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

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 ConsortiumSIGMA T2D Consortium

Research output: Contribution to journalArticle

39 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Medical problems
Type 2 Diabetes Mellitus
Haplotypes
CD147 Antigens
Mexico
Lipid Metabolism
Hispanic Americans
Liver
Protons
Fatty Acids
Genes
Alleles
Population

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

MEDIA Consortium, the FIND Consortium, the eMERGE Consortium, the DIAGRAM Consortium, the MuTHER Consortium, SIGMA T2D Consortium, ... 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

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

In: Cell, Vol. 170, No. 1, 29.06.2017, p. 199-212.e20.

Research output: Contribution to journalArticle

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
MEDIA Consortium, the FIND Consortium, the eMERGE Consortium, the DIAGRAM Consortium, the MuTHER Consortium, SIGMA T2D Consortium et al. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms. Cell. 2017 Jun 29;170(1):199-212.e20. https://doi.org/10.1016/j.cell.2017.06.011
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. / Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms. In: Cell. 2017 ; Vol. 170, No. 1. pp. 199-212.e20.
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AU - the FIND Consortium

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AU - Hoch, Eitan

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AU - DeRan, Michael

AU - Guzman, Gaelen

AU - Deik, Amy A.

AU - Pierce, Kerry A.

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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 - Bielinski, Suzette J

AU - Ng, Maggie C.Y.

AU - Chen, Brian H.

AU - Centeno-Cruz, Federico

AU - Orozco, Lorena

AU - Zerrweck, Carlos

AU - Altshuler, David M.

AU - Altshuler, David M.

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AU - Florez, Jose C.

AU - Altshuler, David M.

AU - Lander, Eric S.

AU - Lander, Eric S.

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AU - Chen, Brian H.

AU - Li, Jiang

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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. Video Abstract [Figure presented]

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. Video Abstract [Figure presented]

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KW - fatty acid metabolism

KW - genetics

KW - lipid metabolism

KW - MCT11

KW - monocarboxylates

KW - precision medicine

KW - SLC16A11

KW - solute carrier (SLC)

KW - type 2 diabetes (T2D)

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