Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

Nature
Authors
Keywords
Abstract

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

Year of Publication
2014
Journal
Nature
Volume
506
Issue
7486
Pages
97-101
Date Published
2014 Feb 06
ISSN
1476-4687
URL
DOI
10.1038/nature12828
PubMed ID
24390345
PubMed Central ID
PMC4127086
Links
Grant list
UM1 CA164973 / CA / NCI NIH HHS / United States
R01 CA80205 / CA / NCI NIH HHS / United States
U01 DK057295 / DK / NIDDK NIH HHS / United States
U01DK085526 / DK / NIDDK NIH HHS / United States
R01DK053889 / DK / NIDDK NIH HHS / United States
R01 DK057295 / DK / NIDDK NIH HHS / United States
R01 CA144034 / CA / NCI NIH HHS / United States
R01 HG006399 / HG / NHGRI NIH HHS / United States
F32 HG005944 / HG / NHGRI NIH HHS / United States
R01 DK047482 / DK / NIDDK NIH HHS / United States
R01 DK042273 / DK / NIDDK NIH HHS / United States
R35 CA053890 / CA / NCI NIH HHS / United States
R01 CA055069 / CA / NCI NIH HHS / United States
R01 CA063464 / CA / NCI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
P01 HL045522 / HL / NHLBI NIH HHS / United States
R01 CA054281 / CA / NCI NIH HHS / United States
U01 CA063464 / CA / NCI NIH HHS / United States
R01 CA080205 / CA / NCI NIH HHS / United States
R01HL24799 / HL / NHLBI NIH HHS / United States
U01 CA164973 / CA / NCI NIH HHS / United States
R37 CA054281 / CA / NCI NIH HHS / United States
R01 DK053889 / DK / NIDDK NIH HHS / United States