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Type 2 Diabetes‐Associated Variants Disrupt Function of SLC16A11, a Proton‐Coupled Monocarboxylate Transporter, Through Two Distinct Mechanisms
Author(s) -
Hoch Eitan,
Rusu Victor,
Schreiber Stuart L.,
Florez Jose C.,
Jacobs Suzanne B. R.,
Lander Eric S.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.950.2
Subject(s) - type 2 diabetes , haplotype , locus (genetics) , genome wide association study , genetic association , biology , genetic variation , genetics , diabetes mellitus , computational biology , medicine , bioinformatics , gene , single nucleotide polymorphism , endocrinology , allele , genotype
Type 2 Diabetes (T2D) affects more than 415 million people and is a leading cause of morbidity and mortality worldwide. While T2D is influenced by environmental factors, it is also a highly heritable disorder, with genetic variation contributing to a disparity in T2D prevalence across populations. An example of this disparity is observed within American populations, where the prevalence of diabetes in individuals of Mexican or Latin American descent is approximately twice that of US non‐Hispanic whites. Through a genome‐wide association study, we recently identified a variant haplotype in SLC16A11 that explains ~20% of the increased T2D prevalence in Mexico. Objective To follow up on the genetic association at SLC16A11 , in order to delineate mechanisms underlying T2D risk at this locus. Results Using a combination of molecular, biochemical, cellular, and physiological approaches we identify two distinct mechanisms that lead to reduced SLC16A11 function. First, we observe a significant reduction in SLC16A11 expression ‐ in a dose‐dependent manner ‐ in carriers of the T2D risk haplotype, in human liver. Second, we demonstrate that T2D risk‐associated coding variants in SLC16A11 attenuate activity by disrupting a key interaction with an ancillary protein, thereby reducing plasma membrane localization. These two independent mechanisms by which T2D‐associated coding and non‐coding variants impact SLC16A11 expression levels and subcellular localization implicate perturbation of SLC16A11 as causal at this locus, and suggest reduced SLC16A11 activity as the T2D‐relevant direction‐of‐effect. To gain insight into how disruption of SLC16A11 function impacts T2D risk, we investigate the activity of this previously uncharacterized transporter and establish that SLC16A11 functions as an H + ‐coupled monocarboxylate transporter. Conclusion Our findings illustrate the path from genetic association to therapeutic hypothesis, through defining the molecular mechanisms by which genetic variation affects SLC16A11 action, and suggest that increasing SLC16A11 function could be therapeutically beneficial for people with T2D. Support or Funding Information This work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico