A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes
Authors: 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 ,   Diabetes Prevention Program Research Group, 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 ,   Broad Genomics Platform, Gabriel Stacey ,   T2D-GENES Consortium, Abboud Hanna E. , Cortes Maria L. , Revilla-Monsalve Cristina , Islas-Andrade Sergio , Soberon Xavier , Curran Joanne E. , Jenkinson Christopher P. , DeFronzo Ralph A. , Lehman Donna M. , Hanis Craig L. , Bell Graeme I. , Boehnke Michael , Blangero John , Duggirala Ravindranath , Saxena Richa , MacArthur Daniel , Ferrer Jorge , McCarroll Steven A. , Torrents David , Knowler William C. , Baier Leslie J. , Burtt Noel , González-Villalpando Clicerio , Haiman Christopher A. , Aguilar-Salinas Carlos A. , Tusié-Luna Teresa , Flannick Jason , Jacobs Suzanne B.R. , Orozco Lorena , Altshuler David , Florez Jose C. 
Published: August 2017

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.