Brian T Steffen1, Weihong Tang1, Pamela L Lutsey1, Ryan T Demmer1,2, Elizabeth Selvin3, Kunihiro Matsushita3,4, Alanna C Morrison5, Weihua Guan6, Mary R Rooney3,4, Faye L Norby7, Nathan Pankratz8, David Couper9, James S Pankow10. 1. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA. 2. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. 3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 4. Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD, USA. 5. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. 6. Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN, USA. 7. Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Health System, Los Angeles, CA, USA. 8. Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA. 9. University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA. 10. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA. panko001@umn.edu.
Abstract
AIMS/HYPOTHESIS: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. METHODS: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. RESULTS: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 × 10-3), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 × 10-3). CONCLUSIONS/ INTERPRETATION: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets.
AIMS/HYPOTHESIS: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. METHODS: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. RESULTS: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 × 10-3), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 × 10-3). CONCLUSIONS/ INTERPRETATION: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets.
Authors: Anubha Mahajan; Jennifer Wessel; Sara M Willems; Wei Zhao; Neil R Robertson; Audrey Y Chu; Wei Gan; Hidetoshi Kitajima; Daniel Taliun; N William Rayner; Xiuqing Guo; Yingchang Lu; Man Li; Richard A Jensen; Yao Hu; Shaofeng Huo; Kurt K Lohman; Weihua Zhang; James P Cook; Bram Peter Prins; Jason Flannick; Niels Grarup; Vassily Vladimirovich Trubetskoy; Jasmina Kravic; Young Jin Kim; Denis V Rybin; Hanieh Yaghootkar; Martina Müller-Nurasyid; Karina Meidtner; Ruifang Li-Gao; Tibor V Varga; Jonathan Marten; Jin Li; Albert Vernon Smith; Ping An; Symen Ligthart; Stefan Gustafsson; Giovanni Malerba; Ayse Demirkan; Juan Fernandez Tajes; Valgerdur Steinthorsdottir; Matthias Wuttke; Cécile Lecoeur; Michael Preuss; Lawrence F Bielak; Marielisa Graff; Heather M Highland; Anne E Justice; Dajiang J Liu; Eirini Marouli; Gina Marie Peloso; Helen R Warren; Saima Afaq; Shoaib Afzal; Emma Ahlqvist; Peter Almgren; Najaf Amin; Lia B Bang; Alain G Bertoni; Cristina Bombieri; Jette Bork-Jensen; Ivan Brandslund; Jennifer A Brody; Noël P Burtt; Mickaël Canouil; Yii-Der Ida Chen; Yoon Shin Cho; Cramer Christensen; Sophie V Eastwood; Kai-Uwe Eckardt; Krista Fischer; Giovanni Gambaro; Vilmantas Giedraitis; Megan L Grove; Hugoline G de Haan; Sophie Hackinger; Yang Hai; Sohee Han; Anne Tybjærg-Hansen; Marie-France Hivert; Bo Isomaa; Susanne Jäger; Marit E Jørgensen; Torben Jørgensen; Annemari Käräjämäki; Bong-Jo Kim; Sung Soo Kim; Heikki A Koistinen; Peter Kovacs; Jennifer Kriebel; Florian Kronenberg; Kristi Läll; Leslie A Lange; Jung-Jin Lee; Benjamin Lehne; Huaixing Li; Keng-Hung Lin; Allan Linneberg; Ching-Ti Liu; Jun Liu; Marie Loh; Reedik Mägi; Vasiliki Mamakou; Roberta McKean-Cowdin; Girish Nadkarni; Matt Neville; Sune F Nielsen; Ioanna Ntalla; Patricia A Peyser; Wolfgang Rathmann; Kenneth Rice; Stephen S Rich; Line Rode; Olov Rolandsson; Sebastian Schönherr; Elizabeth Selvin; Kerrin S Small; Alena Stančáková; Praveen Surendran; Kent D Taylor; Tanya M Teslovich; Barbara Thorand; Gudmar Thorleifsson; Adrienne Tin; Anke Tönjes; Anette Varbo; Daniel R Witte; Andrew R Wood; Pranav Yajnik; Jie Yao; Loïc Yengo; Robin Young; Philippe Amouyel; Heiner Boeing; Eric Boerwinkle; Erwin P Bottinger; Rajiv Chowdhury; Francis S Collins; George Dedoussis; Abbas Dehghan; Panos Deloukas; Marco M Ferrario; Jean Ferrières; Jose C Florez; Philippe Frossard; Vilmundur Gudnason; Tamara B Harris; Susan R Heckbert; Joanna M M Howson; Martin Ingelsson; Sekar Kathiresan; Frank Kee; Johanna Kuusisto; Claudia Langenberg; Lenore J Launer; Cecilia M Lindgren; Satu Männistö; Thomas Meitinger; Olle Melander; Karen L Mohlke; Marie Moitry; Andrew D Morris; Alison D Murray; Renée de Mutsert; Marju Orho-Melander; Katharine R Owen; Markus Perola; Annette Peters; Michael A Province; Asif Rasheed; Paul M Ridker; Fernando Rivadineira; Frits R Rosendaal; Anders H Rosengren; Veikko Salomaa; Wayne H-H Sheu; Rob Sladek; Blair H Smith; Konstantin Strauch; André G Uitterlinden; Rohit Varma; Cristen J Willer; Matthias Blüher; Adam S Butterworth; John Campbell Chambers; Daniel I Chasman; John Danesh; Cornelia van Duijn; Josée Dupuis; Oscar H Franco; Paul W Franks; Philippe Froguel; Harald Grallert; Leif Groop; Bok-Ghee Han; Torben Hansen; Andrew T Hattersley; Caroline Hayward; Erik Ingelsson; Sharon L R Kardia; Fredrik Karpe; Jaspal Singh Kooner; Anna Köttgen; Kari Kuulasmaa; Markku Laakso; Xu Lin; Lars Lind; Yongmei Liu; Ruth J F Loos; Jonathan Marchini; Andres Metspalu; Dennis Mook-Kanamori; Børge G Nordestgaard; Colin N A Palmer; James S Pankow; Oluf Pedersen; Bruce M Psaty; Rainer Rauramaa; Naveed Sattar; Matthias B Schulze; Nicole Soranzo; Timothy D Spector; Kari Stefansson; Michael Stumvoll; Unnur Thorsteinsdottir; Tiinamaija Tuomi; Jaakko Tuomilehto; Nicholas J Wareham; James G Wilson; Eleftheria Zeggini; Robert A Scott; Inês Barroso; Timothy M Frayling; Mark O Goodarzi; James B Meigs; Michael Boehnke; Danish Saleheen; Andrew P Morris; Jerome I Rotter; Mark I McCarthy Journal: Nat Genet Date: 2018-04-09 Impact factor: 38.330
Authors: Derrick A Bennett; Huaidong Du; Fiona Bragg; Yu Guo; Neil Wright; Ling Yang; Zheng Bian; Yiping Chen; Canqing Yu; Sisi Wang; Fanwen Meng; Jun Lv; Junshi Chen; Liming Li; Robert Clarke; Zhengming Chen Journal: BMJ Open Diabetes Res Care Date: 2019-12-18
Authors: Robert A Scott; Laura J Scott; Reedik Mägi; Letizia Marullo; Kyle J Gaulton; Marika Kaakinen; Natalia Pervjakova; Tune H Pers; Andrew D Johnson; John D Eicher; Anne U Jackson; Teresa Ferreira; Yeji Lee; Clement Ma; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Lu Qi; Natalie R Van Zuydam; Anubha Mahajan; Han Chen; Peter Almgren; Ben F Voight; Harald Grallert; Martina Müller-Nurasyid; Janina S Ried; Nigel W Rayner; Neil Robertson; Lennart C Karssen; Elisabeth M van Leeuwen; Sara M Willems; Christian Fuchsberger; Phoenix Kwan; Tanya M Teslovich; Pritam Chanda; Man Li; Yingchang Lu; Christian Dina; Dorothee Thuillier; Loic Yengo; Longda Jiang; Thomas Sparso; Hans A Kestler; Himanshu Chheda; Lewin Eisele; Stefan Gustafsson; Mattias Frånberg; Rona J Strawbridge; Rafn Benediktsson; Astradur B Hreidarsson; Augustine Kong; Gunnar Sigurðsson; Nicola D Kerrison; Jian'an Luan; Liming Liang; Thomas Meitinger; Michael Roden; Barbara Thorand; Tõnu Esko; Evelin Mihailov; Caroline Fox; Ching-Ti Liu; Denis Rybin; Bo Isomaa; Valeriya Lyssenko; Tiinamaija Tuomi; David J Couper; James S Pankow; Niels Grarup; Christian T Have; Marit E Jørgensen; Torben Jørgensen; Allan Linneberg; Marilyn C Cornelis; Rob M van Dam; David J Hunter; Peter Kraft; Qi Sun; Sarah Edkins; Katharine R Owen; John R B Perry; Andrew R Wood; Eleftheria Zeggini; Juan Tajes-Fernandes; Goncalo R Abecasis; Lori L Bonnycastle; Peter S Chines; Heather M Stringham; Heikki A Koistinen; Leena Kinnunen; Bengt Sennblad; Thomas W Mühleisen; Markus M Nöthen; Sonali Pechlivanis; Damiano Baldassarre; Karl Gertow; Steve E Humphries; Elena Tremoli; Norman Klopp; Julia Meyer; Gerald Steinbach; Roman Wennauer; Johan G Eriksson; Satu Mӓnnistö; Leena Peltonen; Emmi Tikkanen; Guillaume Charpentier; Elodie Eury; Stéphane Lobbens; Bruna Gigante; Karin Leander; Olga McLeod; Erwin P Bottinger; Omri Gottesman; Douglas Ruderfer; Matthias Blüher; Peter Kovacs; Anke Tonjes; Nisa M Maruthur; Chiara Scapoli; Raimund Erbel; Karl-Heinz Jöckel; Susanne Moebus; Ulf de Faire; Anders Hamsten; Michael Stumvoll; Panagiotis Deloukas; Peter J Donnelly; Timothy M Frayling; Andrew T Hattersley; Samuli Ripatti; Veikko Salomaa; Nancy L Pedersen; Bernhard O Boehm; Richard N Bergman; Francis S Collins; Karen L Mohlke; Jaakko Tuomilehto; Torben Hansen; Oluf Pedersen; Inês Barroso; Lars Lannfelt; Erik Ingelsson; Lars Lind; Cecilia M Lindgren; Stephane Cauchi; Philippe Froguel; Ruth J F Loos; Beverley Balkau; Heiner Boeing; Paul W Franks; Aurelio Barricarte Gurrea; Domenico Palli; Yvonne T van der Schouw; David Altshuler; Leif C Groop; Claudia Langenberg; Nicholas J Wareham; Eric Sijbrands; Cornelia M van Duijn; Jose C Florez; James B Meigs; Eric Boerwinkle; Christian Gieger; Konstantin Strauch; Andres Metspalu; Andrew D Morris; Colin N A Palmer; Frank B Hu; Unnur Thorsteinsdottir; Kari Stefansson; Josée Dupuis; Andrew P Morris; Michael Boehnke; Mark I McCarthy; Inga Prokopenko Journal: Diabetes Date: 2017-05-31 Impact factor: 9.337