A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes

• DOI: 10.2337/db17-0187
• Publication Date: 2017-08-25T00:20:21Z
• Authors: Josep M. Mercader; Rachel G. Liao; Avery D. Bell; Zachary Dymek; Karol Estrada; Taru Tukiainen; Alicia Huerta-Cha...; Hortensia Moreno-...; Kathleen A. Jablo...; Robert L. Hanson; Geoffrey A. Walford; Ignasi Moran; Ling Chen; Vineeta Agarwala; María Luisa Ordoñ...; Rosario Rodríguez...; Maribel Rodríguez...; Yayoi Segura-Kato; Humberto García-O...; Federico Centeno-...; Francisco Barajas...; Lizz Caulkins; Sobha Puppala; Pierre Fontanillas; Amy L. Williams; Sílvia Bonàs-Guarch; Chris Hartl; Stephan Ripke; ; Katherine Tooley; Jacqueline Lane; Carlos Zerrweck; Angélica Martínez...; Emilio J. Córdova; Elvia Mendoza-Caamal; Cecilia Contreras...; María E. González...; Ivette Cruz-Bautista; Liliana Muñoz-Her...; Donaji Gómez-Velasco; Ulises Alvirde; Brian E. Henderson; Lynne R. Wilkens; Loic Le Marchand; Olimpia Arellano-...; Laura Riba; Maegan Harden; ; Stacey Gabriel; ; Hanna E. Abboud; Maria L. Cortes; Cristina Revilla-...; Sergio Islas-Andrade; Xavier Soberon; Joanne E. Curran; Christopher P. Je...; Ralph A. DeFronzo; Donna M. Lehman; Craig L. Hanis; Graeme I. Bell; Michael Boehnke; John Blangero; Ravindranath Dugg...; Richa Saxena; Daniel MacArthur; Jorge Ferrer; Steven A. McCarroll; David Torrents; William C. Knowler; Leslie J. Baier; Noel Burtt; Clicerio González...; Christopher A. Ha...; Carlos A. Aguilar...; Teresa Tusié-Luna; Jason Flannick; Suzanne B.R. Jacobs; Lorena Orozco; David Altshuler; Jose C. Florez
• Keywords: 0301 basic medicine; Genotype; European Continental Ancestry Group; LOCI; 610; SUSCEPTIBILITY; TRIGLYCERIDE LEVELS; DISEASE; White People; GENETIC ARCHITECTURE; Cell Line; Endocrinology & Metabolism; 03 medical and health sciences; QUALITY-CONTROL; Insulin-Like Growth Factor II; Mexican Americans; Diabetes Mellitus; Humans; Protein Isoforms; RNA-SEQ; GENOME-WIDE ASSOCIATION; Mexico; 11 Medical and Health Sciences; Broad Genomics Platform; 0303 health sciences; Science & Technology; Stem Cells; Genetic Variation; Genetics/Genomes/Proteomics/Metabolomics; GROWTH-FACTOR-II; T2D-GENES Consortium; 3. Good health; Diabetes Prevention Program Research Group; SIGMA T2D Genetics Consortium; Adipose Tissue; Diabetes Mellitus, Type 2; Gene Expression Regulation; Liver; RNA Splice Sites; Life Sciences & Biomedicine; Type 2; MEXICAN-AMERICANS

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.