MassIVE MSV000081105

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Type 2 diabetes-associated variants disrupt function of SLC16A11, a proton-coupled monocarboxylate transporter, through two distinct mechanisms

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Description

Rusu V, Hoch E, Mercader JM, Tenen DE, Gymrek M, Hartigan CR, von Grotthuss M, Fontanillas P, Spooner A, Guzman G, Carr SA, Schenone M, Ng MCY, Chen BH, MEDIA Consortium, SIGMA T2D Consortium, Orozco L, Altshuler DM, Schreiber SL, Florez JC, Jacobs SBR, Lander ES. 2017 Cell. Type 2 Diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype in SLC16A11 that explains ~20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a reduced set of tightly-linked common variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreased expression of the SLC16A11 gene in human liver and (2) missense changes in the SLC16A11 protein that disrupt a key interaction with the chaperone basigin, thereby reducing plasma membrane localization. Both independent mechanisms reduce SLC16A11 function, and together suggest that SLC16A11 is the causal gene. To gain insight into how disruption of SLC16A11 impacts T2D risk, we investigate this previously uncharacterized transporter and categorize SLC16A11 as a proton-coupled monocarboxylate transporter. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: iTRAQ ; Diabetes ; SLC16A11

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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