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A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.
Mercader, Josep M; Liao, Rachel G; Bell, Avery D; Dymek, Zachary; Estrada, Karol; Tukiainen, Taru; Huerta-Chagoya, Alicia; Moreno-Macías, Hortensia; Jablonski, Kathleen A; Hanson, Robert L; Walford, Geoffrey A; Moran, Ignasi; Chen, Ling; Agarwala, Vineeta; Ordoñez-Sánchez, María Luisa; Rodríguez-Guillen, Rosario; Rodríguez-Torres, Maribel; Segura-Kato, Yayoi; García-Ortiz, Humberto; Centeno-Cruz, Federico; Barajas-Olmos, Francisco; Caulkins, Lizz; Puppala, Sobha; Fontanillas, Pierre; Williams, Amy L; Bonàs-Guarch, Sílvia; Hartl, Chris; Ripke, Stephan; Tooley, Katherine; Lane, Jacqueline; Zerrweck, Carlos; Martínez-Hernández, Angélica; Córdova, Emilio J; Mendoza-Caamal, Elvia; Contreras-Cubas, Cecilia; González-Villalpando, María E; Cruz-Bautista, Ivette; Muñoz-Hernández, Liliana; Gómez-Velasco, Donaji; Alvirde, Ulises; Henderson, Brian E; Wilkens, Lynne R; Le Marchand, Loic; Arellano-Campos, Olimpia; Riba, Laura; Harden, Maegan; Gabriel, Stacey; Abboud, Hanna E; Cortes, Maria L; Revilla-Monsalve, Cristina.
Afiliación
  • Mercader JM; Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Liao RG; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
  • Bell AD; Barcelona Supercomputing Center, Joint BSC-CRG-IRB Research Programme in Computational Biology, Barcelona, Spain.
  • Dymek Z; Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Estrada K; Department of Genetics, Harvard Medical School, Boston, MA.
  • Tukiainen T; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
  • Huerta-Chagoya A; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Moreno-Macías H; Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Jablonski KA; Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Hanson RL; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
  • Walford GA; Department of Medicine, Harvard Medical School, Boston, MA.
  • Moran I; Department of Genetics, Harvard Medical School, Boston, MA.
  • Chen L; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Agarwala V; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
  • Ordoñez-Sánchez ML; Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Rodríguez-Guillen R; Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México/Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Rodríguez-Torres M; Universidad Autónoma Metropolitana, Mexico City, Mexico.
  • Segura-Kato Y; The Biostatistics Center, The George Washington University, Rockville, MD.
  • García-Ortiz H; Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
  • Centeno-Cruz F; Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Barajas-Olmos F; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
  • Caulkins L; Department of Medicine, Harvard Medical School, Boston, MA.
  • Puppala S; Department of Medicine, Imperial College London, London, U.K.
  • Fontanillas P; Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Williams AL; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
  • Bonàs-Guarch S; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Hartl C; Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Ripke S; Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Tooley K; Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Lane J; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Zerrweck C; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Martínez-Hernández A; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Córdova EJ; Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Mendoza-Caamal E; Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
  • Contreras-Cubas C; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • González-Villalpando ME; Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY.
  • Cruz-Bautista I; Barcelona Supercomputing Center, Joint BSC-CRG-IRB Research Programme in Computational Biology, Barcelona, Spain.
  • Muñoz-Hernández L; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Gómez-Velasco D; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
  • Alvirde U; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
  • Henderson BE; Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Le Marchand L; Department of Genetics, Harvard Medical School, Boston, MA.
  • Arellano-Campos O; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
  • Riba L; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Harden M; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
  • Gabriel S; Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
  • Abboud HE; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Cortes ML; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Revilla-Monsalve C; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
Diabetes ; 66(11): 2903-2914, 2017 11.
Article en En | MEDLINE | ID: mdl-28838971
Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor II del Crecimiento Similar a la Insulina / Sitios de Empalme de ARN / Diabetes Mellitus Tipo 2 Tipo de estudio: Prognostic_studies Límite: Humans País/Región como asunto: Mexico Idioma: En Revista: Diabetes Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor II del Crecimiento Similar a la Insulina / Sitios de Empalme de ARN / Diabetes Mellitus Tipo 2 Tipo de estudio: Prognostic_studies Límite: Humans País/Región como asunto: Mexico Idioma: En Revista: Diabetes Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos