2. Academic Validation
  3. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

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.
Victor Rusu 1,  Eitan Hoch 2,  Josep M Mercader 3,  Danielle E Tenen 4,  Melissa Gymrek 5,  Christina R Hartigan 6,  Michael DeRan 6,  Marcin von Grotthuss 7,  Pierre Fontanillas 7,  Alexandra Spooner 7,  Gaelen Guzman 6,  Amy A Deik 6,  Kerry A Pierce 6,  Courtney Dennis 6,  Clary B Clish 8,  Steven A Carr 6,  Bridget K Wagner 6,  Monica Schenone 6,  Maggie C Y Ng 9,  Brian H Chen 10,  MEDIA Consortium,  SIGMA T2D Consortium,  Federico Centeno-Cruz 11,  Carlos Zerrweck 12,  Lorena Orozco 11,  David M Altshuler 13,  Stuart L Schreiber 6,  Jose C Florez 14,  Suzanne B R Jacobs 15,  Eric S Lander 16
Affiliations

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: [email protected].
  • 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: [email protected].
PMID: 28666119 DOI: 10.1016/j.cell.2017.06.011
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).

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