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Nature. 2014 Feb 6;506(7486):97-101. doi: 10.1038/nature12828. Epub 2013 Dec 25.

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

Collaborators (152)

Williams AL, Jacobs SB, Moreno-Macías H, Huerta-Chagoya A, Churchhouse C, Márquez-Luna C, García-Ortíz H, Gómez-Vázquez MJ, Burtt NP, Aguilar-Salinas CA, González-Villalpando C, Florez JC, Orozco L, Haiman CA, Tusié-Luna T, Altshuler D, Williams AL, Márquez-Luna C, Huerta-Chagoya A, Ripke S, Gómez-Vázquez MJ, Manning AK, Moreno-Macías H, García-Ortíz H, Neale B, Burtt NP, Aguilar-Salinas CA, Reich D, Stram DO, Fernández-López JC, Romero-Hidalgo S, Altshuler D, Florez JC, Tusié-Luna T, Patterson N, Haiman CA, Aguilar-Delfín I, Martínez-Hernández A, Centeno-Cruz F, Mendoza-Caamal E, Revilla-Monsalve C, Islas-Andrade S, Córdova E, Rodríguez-Arellano E, Soberón X, Orozco L, Florez JC, González-Villalpando C, González-Villalpando ME, Haiman CA, Henderson BE, Monroe K, Wilkens L, Kolonel LN, Le Marchand L, Riba L, Ordóñez-Sánchez ML, Rodríguez-Guillén R, Cruz-Bautista I, Rodríguez-Torres M, Muñoz-Hernández LL, Sáenz T, Gómez D, Alvirde U, Burtt NP, Onofrio RC, Brodeur WM, Gage D, Murphy J, Franklin J, Mahan S, Ardlie K, Crenshaw AT, Winckler W, Prüfer K, Shunkov MV, Sawyer S, Stenzel U, Kelso J, Lek M, Sankararaman S, Williams AL, Patterson N, MacArthur DG, Reich D, Derevianko AP, Pääbo S, Jacobs SB, Churchhouse C, Gopal S, Grammatikos JA, Smith IC, Bullock KH, Deik AA, Souza AL, Pierce KA, Clish CB, Altshuler D, Fennell T, Farjoun Y, Gabriel S, Stram DO, Gross MD, Pereira MA, Seielstad M, Koh WP, Tai ES, Flannick J, Fontanillas P, Morris A, Teslovich TM, Burtt NP, Atzmon G, Blangero J, Bowden DW, Chambers J, Cho YS, Duggirala R, Glaser B, Hanis C, Kooner J, Laakso M, Lee JY, Tai ES, Teo YY, Wilson JG, Haiman CA, Henderson BE, Monroe K, Wilkens L, Kolonel LN, Le Marchand L, Puppala S, Farook VS, Thameem F, Abboud HE, DeFronzo RA, Jenkinson CP, Lehman DM, Curran JE, Blangero J, Duggirala R, Burtt NP, Cortes ML, Altshuler D, Florez JC, Haiman CA, Henderson BE, Aguilar-Salinas CA, González-Villalpando C, Orozco L, Tusié-Luna T.

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.

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PMID:
24390345
PMCID:
PMC4127086
DOI:
10.1038/nature12828
[Indexed for MEDLINE]
Free PMC Article

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