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Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.
Rusu, Victor; Hoch, Eitan; Mercader, Josep M; Tenen, Danielle E; Gymrek, Melissa; Hartigan, Christina R; DeRan, Michael; von Grotthuss, Marcin; Fontanillas, Pierre; Spooner, Alexandra; Guzman, Gaelen; Deik, Amy A; Pierce, Kerry A; Dennis, Courtney; Clish, Clary B; Carr, Steven A; Wagner, Bridget K; Schenone, Monica; Ng, Maggie C Y; Chen, Brian H; Centeno-Cruz, Federico; Zerrweck, Carlos; Orozco, Lorena; Altshuler, David M; Schreiber, Stuart L; Florez, Jose C; Jacobs, Suzanne B R; Lander, Eric S.
Afiliación
  • Rusu V; 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.
  • Hoch E; 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.
  • Mercader JM; 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 B
  • Tenen DE; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  • Gymrek M; 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.
  • Hartigan CR; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • DeRan M; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • von Grotthuss M; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Fontanillas P; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Spooner A; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Guzman G; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Deik AA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Pierce KA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Dennis C; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Clish CB; Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Carr SA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Wagner BK; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Schenone M; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Ng MCY; Center for Genomics and Personalized Medicine Research, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Chen BH; Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
  • Centeno-Cruz F; Instituto Nacional de Medicina Genómica, Tlalpan, 14610 Mexico City, Mexico.
  • Zerrweck C; The Obesity Clinic at Hospital General Tlahuac, 13250 Mexico City, Mexico.
  • Orozco L; Instituto Nacional de Medicina Genómica, Tlalpan, 14610 Mexico City, Mexico.
  • Altshuler DM; 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 Med
  • Schreiber SL; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Florez JC; 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
  • Jacobs SBR; 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.
  • Lander ES; 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: lander@broadinstitute.org.
Cell ; 170(1): 199-212.e20, 2017 Jun 29.
Article en En | MEDLINE | ID: mdl-28666119
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transportadores de Ácidos Monocarboxílicos / Diabetes Mellitus Tipo 2 Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transportadores de Ácidos Monocarboxílicos / Diabetes Mellitus Tipo 2 Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos