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

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; MEDIA Consortium; SIGMA T2D Consortium; Federico Centeno-Cruz; Carlos Zerrweck; Lorena Orozco; David M Altshuler; Stuart L Schreiber; Jose C Florez; Suzanne B R Jacobs; Eric S Lander

doi:10.1016/j.cell.2017.06.011

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

Cell. 2017 Jun 29;170(1):199-212.e20. doi: 10.1016/j.cell.2017.06.011.

Authors

Victor Rusu¹, Eitan Hoch², Josep M Mercader³, Danielle E Tenen⁴, Melissa Gymrek⁵, Christina R Hartigan⁶, Michael DeRan⁶, Marcin von Grotthuss⁷, Pierre Fontanillas⁷, Alexandra Spooner⁷, Gaelen Guzman⁶, Amy A Deik⁶, Kerry A Pierce⁶, Courtney Dennis⁶, Clary B Clish⁸, Steven A Carr⁶, Bridget K Wagner⁶, Monica Schenone⁶, Maggie C Y Ng⁹, Brian H Chen¹⁰; MEDIA Consortium; SIGMA T2D Consortium; Federico Centeno-Cruz¹¹, Carlos Zerrweck¹², Lorena Orozco¹¹, David M Altshuler¹³, Stuart L Schreiber⁶, Jose C Florez¹⁴, Suzanne B R Jacobs¹⁵, Eric S Lander¹⁶

Collaborators

Maggie C Y Ng, Daniel Shriner, Brian H Chen, 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 Jr, 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 Jr, 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, Josep M Mercader, 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, Jose C Florez, Angélica Martínez-Hernández, Federico Centeno-Cruz, Francisco Martin Barajas-Olmos, Carlos Zerrweck, Cecilia Contreras-Cubas, Elvia Mendoza-Caamal, Cristina Revilla-Monsalve, Sergio Islas-Andrade, Emilio Córdova, Xavier Soberón, Lorena Orozco, 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

Affiliations

¹ Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain.
⁴ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁸ Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁹ Center for Genomics and Personalized Medicine Research, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
¹⁰ Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
¹¹ Instituto Nacional de Medicina Genómica, Tlalpan, 14610 Mexico City, Mexico.
¹² The Obesity Clinic at Hospital General Tlahuac, 13250 Mexico City, Mexico.
¹³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jcflorez@mgh.harvard.edu.
¹⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁶ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: lander@broadinstitute.org.

Abstract

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.

Keywords: MCT11; SLC16A11; disease mechanism; fatty acid metabolism; genetics; lipid metabolism; monocarboxylates; precision medicine; solute carrier (SLC); type 2 diabetes (T2D).

MeSH terms

Basigin / metabolism
Cell Membrane / metabolism
Chromosomes, Human, Pair 17 / metabolism
Diabetes Mellitus, Type 2 / metabolism*
Gene Knockdown Techniques
Haplotypes
Hepatocytes / metabolism
Heterozygote
Histone Code
Humans
Liver / metabolism
Models, Molecular
Monocarboxylic Acid Transporters / chemistry
Monocarboxylic Acid Transporters / genetics*
Monocarboxylic Acid Transporters / metabolism*

Substances

BSG protein, human
Monocarboxylic Acid Transporters
SLC16A11 protein, human
Basigin

Abstract

MeSH terms

Substances

Grants and funding