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. Tenen; Christina 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

doi:10.1016/j.cell.2017.06.011

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

Epidemiology

Research output: Contribution to journal › Article › peer-review

111 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.

Original language	English (US)
Pages (from-to)	199-212.e20
Journal	Cell
Volume	170
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2017.06.011
State	Published - 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 Pinós 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.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1016/j.cell.2017.06.011

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562285

OpenUrl availability

Full text

Cite this

Rusu, V., Rusu, V., Hoch, E., Mercader, J. M., Gymrek, M., von Grotthuss, M., Fontanillas, P., Spooner, A., Altshuler, D. M., Florez, J. C., Jacobs, S. B. R., Hoch, E., Clish, C. B., Florez, J. C., Jacobs, S. B. R., Mercader, J. M., Florez, J. C., Jacobs, S. B. R., Mercader, J. M., ... SIGMA T2D Consortium (2017). Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms. Cell, 170(1), 199-212.e20. https://doi.org/10.1016/j.cell.2017.06.011

Rusu, V, Rusu, V, Hoch, E, Mercader, JM, Gymrek, M, von Grotthuss, M, Fontanillas, P, Spooner, A, Altshuler, DM, Florez, JC, Jacobs, SBR, Hoch, E, Clish, CB, Florez, JC, Jacobs, SBR, Mercader, JM, Florez, JC, Jacobs, SBR, Mercader, JM, Tenen, DE, Hartigan, CR, DeRan, M, Guzman, G, Deik, AA, Pierce, KA, Dennis, C, Clish, CB, Carr, SA, Wagner, BK, Schenone, M, Schreiber, SL, Lander, ES, Tenen, DE, Gymrek, M, Ng, MCY, Chen, BH, Centeno-Cruz, F, Orozco, L, Zerrweck, C, Altshuler, DM, Altshuler, DM, Altshuler, DM, Florez, JC, Altshuler, DM, Lander, ES, Lander, ES, Ng, MCY, Shriner, D, Chen, BH, Pankow, JS, 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 2017, 'Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms', Cell, vol. 170, no. 1, pp. 199-212.e20. https://doi.org/10.1016/j.cell.2017.06.011

@article{44d6d36d88d2407a9c651907f28f9850,

title = "Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms",

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.",

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

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

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{\'o}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. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = jun,

day = "29",

doi = "10.1016/j.cell.2017.06.011",

language = "English (US)",

volume = "170",

pages = "199--212.e20",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

AU - Rusu, Victor

AU - Hoch, Eitan

AU - Mercader, Josep M.

AU - Gymrek, Melissa

AU - von Grotthuss, Marcin

AU - Fontanillas, Pierre

AU - Spooner, Alexandra

AU - Altshuler, David M.

AU - Florez, Jose C.

AU - Jacobs, Suzanne B.R.

AU - Hoch, Eitan

AU - Clish, Clary B.

AU - Florez, Jose C.

AU - Jacobs, Suzanne B.R.

AU - Mercader, Josep M.

AU - Florez, Jose C.

AU - Jacobs, Suzanne B.R.

AU - Mercader, Josep M.

AU - Tenen, Danielle E.

AU - Hartigan, Christina R.

AU - DeRan, Michael

AU - Guzman, Gaelen

AU - Deik, Amy A.

AU - Pierce, Kerry A.

AU - Dennis, Courtney

AU - Clish, Clary B.

AU - Carr, Steven A.

AU - Wagner, Bridget K.

AU - Schenone, Monica

AU - Schreiber, Stuart L.

AU - Lander, Eric S.

AU - Tenen, Danielle E.

AU - Gymrek, Melissa

AU - Ng, Maggie C.Y.

AU - Chen, Brian H.

AU - Centeno-Cruz, Federico

AU - Orozco, Lorena

AU - Zerrweck, Carlos

AU - Altshuler, David M.

AU - Florez, Jose C.

AU - Altshuler, David M.

AU - Lander, Eric S.

AU - Ng, Maggie C.Y.

AU - Shriner, Daniel

AU - Chen, Brian H.

AU - Pankow, James S.

AU - MEDIA Consortium

AU - the FIND Consortium

AU - the eMERGE Consortium

AU - the DIAGRAM Consortium

AU - the MuTHER Consortium

AU - SIGMA T2D Consortium

AU - the FIND Consortium

AU - the eMERGE Consortium

AU - the DIAGRAM Consortium

AU - the MuTHER Consortium

AU - SIGMA T2D Consortium

AU - the eMERGE Consortium

AU - the DIAGRAM Consortium

AU - the MuTHER Consortium

AU - SIGMA T2D Consortium

AU - the DIAGRAM Consortium

AU - the MuTHER Consortium

AU - SIGMA T2D Consortium

AU - the MuTHER Consortium

AU - SIGMA T2D Consortium

N1 - 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 Pinós 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. Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/6/29

Y1 - 2017/6/29

N2 - 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.

AB - 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.

KW - MCT11

KW - SLC16A11

KW - disease mechanism

KW - fatty acid metabolism

KW - genetics

KW - lipid metabolism

KW - monocarboxylates

KW - precision medicine

KW - solute carrier (SLC)

KW - type 2 diabetes (T2D)

UR - http://www.scopus.com/inward/record.url?scp=85021628341&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021628341&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.06.011

DO - 10.1016/j.cell.2017.06.011

M3 - Article

C2 - 28666119

AN - SCOPUS:85021628341

SN - 0092-8674

VL - 170

SP - 199-212.e20

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this