Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

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 like...

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Main Authors: Rusu, Victor (Author), Hoch, Eitan (Author), Mercader, Josep M. (Author), Tenen, Danielle E. (Author), Gymrek, Melissa (Author), Hartigan, Christina R. (Author), DeRan, Michael (Author), von Grotthuss, Marcin (Author), Fontanillas, Pierre (Author), Spooner, Alexandra (Author), Guzman, Gaelen (Author), Deik, Amy A. (Author), Pierce, Kerry A. (Author), Dennis, Courtney (Author), Clish, Clary B. (Author), Carr, Steven A. (Author), Wagner, Bridget K. (Author), Schenone, Monica (Author), Ng, Maggie C.Y (Author), Chen, Brian H. (Author), Centeno-Cruz, Federico (Author), Zerrweck, Carlos (Author), Orozco, Lorena (Author), Schreiber, Stuart L. (Author), Florez, Jose C. (Author), Jacobs, Suzanne B.R (Author), Shriner, Daniel (Author), Li, Jiang (Author), Chen, Wei-Min (Author), Guo, Xiuqing (Author), Liu, Jiankang (Author), Bielinski, Suzette J. (Author), Yanek, Lisa R. (Author), Nalls, Michael A. (Author), Comeau, Mary E. (Author), Rasmussen-Torvik, Laura J. (Author), Jensen, Richard A. (Author), Evans, Daniel S. (Author), Sun, Yan V. (Author), An, Ping (Author), Patel, Sanjay R. (Author), Lu, Yingchang (Author), Long, Jirong (Author), Armstrong, Loren L. (Author), Wagenknecht, Lynne (Author), Yang, Lingyao (Author), Snively, Beverly M. (Author), Palmer, Nicholette D. (Author), Mudgal, Poorva (Author), Langefeld, Carl D. (Author), Keene, Keith L. (Author), Freedman, Barry I. (Author), Mychaleckyj, Josyf C. (Author), Nayak, Uma (Author), Raffel, Leslie J. (Author), Goodarzi, Mark O. (Author), Chen, Y-D Ida (Author), Taylor, Herman A. (Author), Correa, Adolfo (Author), Sims, Mario (Author), Couper, David (Author), Pankow, James S. (Author), Boerwinkle, Eric (Author), Adeyemo, Adebowale (Author), Doumatey, Ayo (Author), Chen, Guanjie (Author), Mathias, Rasika A. (Author), Vaidya, Dhananjay (Author), Singleton, Andrew B. (Author), Zonderman, Alan B. (Author), Igo, Robert P. (Author), Sedor, John R. (Author), Kabagambe, Edmond K. (Author), Siscovick, David S. (Author), McKnight, Barbara (Author), Rice, Kenneth (Author), Liu, Yongmei (Author), Hsueh, Wen-Chi (Author), Zhao, Wei (Author), Bielak, Lawrence F. (Author), Kraja, Aldi (Author), Province, Michael A. (Author), Bottinger, Erwin P. (Author), Gottesman, Omri (Author), Cai, Qiuyin (Author), Zheng, Wei (Author), Blot, William J. (Author), Lowe, William L. (Author), Pacheco, Jennifer A. (Author), Crawford, Dana C. (Author), Grundberg, Elin (Author), Rich, Stephen S. (Author), Hayes, M. Geoffrey (Author), Shu, Xiao-Ou (Author), Loos, Ruth J.F (Author), Borecki, Ingrid B. (Author), Peyser, Patricia A. (Author), Cummings, Steven R. (Author), Psaty, Bruce M. (Author), Fornage, Myriam (Author), Iyengar, Sudha K. (Author), Evans, Michele K. (Author), Becker, Diane M. (Author), Kao, W.H. Linda (Author), Wilson, James G. (Author), Rotter, Jerome I. (Author), Sale, Michèle M. (Author), Liu, Simin (Author), Rotimi, Charles N. (Author), Bowden, Donald W. (Author), Huerta-Chagoya, Alicia (Author), García-Ortiz, Humberto (Author), Moreno-Macías, Hortensia (Author), Manning, Alisa (Author), Caulkins, Lizz (Author), Burtt, Noël P. (Author), Flannick, Jason (Author), Patterson, Nick (Author), Aguilar-Salinas, Carlos A. (Author), Tusié-Luna, Teresa (Author), Altshuler, David (Author), Martínez-Hernández, Angélica (Author), Barajas-Olmos, Francisco Martin (Author), Contreras-Cubas, Cecilia (Author), Mendoza-Caamal, Elvia (Author), Revilla-Monsalve, Cristina (Author), Islas-Andrade, Sergio (Author), Córdova, Emilio (Author), Soberón, Xavier (Author), González-Villalpando, Clicerio (Author), González-Villalpando, María Elena (Author), Haiman, Christopher A. (Author), Wilkens, Lynne (Author), Le Marchand, Loic (Author), Monroe, Kristine (Author), Kolonel, Laurence (Author), Arellano-Campos, Olimpia (Author), Ordóñez-Sánchez, Maria L. (Author), Rodríguez-Torres, Maribel (Author), Segura-Kato, Yayoi (Author), Rodríguez-Guillén, Rosario (Author), Cruz-Bautista, Ivette (Author), Muñoz-Hernandez, Linda Liliana (Author), Sáenz, Tamara (Author), Gómez, Donají (Author), Alvirde, Ulices (Author), Almeda-Valdés, Paloma (Author), Cortes, Maria L. (Author), Lander, Eric Steven (Contributor)
Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Altshuler, David M (Contributor)
Format: Article
Language:English
Published: Elsevier BV, 2018-08-01T17:24:05Z.
Subjects:
Online Access:Get fulltext
LEADER 08428 am a22020413u 4500
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100 1 0 |a Rusu, Victor  |e author 
100 1 0 |a Massachusetts Institute of Technology. Department of Biology  |e contributor 
100 1 0 |a Altshuler, David M  |e contributor 
100 1 0 |a Lander, Eric Steven  |e contributor 
700 1 0 |a Hoch, Eitan  |e author 
700 1 0 |a Mercader, Josep M.  |e author 
700 1 0 |a Tenen, Danielle E.  |e author 
700 1 0 |a Gymrek, Melissa  |e author 
700 1 0 |a Hartigan, Christina R.  |e author 
700 1 0 |a DeRan, Michael  |e author 
700 1 0 |a von Grotthuss, Marcin  |e author 
700 1 0 |a Fontanillas, Pierre  |e author 
700 1 0 |a Spooner, Alexandra  |e author 
700 1 0 |a Guzman, Gaelen  |e author 
700 1 0 |a Deik, Amy A.  |e author 
700 1 0 |a Pierce, Kerry A.  |e author 
700 1 0 |a Dennis, Courtney  |e author 
700 1 0 |a Clish, Clary B.  |e author 
700 1 0 |a Carr, Steven A.  |e author 
700 1 0 |a Wagner, Bridget K.  |e author 
700 1 0 |a Schenone, Monica  |e author 
700 1 0 |a Ng, Maggie C.Y.  |e author 
700 1 0 |a Chen, Brian H.  |e author 
700 1 0 |a Centeno-Cruz, Federico  |e author 
700 1 0 |a Zerrweck, Carlos  |e author 
700 1 0 |a Orozco, Lorena  |e author 
700 1 0 |a Schreiber, Stuart L.  |e author 
700 1 0 |a Florez, Jose C.  |e author 
700 1 0 |a Jacobs, Suzanne B.R.  |e author 
700 1 0 |a Ng, Maggie C.Y.  |e author 
700 1 0 |a Shriner, Daniel  |e author 
700 1 0 |a Chen, Brian H.  |e author 
700 1 0 |a Li, Jiang  |e author 
700 1 0 |a Chen, Wei-Min  |e author 
700 1 0 |a Guo, Xiuqing  |e author 
700 1 0 |a Liu, Jiankang  |e author 
700 1 0 |a Bielinski, Suzette J.  |e author 
700 1 0 |a Yanek, Lisa R.  |e author 
700 1 0 |a Nalls, Michael A.  |e author 
700 1 0 |a Comeau, Mary E.  |e author 
700 1 0 |a Rasmussen-Torvik, Laura J.  |e author 
700 1 0 |a Jensen, Richard A.  |e author 
700 1 0 |a Evans, Daniel S.  |e author 
700 1 0 |a Sun, Yan V.  |e author 
700 1 0 |a An, Ping  |e author 
700 1 0 |a Patel, Sanjay R.  |e author 
700 1 0 |a Lu, Yingchang  |e author 
700 1 0 |a Long, Jirong  |e author 
700 1 0 |a Armstrong, Loren L.  |e author 
700 1 0 |a Wagenknecht, Lynne  |e author 
700 1 0 |a Yang, Lingyao  |e author 
700 1 0 |a Snively, Beverly M.  |e author 
700 1 0 |a Palmer, Nicholette D.  |e author 
700 1 0 |a Mudgal, Poorva  |e author 
700 1 0 |a Langefeld, Carl D.  |e author 
700 1 0 |a Keene, Keith L.  |e author 
700 1 0 |a Freedman, Barry I.  |e author 
700 1 0 |a Mychaleckyj, Josyf C.  |e author 
700 1 0 |a Nayak, Uma  |e author 
700 1 0 |a Raffel, Leslie J.  |e author 
700 1 0 |a Goodarzi, Mark O.  |e author 
700 1 0 |a Chen, Y-D Ida  |e author 
700 1 0 |a Taylor, Herman A.  |e author 
700 1 0 |a Correa, Adolfo  |e author 
700 1 0 |a Sims, Mario  |e author 
700 1 0 |a Couper, David  |e author 
700 1 0 |a Pankow, James S.  |e author 
700 1 0 |a Boerwinkle, Eric  |e author 
700 1 0 |a Adeyemo, Adebowale  |e author 
700 1 0 |a Doumatey, Ayo  |e author 
700 1 0 |a Chen, Guanjie  |e author 
700 1 0 |a Mathias, Rasika A.  |e author 
700 1 0 |a Vaidya, Dhananjay  |e author 
700 1 0 |a Singleton, Andrew B.  |e author 
700 1 0 |a Zonderman, Alan B.  |e author 
700 1 0 |a Igo, Robert P.  |e author 
700 1 0 |a Sedor, John R.  |e author 
700 1 0 |a Kabagambe, Edmond K.  |e author 
700 1 0 |a Siscovick, David S.  |e author 
700 1 0 |a McKnight, Barbara  |e author 
700 1 0 |a Rice, Kenneth  |e author 
700 1 0 |a Liu, Yongmei  |e author 
700 1 0 |a Hsueh, Wen-Chi  |e author 
700 1 0 |a Zhao, Wei  |e author 
700 1 0 |a Bielak, Lawrence F.  |e author 
700 1 0 |a Kraja, Aldi  |e author 
700 1 0 |a Province, Michael A.  |e author 
700 1 0 |a Bottinger, Erwin P.  |e author 
700 1 0 |a Gottesman, Omri  |e author 
700 1 0 |a Cai, Qiuyin  |e author 
700 1 0 |a Zheng, Wei  |e author 
700 1 0 |a Blot, William J.  |e author 
700 1 0 |a Lowe, William L.  |e author 
700 1 0 |a Pacheco, Jennifer A.  |e author 
700 1 0 |a Crawford, Dana C.  |e author 
700 1 0 |a Grundberg, Elin  |e author 
700 1 0 |a Rich, Stephen S.  |e author 
700 1 0 |a Hayes, M. Geoffrey  |e author 
700 1 0 |a Shu, Xiao-Ou  |e author 
700 1 0 |a Loos, Ruth J.F.  |e author 
700 1 0 |a Borecki, Ingrid B.  |e author 
700 1 0 |a Peyser, Patricia A.  |e author 
700 1 0 |a Cummings, Steven R.  |e author 
700 1 0 |a Psaty, Bruce M.  |e author 
700 1 0 |a Fornage, Myriam  |e author 
700 1 0 |a Iyengar, Sudha K.  |e author 
700 1 0 |a Evans, Michele K.  |e author 
700 1 0 |a Becker, Diane M.  |e author 
700 1 0 |a Kao, W.H. Linda  |e author 
700 1 0 |a Wilson, James G.  |e author 
700 1 0 |a Rotter, Jerome I.  |e author 
700 1 0 |a Sale, Michèle M.  |e author 
700 1 0 |a Liu, Simin  |e author 
700 1 0 |a Rotimi, Charles N.  |e author 
700 1 0 |a Bowden, Donald W.  |e author 
700 1 0 |a Mercader, Josep M.  |e author 
700 1 0 |a Huerta-Chagoya, Alicia  |e author 
700 1 0 |a García-Ortiz, Humberto  |e author 
700 1 0 |a Moreno-Macías, Hortensia  |e author 
700 1 0 |a Manning, Alisa  |e author 
700 1 0 |a Caulkins, Lizz  |e author 
700 1 0 |a Burtt, Noël P.  |e author 
700 1 0 |a Flannick, Jason  |e author 
700 1 0 |a Patterson, Nick  |e author 
700 1 0 |a Aguilar-Salinas, Carlos A.  |e author 
700 1 0 |a Tusié-Luna, Teresa  |e author 
700 1 0 |a Altshuler, David  |e author 
700 1 0 |a Florez, Jose C.  |e author 
700 1 0 |a Martínez-Hernández, Angélica  |e author 
700 1 0 |a Centeno-Cruz, Federico  |e author 
700 1 0 |a Barajas-Olmos, Francisco Martin  |e author 
700 1 0 |a Zerrweck, Carlos  |e author 
700 1 0 |a Contreras-Cubas, Cecilia  |e author 
700 1 0 |a Mendoza-Caamal, Elvia  |e author 
700 1 0 |a Revilla-Monsalve, Cristina  |e author 
700 1 0 |a Islas-Andrade, Sergio  |e author 
700 1 0 |a Córdova, Emilio  |e author 
700 1 0 |a Soberón, Xavier  |e author 
700 1 0 |a Orozco, Lorena  |e author 
700 1 0 |a González-Villalpando, Clicerio  |e author 
700 1 0 |a González-Villalpando, María Elena  |e author 
700 1 0 |a Haiman, Christopher A.  |e author 
700 1 0 |a Wilkens, Lynne  |e author 
700 1 0 |a Le Marchand, Loic  |e author 
700 1 0 |a Monroe, Kristine  |e author 
700 1 0 |a Kolonel, Laurence  |e author 
700 1 0 |a Arellano-Campos, Olimpia  |e author 
700 1 0 |a Ordóñez-Sánchez, Maria L.  |e author 
700 1 0 |a Rodríguez-Torres, Maribel  |e author 
700 1 0 |a Segura-Kato, Yayoi  |e author 
700 1 0 |a Rodríguez-Guillén, Rosario  |e author 
700 1 0 |a Cruz-Bautista, Ivette  |e author 
700 1 0 |a Muñoz-Hernandez, Linda Liliana  |e author 
700 1 0 |a Sáenz, Tamara  |e author 
700 1 0 |a Gómez, Donají  |e author 
700 1 0 |a Alvirde, Ulices  |e author 
700 1 0 |a Almeda-Valdés, Paloma  |e author 
700 1 0 |a Cortes, Maria L.  |e author 
700 1 0 |a Lander, Eric Steven  |e author 
700 1 0 |a Altshuler, David  |e author 
245 0 0 |a Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms 
260 |b Elsevier BV,   |c 2018-08-01T17:24:05Z. 
856 |z Get fulltext  |u http://hdl.handle.net/1721.1/117265 
520 |a 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 
655 7 |a Article 
773 |t Cell