دورية أكاديمية
GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification
| العنوان: | GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification |
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| المؤلفون: | Lagou, Vasiliki, Jiang, Longda, Ulrich, Anna, Zudina, Liudmila, González, Karla Sofia Gutiérrez, Balkhiyarova, Zhanna, Faggian, Alessia, Maina, Jared G., Chen, Shiqian, Todorov, Petar V., Sharapov, Sodbo, David, Alessia, Marullo, Letizia, Mägi, Reedik, Rujan, Roxana-Maria, Ahlqvist, Emma, Thorleifsson, Gudmar, Gao, Ηe, Εvangelou, Εvangelos, Benyamin, Beben, Scott, Robert A., Isaacs, Aaron, Zhao, Jing Hua, Willems, Sara M., Johnson, Toby, Gieger, Christian, Grallert, Harald, Meisinger, Christa, Müller-Nurasyid, Martina, Strawbridge, Rona J., Goel, Anuj, Rybin, Denis, Albrecht, Eva, Jackson, Anne U., Stringham, Heather M., Corrêa, Ivan R., Farber-Eger, Eric, Steinthorsdottir, Valgerdur, Uitterlinden, André G., Munroe, Patricia B., Brown, Morris J., Schmidberger, Julian, Holmen, Oddgeir Lingaas, Thorand, Barbara, Hveem, Kristian, Wilsgaard, Tom, Mohlke, Karen L., Wang, Zhe, Shmeliov, Aleksey, den Hoed, Marcel, Loos, Ruth J. F., Kratzer, Wolfgang, Haenle, Mark, Koenig, Wolfgang, Boehm, Bernhard O., Tan, Tricia M., Tomas, Alejandra, Salem, Victoria, Barroso, Inês, Tuomilehto, Jaakko, Boehnke, Michael, Florez, Jose C., Hamsten, Anders, Watkins, Hugh, Njølstad, Inger, Wichmann, H.-Erich, Caulfield, Mark J., Khaw, Kay-Tee, van Duijn, Cornelia M., Hofman, Albert, Wareham, Nicholas J., Langenberg, Claudia, Whitfield, John B., Martin, Nicholas G., Montgomery, Grant, Scapoli, Chiara, Tzoulaki, Ioanna, Elliott, Paul, Thorsteinsdottir, Unnur, Stefansson, Kari, Brittain, Evan L., McCarthy, Mark I., Froguel, Philippe, Sexton, Patrick M., Wootten, Denise, Groop, Leif, Dupuis, Josée, Meigs, James B., Deganutti, Giuseppe, Demirkan, Ayse, Pers, Tune H., Reynolds, Christopher A., Aulchenko, Yurii S., Kaakinen, Marika A., Jones, Ben, Prokopenko, Inga |
| بيانات النشر: | Springer Nature |
| سنة النشر: | 2023 |
| المجموعة: | University of Tromsø: Munin Open Research Archive |
| الوصف: | Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1061-4036 1546-1718 |
| العلاقة: | Nature Genetics; info:eu-repo/grantAgreement/EC/FP7-HEALTH/601456/?/Exploitation of genomic variants affecting coronary artery disease and stroke risk for therapeutic intervention/CVGENES-AT-TARGET/; info:eu-repo/grantAgreement/EC/?/037273?/?/?/?/; info:eu-repo/grantAgreement/EC/H2020/874739/?/Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases/LONGITOOLS/; Lagou, Jiang, Ulrich, Zudina, González, Balkhiyarova, Faggian, Maina, Chen, Todorov, Sharapov, David, Marullo, Mägi, Rujan, Ahlqvist, Thorleifsson, Gao, Εvangelou, Benyamin, Scott, Isaacs, Zhao, Willems, Johnson, Gieger, Grallert, Meisinger, Müller-Nurasyid, Strawbridge, Goel, Rybin, Albrecht, Jackson, Stringham, Corrêa, Farber-Eger, Steinthorsdottir, Uitterlinden, Munroe, Brown, Schmidberger, Holmen, Thorand, Hveem, Wilsgaard, Mohlke, Wang, Shmeliov, den Hoed, Loos, Kratzer, Haenle, Koenig, Boehm, Tan, Tomas, Salem, Barroso, Tuomilehto, Boehnke, Florez, Hamsten, Watkins, Njølstad, Wichmann, Caulfield, Khaw, van Duijn, Hofman, Wareham, Langenberg, Whitfield, Martin, Montgomery, Scapoli, Tzoulaki, Elliott, Thorsteinsdottir, Stefansson, Brittain, McCarthy, Froguel, Sexton, Wootten, Groop, Dupuis, Meigs, Deganutti, Demirkan, Pers, Reynolds, Aulchenko, Kaakinen, Jones, Prokopenko. GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification. Nature Genetics. 2023;55(9):1448-1461; FRIDAID 2181699; https://hdl.handle.net/10037/31986Test |
| DOI: | 10.1038/s41588-023-01462-3 |
| الإتاحة: | https://doi.org/10.1038/s41588-023-01462-3Test https://hdl.handle.net/10037/31986Test |
| حقوق: | Attribution 4.0 International (CC BY 4.0) ; openAccess ; Copyright 2023 The Author(s) ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.6E7D02D3 |
| قاعدة البيانات: | BASE |
| تدمد: | 10614036 15461718 |
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| DOI: | 10.1038/s41588-023-01462-3 |