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

Abstract

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. We analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and Latin Americans: 3,848 with type 2 diabetes (T2D) and 4,366 non-diabetic controls. In addition to replicating previous findings2–4, we identified a novel locus associated with T2D 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 T2D, 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 rare in European and African samples. Analysis of an archaic genome sequence indicated the risk haplotype introgressed into modern humans via admixture with Neandertals. The SLC16A11 mRNA 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 T2D having been well studied by genome-wide association studies (GWAS) in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for T2D with a possible role in triacylglycerol metabolism.

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…Based on human mRNA expression data, MCT11 is highly expressed in the thyroid, liver, and salivary gland 24. Peak gene expression levels of MCT12 were observed in the eyes, lungs, kidneys, and testis 25.…”

“…A genomewide association study in a Latin American population with patients with type 2 diabetes mellitus (T2DM) and nondiabetic controls identified a novel locus reaching genomewide significance spanning the genes SLC16A11 and SLC16A13 24. The risk haplotype consists of five SNPs, whereby the tag‐SNP for the risk haplotype rs17767867 is found most frequently in Native American populations (∼50%), at intermediate frequency in Asians (∼10%), but occurs rarely in Europe or Africa and might explain, in part, the higher prevalence of T2DM in Mexican Americans 24.…”

“…The risk haplotype consists of five SNPs, whereby the tag‐SNP for the risk haplotype rs17767867 is found most frequently in Native American populations (∼50%), at intermediate frequency in Asians (∼10%), but occurs rarely in Europe or Africa and might explain, in part, the higher prevalence of T2DM in Mexican Americans 24. The five SNP haplotype comprises a synonymous as well as four missense variants in SLC16A11 , of which one was predicted to be damaging, indicating that SLC16A11 , encoding for MCT11, is the causal gene for the link with T2DM.…”

MOL2NET: FROM MOLECULES TO NETWORKS (PROCEEDINGS BOOK), 2017, 3rd edition.

“…Adiponectin (ADN) is a protein hormone secreted by adipose tissue that circulates the blood in different molecular weighted forms (Kogan, et al, 2013). Structurally speaking, ADN is a protein consisting of 244 amino acids and can be distinguished by its N-terminal variance region, collagenous domain, and C-terminal globular domain (Orrù, et al, 2017). ADN is also known as an insulinsensitizing adipokine that improves insulin sensitivity by stimulating glucose uptake and inhibiting gluconeogenesis Insulin-like growth factor 1 (IGF-1) is a protein produced by the liver consisting of 70 amino acids and has various functions throughout the body, specifically muscle growth and insulin-like activities (Orrù et al, 2017).…”

“…Structurally speaking, ADN is a protein consisting of 244 amino acids and can be distinguished by its N-terminal variance region, collagenous domain, and C-terminal globular domain (Orrù, et al, 2017). ADN is also known as an insulinsensitizing adipokine that improves insulin sensitivity by stimulating glucose uptake and inhibiting gluconeogenesis Insulin-like growth factor 1 (IGF-1) is a protein produced by the liver consisting of 70 amino acids and has various functions throughout the body, specifically muscle growth and insulin-like activities (Orrù et al, 2017). Recent studies provide evidence that shows ADN, IGF-1, and insulin share common pathways, demonstrating an interconnection to obesity and other metabolic diseases such as T2D (Orrù et al, 2017).…”