Tien Y, Zeggini Eleftheria, Laakso Markku, Borecki Ingrid B, Chasman Daniel I, Pedersen Oluf, Psaty Bruce M, Tai E Shyong, van Duijn Cornelia M, Wareham Nicholas J, Waterworth Dawn M, Boerwinkle Eric, Kao W H Linda, Florez Jose C, Loos Ruth J F, Wilson James G, Frayling Timothy M, Siscovick David S, Dupuis Josée, Rotter Jerome I, Meigs James B, Scott Robert A, Goodarzi Mark O
机构信息
1] Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
出版信息
Nat Commun. 2015 Jan 29;6:5897. doi: 10.1038/ncomms6897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
空腹血糖和胰岛素是2型糖尿病的中间性状。在此，我们通过分析人类外显子芯片上的变异，在60564名非糖尿病个体、16491例2型糖尿病病例和81877名对照中，探讨编码变异对这些性状的作用。我们发现GLP1R基因中一个低频非同义单核苷酸变异（A316T；rs10305492；MAF = 1.4%）与较低的空腹血糖（β=-0.09±0.01 mmol·l⁻¹，P = 3.4×10⁻¹²）、2型糖尿病风险（OR[95%CI]=0.86[0.76 - 0.96]，P = 0.010）、早期胰岛素分泌（β=-0.07±0.035 pmol胰岛素·mmol葡萄糖⁻¹，P = 0.048）相关，但与较高的2小时血糖（β=0.16±0.05 mmol·l⁻¹，P = 4.3×10⁻⁴）相关。我们发现由四个罕见的蛋白质编码单核苷酸变异（H177Y、Y207S、R283X和S324P）驱动，G6PC2基因与空腹血糖存在基于基因的关联（pSKAT = 6.8×10⁻⁶）。我们在ABO基因第一个内含子中位于一个反义长链非编码RNA假定启动子处发现rs651007（MAF = 20%），其与较高的空腹血糖相关（β=0.02±0.004 mmol·l⁻¹，P = 1.3×10⁻⁸）。我们的方法识别出了新的编码变异关联，并扩展了与糖尿病相关定量性状和2型糖尿病易感性相关的变异等位基因谱。
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