TY - JOUR
T1 - Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms
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
AU - SIGMA T2D Consortium
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 eMERGE Consortium
AU - the DIAGRAM Consortium
AU - the MuTHER Consortium
AU - SIGMA T2D Consortium
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 - Clish, Clary B.
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 - Carr, Steven A.
AU - Wagner, Bridget K.
AU - Schenone, Monica
AU - Schreiber, Stuart L.
AU - Lander, Eric S.
AU - Ng, Maggie C.Y.
AU - Chen, Brian H.
AU - Centeno-Cruz, Federico
AU - Orozco, Lorena
AU - Zerrweck, Carlos
AU - Shriner, Daniel
AU - Li, Jiang
AU - Chen, Wei Min
AU - Guo, Xiuqing
AU - Liu, Jiankang
AU - Bielinski, Suzette J.
AU - Yanek, Lisa R.
AU - Nalls, Michael A.
AU - Comeau, Mary E.
AU - Rasmussen-Torvik, Laura J.
AU - Jensen, Richard A.
AU - Evans, Daniel S.
AU - Sun, Yan V.
AU - An, Ping
AU - Patel, Sanjay R.
AU - Lu, Yingchang
AU - Long, Jirong
AU - Armstrong, Loren L.
AU - Wagenknecht, Lynne
AU - Yang, Lingyao
AU - Kraja, Aldi
AU - Province, Michael A.
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
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 -