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

Abstract

A risk haplotype for type 2 diabetes is identified with four amino acid substitutions in SLC16A11, which is present at ∼50% frequency in Native American samples and ∼10% in east Asian samples, but is rare in European and African samples; SLC16A11 may alter hepatic lipid metabolism, causing an increase in triacylglycerol levels. Genome-wide association studies (GWASs) have discovered thousands of genetic variants associated with common disease. This study demonstrates the potential of a comparative approach, whereby analysis of genetic variation in diverse 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. The SIGMA Type 2 Diabetes Genetics Consortium undertook a GWAS for propensity to type 2 diabetes in more than 8,000 samples in a Latin American population. They identified a risk haplotype, SLC16A11, with four amino acid substitutions in the solute carrier SLC16A11, which is present at about 50% frequency in Native American samples and 10% in East Asian, but rare in European and African samples. SLC16A11 appears to alter lipid metabolism, causing an increase in intracellular triacylglycerol levels. Intriguingly, the haplotype was introduced into the modern human population via admixture with Neanderthals. Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, 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 findings2,3,4, 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.