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Cell. 2017 Jun 29;170(1):199-212.e20. doi: 10.1016/j.cell.2017.06.011.

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

Collaborators (129)

Ng MCY, Shriner D, Chen BH, Li J, Chen WM, Guo X, Liu J, Bielinski SJ, Yanek LR, Nalls MA, Comeau ME, Rasmussen-Torvik LJ, Jensen RA, Evans DS, Sun YV, An P, Patel SR, Lu Y, Long J, Armstrong LL, Wagenknecht L, Yang L, Snively BM, Palmer ND, Mudgal P, Langefeld CD, Keene KL, Freedman BI, Mychaleckyj JC, Nayak U, Raffel LJ, Goodarzi MO, Chen YI, Taylor HA Jr, Correa A, Sims M, Couper D, Pankow JS, Boerwinkle E, Adeyemo A, Doumatey A, Chen G, Mathias RA, Vaidya D, Singleton AB, Zonderman AB, Igo RP Jr, Sedor JR, Kabagambe EK, Siscovick DS, McKnight B, Rice K, Liu Y, Hsueh WC, Zhao W, Bielak LF, Kraja A, Province MA, Bottinger EP, Gottesman O, Cai Q, Zheng W, Blot WJ, Lowe WL, Pacheco JA, Crawford DC, Grundberg E, Rich SS, Hayes MG, Shu XO, Loos RJF, Borecki IB, Peyser PA, Cummings SR, Psaty BM, Fornage M, Iyengar SK, Evans MK, Becker DM, Kao WHL, Wilson JG, Rotter JI, Sale MM, Liu S, Rotimi CN, Bowden DW, Mercader JM, Huerta-Chagoya A, García-Ortiz H, Moreno-Macías H, Manning A, Caulkins L, Burtt NP, Flannick J, Patterson N, Aguilar-Salinas CA, Tusié-Luna T, Altshuler D, Florez JC, Martínez-Hernández A, Centeno-Cruz F, Barajas-Olmos FM, Zerrweck C, Contreras-Cubas C, Mendoza-Caamal E, Revilla-Monsalve C, Islas-Andrade S, Córdova E, Soberón X, Orozco L, González-Villalpando C, González-Villalpando ME, Haiman CA, Wilkens L, Le Marchand L, Monroe K, Kolonel L, Arellano-Campos O, Ordóñez-Sánchez ML, Rodríguez-Torres M, Segura-Kato Y, Rodríguez-Guillén R, Cruz-Bautista I, Muñoz-Hernandez LL, Sáenz T, Gómez D, Alvirde U, Almeda-Valdés P, Cortes ML.

Author information

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: jcflorez@mgh.harvard.edu.
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: lander@broadinstitute.org.

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)

PMID:
28666119
PMCID:
PMC5562285
DOI:
10.1016/j.cell.2017.06.011
[Indexed for MEDLINE]
Free PMC Article

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