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Diabetes. 2017 Nov;66(11):2903-2914. doi: 10.2337/db17-0187. Epub 2017 Aug 24.

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

Author information

1
Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
2
Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
3
Barcelona Supercomputing Center, Joint BSC-CRG-IRB Research Programme in Computational Biology, Barcelona, Spain.
4
Department of Genetics, Harvard Medical School, Boston, MA.
5
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
6
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
7
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
8
Department of Medicine, Harvard Medical School, Boston, MA.
9
Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
10
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.
11
Universidad Autónoma Metropolitana, Mexico City, Mexico.
12
The Biostatistics Center, The George Washington University, Rockville, MD.
13
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
14
Department of Medicine, Imperial College London, London, U.K.
15
Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
16
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
17
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY.
18
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
19
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
20
Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
21
Clínica Integral de Cirugía para la Obesidad y Enfermedades Metabólicas, Hospital General Tláhuac, Mexico City, Mexico.
22
Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico.
23
Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
24
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
25
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI.
26
The Genomics Platform, Broad Institute, Cambridge, MA.
27
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX.
28
Broad Institute, Cambridge, MA.
29
Unidad de Investigación Médica en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
30
South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX.
31
South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX.
32
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX.
33
Departments of Medicine and Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX.
34
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX.
35
Department of Medicine, The University of Chicago, Chicago, IL.
36
Department of Human Genetics, The University of Chicago, Chicago, IL.
37
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI.
38
Genomic Programming of Beta Cells and Diabetes, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
39
CIBERDEM, Barcelona, Spain.
40
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
41
Department of Molecular Biology, Harvard Medical School, Boston, MA.
42
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
43
Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA jcflorez@mgh.harvard.edu.

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 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.

PMID:
28838971
PMCID:
PMC5652606
DOI:
10.2337/db17-0187
[Indexed for MEDLINE]
Free PMC Article

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