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

Victor Rusu, Victor Rusu, Eitan Hoch, Josep M. Mercader, Melissa Gymrek, Marcin von Grotthuss, Pierre Fontanillas, Alexandra Spooner, David M. Altshuler, Jose C. Florez, Suzanne B.R. Jacobs, Eitan Hoch, Clary B. Clish, Jose C. Florez, Suzanne B.R. Jacobs, Josep M. Mercader, Jose C. Florez, Suzanne B.R. Jacobs, Josep M. Mercader, Danielle E. TenenChristina R. Hartigan, Michael DeRan, Gaelen Guzman, Amy A. Deik, Kerry A. Pierce, Courtney Dennis, Clary B. Clish, Steven A. Carr, Bridget K. Wagner, Monica Schenone, Stuart L. Schreiber, Eric S. Lander, Danielle E. Tenen, Melissa Gymrek, Maggie C.Y. Ng, Brian H. Chen, Federico Centeno-Cruz, Lorena Orozco, Carlos Zerrweck, David M. Altshuler, David M. Altshuler, David M. Altshuler, Jose C. Florez, David M. Altshuler, Eric S. Lander, Eric S. Lander, Maggie C.Y. Ng, Daniel Shriner, Brian H. Chen, James S. Pankow, MEDIA Consortium, the FIND Consortium, the eMERGE Consortium, the DIAGRAM Consortium, the MuTHER Consortium, SIGMA T2D Consortium, the FIND Consortium, the eMERGE Consortium, the DIAGRAM Consortium, the MuTHER Consortium, SIGMA T2D Consortium, the eMERGE Consortium, the DIAGRAM Consortium, the MuTHER Consortium, SIGMA T2D Consortium, the DIAGRAM Consortium, the MuTHER Consortium, SIGMA T2D Consortium, the MuTHER Consortium, SIGMA T2D Consortium, SIGMA T2D Consortium

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58 Scopus citations

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 [Figure presented]

Original languageEnglish (US)
Pages (from-to)199-212.e20
JournalCell
Volume170
Issue number1
DOIs
StatePublished - Jun 29 2017

Bibliographical note

Funding Information:
The authors thank Jason Wright, Jessica Gasser, Jamie Marshall, and Daniel O'Connell for many helpful discussions; Bryan MacDonald for discussions and critical reading of the manuscript; Kasper Lage for guidance on GeNets analysis; Zach Dymek for lab management support; and Lior Friedman and Leslie Gaffney for graphic design input. We also acknowledge the many discussions with the Lander, Schreiber, Altshuler, and Florez laboratories and the Diabetes Research Group at the Broad Institute. The Meta-analysis of Type 2 Diabetes in African Americans (MEDIA) Consortium was partly supported by NIH R01 DK066358 to Donald Bowden. J.M.M. was supported by Beatriu de Pin?s fellowship from the Agency for Management of University and Research Grants (2014 BP-B 00227). E.H. is a Klarman Family Foundation fellow. E.S.L. is supported in part by NIH UM1HG008895. This work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico. S.L.S. is a cofounder and a scientific advisor to Jnana Therapeutics. V.R. is now an employee of Jnana Therapeutics. E.S.L. has no financial conflict of interest related to work on SLC16A11 or type 2 diabetes.

Keywords

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

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