December 26, 2013

Mexicans got type 2 diabetes risk allele from Neandertals

Nature (2013) doi:10.1038/nature12828

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

The SIGMA Type 2 Diabetes Consortium

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.

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2 comments:

Chris Davies said...

There are 2 Human Leukocyte Antigen (HLA) alleles which confer susceptibility to Type 2 Diabetes in Han Chinese, according to this paper: http://www.hindawi.com/journals/jdr/2013/452537/ The alleles are: HLA-DQA1*0301 and HLA-DQA1*0501. Of these 2 alleles, HLA-DQA1*0301 is also found at very high frequency in several Mexican populations (eg. 40% in Oaxaca Mixtec [N=103]; 38.3% in Oaxaca Zapotec [N=90]; and 28.8% in Highlands Mestizos [N=160] - See www.allelefrequencies.net). However both of these alleles are nevertheless found in sub-Saharan African populations at notable frequencies. In the case of HLA-DQA1*0301: 7.5% in Gabon Haut-Ogooue Dienga [N=167]; 5.9% in Zimbabwe Harare Shona [N=230]; 3.4% in Kenya [N=144]; and 1.1% in Congo Kinshasa Bantu [N=90] (again see: www.allelefrequencies.net). I am not convinced that Type 2 Diabetes susceptibility in Mexican populations is due to Neanderthal admixture. Rather there are genetic markers involved in T2D susceptibility which are likely derived from ancestral populations in SSA and still present in extant African populations

Susy Derkins said...

The analysis described in the paper maps the susceptibility allele to a region of chromosome 17 containing the SLC16A11 and SLC16A13 genes: there is no evidence of association with regions in chromosome 6, where the HLA locus is located. As for the Neanderthal ancestry of the region, that is inferred from finding the haplotype in actual Neanderthal and Denisovan genomes.

I mean, with the density of SNPs used (9.2 million!) the authors get a pretty precise mapping, so it is indeed evidence of a T2D susceptibility allele on chr 17 and it has nothing to do with either the HLA or regions from ancestral SSA populations.