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

Citation
Mercader, J. M., et al. “A Loss-Of-Function Splice Acceptor Variant In Is Protective For Type 2 Diabetes.”. Diabetes, pp. 2903-2914.
Center University of Michigan Vanderbilt University University of Chicago University of Washington
Multicenter
Multicenter
Author Josep M Mercader, Rachel G Liao, Avery D Bell, Zachary Dymek, Karol Estrada, Taru Tukiainen, Alicia Huerta-Chagoya, Hortensia Moreno-Macías, Kathleen A Jablonski, Robert L Hanson, Geoffrey A Walford, Ignasi Moran, Ling Chen, Vineeta Agarwala, María Luisa Ordoñez-Sánchez, Rosario Rodríguez-Guillen, Maribel Rodríguez-Torres, Yayoi Segura-Kato, Humberto García-Ortiz, Federico Centeno-Cruz, Francisco Barajas-Olmos, Lizz Caulkins, Sobha Puppala, Pierre Fontanillas, Amy L Williams, Sílvia Bonàs-Guarch, Chris Hartl, Stephan Ripke, Diabetes Prevention Program Research Group, Katherine Tooley, Jacqueline Lane, Carlos Zerrweck, Angélica Martínez-Hernández, Emilio J Córdova, Elvia Mendoza-Caamal, Cecilia Contreras-Cubas, María E González-Villalpando, Ivette Cruz-Bautista, Liliana Muñoz-Hernández, Donaji Gómez-Velasco, Ulises Alvirde, Brian E Henderson, Lynne R Wilkens, Loïc Le Marchand, Olimpia Arellano-Campos, Laura Riba, Maegan Harden, Broad Genomics Platform, Stacey Gabriel, T2D-Genes Consortium, Hanna E Abboud, Maria L Cortes, Cristina Revilla-Monsalve, Sergio Islas-Andrade, Xavier Soberón, Joanne E Curran, Christopher P Jenkinson, Ralph A DeFronzo, Donna M Lehman, Craig L Hanis, Graeme I Bell, Michael Boehnke, John Blangero, Ravindranath Duggirala, Richa Saxena, Daniel MacArthur, Jorge Ferrer, Steven A McCarroll, David Torrents, William C Knowler, Leslie J Baier, Noel Burtt, Clicerio González-Villalpando, Christopher A Haiman, Carlos A Aguilar-Salinas, Teresa Tusié-Luna, Jason Flannick, Suzanne B R Jacobs, Lorena Orozco, David Altshuler, Jose C Florez, SIGMA T2D Genetics Consortium
Abstract

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 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 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 isoform 2. In individuals who do not carry the protective allele, expression of 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 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 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.

Year of Publication
2017
Journal
Diabetes
Volume
66
Issue
11
Number of Pages
2903-2914
Date Published
12/2017
ISSN Number
1939-327X
DOI
10.2337/db17-0187
Alternate Journal
Diabetes
PMID
28838971
PMCID
PMC5652606
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