| Autor: |
Victor Rusu, Eitan Hoch, Josep M. Mercader, Danielle E. Tenen, Melissa Gymrek, Christina R. Hartigan, Michael DeRan, Marcin von Grotthuss, Pierre Fontanillas, Alexandra Spooner, Gaelen Guzman, Amy A. Deik, Kerry A. Pierce, Courtney Dennis, Clary B. Clish, Steven A. Carr, Bridget K. Wagner, Monica Schenone, Maggie C.Y. Ng, Brian H. Chen, Federico Centeno-Cruz, Carlos Zerrweck, Lorena Orozco, David M. Altshuler, Stuart L. Schreiber, Jose C. Florez, Suzanne B.R. Jacobs, Eric S. Lander, Daniel Shriner, Jiang Li, Wei-Min Chen, Xiuqing Guo, Jiankang Liu, Suzette J. Bielinski, Lisa R. Yanek, Michael A. Nalls, Mary E. Comeau, Laura J. Rasmussen-Torvik, Richard A. Jensen, Daniel S. Evans, Yan V. Sun, Ping An, Sanjay R. Patel, Yingchang Lu, Jirong Long, Loren L. Armstrong, Lynne Wagenknecht, Lingyao Yang, Beverly M. Snively, Nicholette D. Palmer, Poorva Mudgal, Carl D. Langefeld, Keith L. Keene, Barry I. Freedman, Josyf C. Mychaleckyj, Uma Nayak, Leslie J. Raffel, Mark O. Goodarzi, Y-D Ida Chen, Herman A. Taylor, Adolfo Correa, Mario Sims, David Couper, James S. Pankow, Eric Boerwinkle, Adebowale Adeyemo, Ayo Doumatey, Guanjie Chen, Rasika A. Mathias, Dhananjay Vaidya, Andrew B. Singleton, Alan B. Zonderman, Robert P. Igo, John R. Sedor, Edmond K. Kabagambe, David S. Siscovick, Barbara McKnight, Kenneth Rice, Yongmei Liu, Wen-Chi Hsueh, Wei Zhao, Lawrence F. Bielak, Aldi Kraja, Michael A. Province, Erwin P. Bottinger, Omri Gottesman, Qiuyin Cai, Wei Zheng, William J. Blot, William L. Lowe, Jennifer A. Pacheco, Dana C. Crawford, Elin Grundberg, Stephen S. Rich, M. Geoffrey Hayes, Xiao-Ou Shu, Ruth J.F. Loos, Ingrid B. Borecki, Patricia A. Peyser, Steven R. Cummings, Bruce M. Psaty, Myriam Fornage, Sudha K. Iyengar, Michele K. Evans, Diane M. Becker, W.H. Linda Kao, James G. Wilson, Jerome I. Rotter, Michèle M. Sale, Simin Liu, Charles N. Rotimi, Donald W. Bowden, Alicia Huerta-Chagoya, Humberto García-Ortiz, Hortensia Moreno-Macías, Alisa Manning, Lizz Caulkins, Noël P. Burtt, Jason Flannick, Nick Patterson, Carlos A. Aguilar-Salinas, Teresa Tusié-Luna, David Altshuler, Angélica Martínez-Hernández, Francisco Martin Barajas-Olmos, Cecilia Contreras-Cubas, Elvia Mendoza-Caamal, Cristina Revilla-Monsalve, Sergio Islas-Andrade, Emilio Córdova, Xavier Soberón, Clicerio González-Villalpando, María Elena González-Villalpando, Christopher A. Haiman, Lynne Wilkens, Loic Le Marchand, Kristine Monroe, Laurence Kolonel, Olimpia Arellano-Campos, Maria L. Ordóñez-Sánchez, Maribel Rodríguez-Torres, Yayoi Segura-Kato, Rosario Rodríguez-Guillén, Ivette Cruz-Bautista, Linda Liliana Muñoz-Hernandez, Tamara Sáenz, Donají Gómez, Ulices Alvirde, Paloma Almeda-Valdés, Maria L. Cortes |
| Přispěvatelé: |
Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Lander, Eric Steven |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
PMC |
| ISSN: |
1097-4172 |
| Popis: |
Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicine |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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