Maggie A Stanislawski1, Elizabeth Litkowski2,3,4, Sridharan Raghavan2,4,5, Kylie K Harrall3,6, Jessica Shaw3, Deborah H Glueck3,6, Ethan M Lange2,7, Dana Dabelea3,6,8, Leslie A Lange2,3. 1. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO maggie.stanislawski@cuanschutz.edu. 2. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO. 3. Department of Epidemiology, University of Colorado School of Public Health, Aurora, CO. 4. Veterans Affairs Eastern Colorado Healthcare System, Aurora, CO. 5. Division of Hospital Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO. 6. Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Aurora, CO. 7. Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO. 8. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
Abstract
OBJECTIVE: The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. RESEARCH DESIGN AND METHODS: We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity. RESULTS: Higher weighted GRS was associated with lower oral disposition index (β = -0.11; 95% CI -0.19, -0.02) and insulinogenic index (β = -0.08; 95% CI -0.17, -0.001), but not with fasting glucose (β = 0.01; 95% CI -0.01, 0.02), 2-h glucose (β = 0.03; 95% CI -0.0004, 0.06), or HOMA-IR (β = 0.02; 95% CI -0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. CONCLUSIONS: Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.
OBJECTIVE: The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. RESEARCH DESIGN AND METHODS: We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity. RESULTS: Higher weighted GRS was associated with lower oral disposition index (β = -0.11; 95% CI -0.19, -0.02) and insulinogenic index (β = -0.08; 95% CI -0.17, -0.001), but not with fasting glucose (β = 0.01; 95% CI -0.01, 0.02), 2-h glucose (β = 0.03; 95% CI -0.0004, 0.06), or HOMA-IR (β = 0.02; 95% CI -0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. CONCLUSIONS: Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.
Authors: Sophia M Rössner; Martin Neovius; Scott M Montgomery; Claude Marcus; Svante Norgren Journal: Diabetes Care Date: 2008-01-17 Impact factor: 19.112
Authors: Rector Arya; Vidya S Farook; Sharon P Fowler; Sobha Puppala; Geetha Chittoor; Roy G Resendez; Srinivas Mummidi; Jairam Vanamala; Laura Almasy; Joanne E Curran; Anthony G Comuzzie; Donna M Lehman; Christopher P Jenkinson; Jane L Lynch; Ralph A DeFronzo; John Blangero; Daniel E Hale; Ravindranath Duggirala; Vincent P Diego Journal: Genet Epidemiol Date: 2018-02-20 Impact factor: 2.135
Authors: Christopher C Chang; Carson C Chow; Laurent Cam Tellier; Shashaank Vattikuti; Shaun M Purcell; James J Lee Journal: Gigascience Date: 2015-02-25 Impact factor: 6.524
Authors: Tessa L Crume; Ann Scherzinger; Elizabeth Stamm; Robert McDuffie; Kimberly J Bischoff; Richard F Hamman; Dana Dabelea Journal: Obesity (Silver Spring) Date: 2013-09-17 Impact factor: 5.002
Authors: Cleliani de Cassia da Silva; Mariana Porto Zambon; Ana Carolina Junqueira Vasques; Daniella Fernandes Camilo; Ana Maria De Bernardi Rodrigues; Maria Ângela Reis de Góes Monteiro Antonio; Ana Raimunda Dâmaso; Sergio Tufik; Marco Tulio de Mello; Raquel Munhoz da Silveira Campos; Bruno Geloneze Journal: PLoS One Date: 2019-03-25 Impact factor: 3.240
Authors: Shylaja Srinivasan; Ling Chen; Jennifer Todd; Jasmin Divers; Samuel Gidding; Steven Chernausek; Rose A Gubitosi-Klug; Megan M Kelsey; Rachana Shah; Mary Helen Black; Lynne E Wagenknecht; Alisa Manning; Jason Flannick; Giuseppina Imperatore; Josep M Mercader; Dana Dabelea; Jose C Florez Journal: Diabetes Date: 2021-01-21 Impact factor: 9.337
Authors: Kristina M Utzschneider; Ronald L Prigeon; Mirjam V Faulenbach; Jenny Tong; Darcy B Carr; Edward J Boyko; Donna L Leonetti; Marguerite J McNeely; Wilfred Y Fujimoto; Steven E Kahn Journal: Diabetes Care Date: 2008-10-28 Impact factor: 19.112
Authors: Christian Fuchsberger; Jason Flannick; Tanya M Teslovich; Anubha Mahajan; Vineeta Agarwala; Kyle J Gaulton; Clement Ma; Pierre Fontanillas; Loukas Moutsianas; Davis J McCarthy; Manuel A Rivas; John R B Perry; Xueling Sim; Thomas W Blackwell; Neil R Robertson; N William Rayner; Pablo Cingolani; Adam E Locke; Juan Fernandez Tajes; Heather M Highland; Josee Dupuis; Peter S Chines; Cecilia M Lindgren; Christopher Hartl; Anne U Jackson; Han Chen; Jeroen R Huyghe; Martijn van de Bunt; Richard D Pearson; Ashish Kumar; Martina Müller-Nurasyid; Niels Grarup; Heather M Stringham; Eric R Gamazon; Jaehoon Lee; Yuhui Chen; Robert A Scott; Jennifer E Below; Peng Chen; Jinyan Huang; Min Jin Go; Michael L Stitzel; Dorota Pasko; Stephen C J Parker; Tibor V Varga; Todd Green; Nicola L Beer; Aaron G Day-Williams; Teresa Ferreira; Tasha Fingerlin; Momoko Horikoshi; Cheng Hu; Iksoo Huh; Mohammad Kamran Ikram; Bong-Jo Kim; Yongkang Kim; Young Jin Kim; Min-Seok Kwon; Juyoung Lee; Selyeong Lee; Keng-Han Lin; Taylor J Maxwell; Yoshihiko Nagai; Xu Wang; Ryan P Welch; Joon Yoon; Weihua Zhang; Nir Barzilai; Benjamin F Voight; Bok-Ghee Han; Christopher P Jenkinson; Teemu Kuulasmaa; Johanna Kuusisto; Alisa Manning; Maggie C Y Ng; Nicholette D Palmer; Beverley Balkau; Alena Stančáková; Hanna E Abboud; Heiner Boeing; Vilmantas Giedraitis; Dorairaj Prabhakaran; Omri Gottesman; James Scott; Jason Carey; Phoenix Kwan; George Grant; Joshua D Smith; Benjamin M Neale; Shaun Purcell; Adam S Butterworth; Joanna M M Howson; Heung Man Lee; Yingchang Lu; Soo-Heon Kwak; Wei Zhao; John Danesh; Vincent K L Lam; Kyong Soo Park; Danish Saleheen; Wing Yee So; Claudia H T Tam; Uzma Afzal; David Aguilar; Rector Arya; Tin Aung; Edmund Chan; Carmen Navarro; Ching-Yu Cheng; Domenico Palli; Adolfo Correa; Joanne E Curran; Denis Rybin; Vidya S Farook; Sharon P Fowler; Barry I Freedman; Michael Griswold; Daniel Esten Hale; Pamela J Hicks; Chiea-Chuen Khor; Satish Kumar; Benjamin Lehne; Dorothée Thuillier; Wei Yen Lim; Jianjun Liu; Yvonne T van der Schouw; Marie Loh; Solomon K Musani; Sobha Puppala; William R Scott; Loïc Yengo; Sian-Tsung Tan; Herman A Taylor; Farook Thameem; Gregory Wilson; Tien Yin Wong; Pål Rasmus Njølstad; Jonathan C Levy; Massimo Mangino; Lori L Bonnycastle; Thomas Schwarzmayr; João Fadista; Gabriela L Surdulescu; Christian Herder; Christopher J Groves; Thomas Wieland; Jette Bork-Jensen; Ivan Brandslund; Cramer Christensen; Heikki A Koistinen; Alex S F Doney; Leena Kinnunen; Tõnu Esko; Andrew J Farmer; Liisa Hakaste; Dylan Hodgkiss; Jasmina Kravic; Valeriya Lyssenko; Mette Hollensted; Marit E Jørgensen; Torben Jørgensen; Claes Ladenvall; Johanne Marie Justesen; Annemari Käräjämäki; Jennifer Kriebel; Wolfgang Rathmann; Lars Lannfelt; Torsten Lauritzen; Narisu Narisu; Allan Linneberg; Olle Melander; Lili Milani; Matt Neville; Marju Orho-Melander; Lu Qi; Qibin Qi; Michael Roden; Olov Rolandsson; Amy Swift; Anders H Rosengren; Kathleen Stirrups; Andrew R Wood; Evelin Mihailov; Christine Blancher; Mauricio O Carneiro; Jared Maguire; Ryan Poplin; Khalid Shakir; Timothy Fennell; Mark DePristo; Martin Hrabé de Angelis; Panos Deloukas; Anette P Gjesing; Goo Jun; Peter Nilsson; Jacquelyn Murphy; Robert Onofrio; Barbara Thorand; Torben Hansen; Christa Meisinger; Frank B Hu; Bo Isomaa; Fredrik Karpe; Liming Liang; Annette Peters; Cornelia Huth; Stephen P O'Rahilly; Colin N A Palmer; Oluf Pedersen; Rainer Rauramaa; Jaakko Tuomilehto; Veikko Salomaa; Richard M Watanabe; Ann-Christine Syvänen; Richard N Bergman; Dwaipayan Bharadwaj; Erwin P Bottinger; Yoon Shin Cho; Giriraj R Chandak; Juliana C N Chan; Kee Seng Chia; Mark J Daly; Shah B Ebrahim; Claudia Langenberg; Paul Elliott; Kathleen A Jablonski; Donna M Lehman; Weiping Jia; Ronald C W Ma; Toni I Pollin; Manjinder Sandhu; Nikhil Tandon; Philippe Froguel; Inês Barroso; Yik Ying Teo; Eleftheria Zeggini; Ruth J F Loos; Kerrin S Small; Janina S Ried; Ralph A DeFronzo; Harald Grallert; Benjamin Glaser; Andres Metspalu; Nicholas J Wareham; Mark Walker; Eric Banks; Christian Gieger; Erik Ingelsson; Hae Kyung Im; Thomas Illig; Paul W Franks; Gemma Buck; Joseph Trakalo; David Buck; Inga Prokopenko; Reedik Mägi; Lars Lind; Yossi Farjoun; Katharine R Owen; Anna L Gloyn; Konstantin Strauch; Tiinamaija Tuomi; Jaspal Singh Kooner; Jong-Young Lee; Taesung Park; Peter Donnelly; Andrew D Morris; Andrew T Hattersley; Donald W Bowden; Francis S Collins; Gil Atzmon; John C Chambers; Timothy D Spector; Markku Laakso; Tim M Strom; Graeme I Bell; John Blangero; Ravindranath Duggirala; E Shyong Tai; Gilean McVean; Craig L Hanis; James G Wilson; Mark Seielstad; Timothy M Frayling; James B Meigs; Nancy J Cox; Rob Sladek; Eric S Lander; Stacey Gabriel; Noël P Burtt; Karen L Mohlke; Thomas Meitinger; Leif Groop; Goncalo Abecasis; Jose C Florez; Laura J Scott; Andrew P Morris; Hyun Min Kang; Michael Boehnke; David Altshuler; Mark I McCarthy Journal: Nature Date: 2016-07-11 Impact factor: 69.504