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

被引：98

作者：

Williams, Amy L. ^{[1
]}

Jacobs, Suzanne B. R. ^{[1
]}

Moreno-Macias, Hortensia ^{[3
]}

Huerta-Chagoya, Alicia

Churchhouse, Claire ^{[1
]}

Marquez-Luna, Carla ^{[6
]}

Garcia-Ortiz, Humberto

Jose Gomez-Vazquez, Maria ^{[4
,7
]}

Burtt, Noel P. ^{[1
]}

Aguilar-Salinas, Carlos A.

Gonzalez-Villalpando, Clicerio ^{[8
]}

Florez, Jose C. ^{[1
]}

Orozco, Lorena ^{[6
]}

Haiman, Christopher A. ^{[11
]}

Tusie-Luna, Teresa ^{[4
]}

Altshuler, David ^{[1
,2
]}

Williams, Amy L. ^{[1
]}

Marquez-Luna, Carla ^{[6
]}

Huerta-Chagoya, Alicia

Ripke, Stephan ^{[1
,12
]}

Jose Gomez-Vazquez, Maria ^{[4
,7
]}

Manning, Alisa K. ^{[1
]}

Moreno-Macias, Hortensia ^{[3
]}

Garcia-Ortiz, Humberto

Neale, Benjamin ^{[1
,12
]}

Burtt, Noel P. ^{[1
]}

Aguilar-Salinas, Carlos A.

Reich, David ^{[1
,2
,5
]}

Stram, Daniel O. ^{[11
]}

Carlos Fernandez-Lopez, Juan ^{[6
]}

Romero-Hidalgo, Sandra ^{[6
]}

Altshuler, David ^{[1
,2
]}

Florez, Jose C. ^{[1
]}

Tusie-Luna, Teresa ^{[4
]}

Patterson, Nick ^{[1
]}

Haiman, Christopher A. ^{[11
]}

Aguilar-Delfin, Irma ^{[6
]}

Martinez-Hernandez, Angelica ^{[6
]}

Centeno-Cruz, Federico ^{[6
]}

Mendoza-Caamal, Elvia ^{[6
]}

Revilla-Monsalve, Cristina ^{[13
]}

Islas-Andrade, Sergio ^{[13
]}

Cordova, Emilio ^{[6
]}

Rodriguez-Arellano, Eunice ^{[14
]}

Soberon, Xavier ^{[6
]}

Orozco, Lorena ^{[6
]}

Florez, Jose C. ^{[1
]}

Gonzalez-Villalpando, Clicerio ^{[8
]}

Elena Gonzalez-Villalpando, Maria ^{[8
]}

Haiman, Christopher A. ^{[11
]}

机构：

[1] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[2] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[3] Univ Autonoma Metropolitana, Mexico City 14387, DF, Mexico

[4] Inst Nacl Nutr Salvador Zubiran, Mexico City 14000, DF, Mexico

[5] Univ Nacl Autonoma Mexico, Unidad Biol Mol & Med Genom, UNAM INCMNSZ, Inst Invest Biomed, Mexico City 04510, DF, Mexico

[6] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico

[7] Univ Autonoma Nuevo Leon, San Nicolas De Los Garza 66451, Nuevo Leon, Mexico

[8] Inst Nacl Salud Publ, Ctr Invest Salud Poblac, Unidad Invest Diabet & Riesgo Cardiovasc, Ctr Estudios Diabet, Mexico City 01120, DF, Mexico

[9] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[10] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA

[11] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA

[12] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[13] Inst Seguro Social SXXI, Unidad Invest Med Enfermedades Metab, Mexico City 06720, DF, Mexico

[14] Inst Seguridad & Serv Sociales Trabajadores Estad, Mexico City 01030, DF, Mexico

[15] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA

[16] Broad Inst Harvard & MIT, Genom Platform, Cambridge, MA 02142 USA

[17] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany

[18] Russian Acad Sci, Siberian Branch, Inst Archaeol & Ethnog, Palaeolith Dept, Novosibirsk 630090, Russia

[19] Broad Inst Harvard & MIT, Metabolite Profiling Platform, Cambridge, MA 02142 USA

[20] Broad Inst Harvard & MIT, Canc Biol Program, Cambridge, MA 02142 USA

[21] Univ Minnesota, Minneapolis, MN 55455 USA

[22] Univ Calif San Francisco, San Francisco, CA 94143 USA

[23] Duke Natl Univ Singapore, Grad Med Sch, Singapore SINGAPORE16, Singapore

[24] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore

[25] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[26] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA

[27] Albert Einstein Coll Med, Dept Genet, Dept Med, Bronx, NY 10461 USA

[28] Texas Biomed Res Inst, Dept Med, San Antonio, TX 78227 USA

[29] Wake Forest Sch Med, Dept Internal Med, Dept Biochem, Ctr Genom & Personalized Med Res,Ctr Diabet Res, Winston Salem, NC 27157 USA

[30] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London SW7 2AZ, England

[31] Imperial Coll Healthcare NHS Trust, London W2 1NY, England

[32] Ealing Hosp Natl Hlth Serv NHS Trust, Southall UB1 3HW, Middx, England

[33] Hallym Univ, Dept Biomed Sci, Chunchon 200702, Gangwon Do, South Korea

[34] Hadassah Hebrew Univ, Sch Med, Endocrinol & Metab Serv, IL-91120 Jerusalem, Israel

[35] E Wolfson Med Ctr, IDRG, Diabet Unit, IL-58100 Holon, Israel

[36] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA

[37] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, NHLI, London W12 0HS, England

[38] Univ Eastern Finland, Dept Med, FI-70211 Kuopio, Finland

[39] Kuopio Univ Hosp, FI-70211 Kuopio, Finland

[40] Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do 363951, South Korea

[41] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117597, Singapore

[42] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA

[43] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, San Antonio, TX 78229 USA

[44] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Diabet, San Antonio, TX 78229 USA

[45] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Clin Epidemiol, San Antonio, TX 78229 USA

[46] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

来源：

NATURE | 2014年 / 506卷 / 7486期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

ASSOCIATION; SUSCEPTIBILITY; TRANSPORTER; ANCESTRY; KCNQ1;

D O I：

10.1038/nature12828

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others(1), 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(2-4), we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P=3.9x10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P=1.1x10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at similar to 50% frequency in Native American samples and similar to 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.

引用

页码：97 / +

页数：15

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