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A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2
Mercader JM, Liao RG, Bell AD, Dymek Z, Estrada K, Tukiainen T, Huerta-Chagoya
A, Moreno-Macías H, Jablonski KA, Hanson RL, Walford GA, Moran I, Chen L,
Agarwala V, Ordoñez-Sánchez ML, Rodríguez-Guillen R, Rodríguez-Torres M,
Segura-Kato Y, García-Ortiz H, Centeno-Cruz F, Barajas-Olmos F, Caulkins L,
Puppala S, Fontanillas P, Williams AL, Bonàs-Guarch S, Hartl C, Ripke S, Tooley
K, Lane J, Zerrweck C, Martínez-Hernández A, Córdova EJ, Mendoza-Caamal E,
Contreras-Cubas C, González-Villalpando ME,
Submitted Externally on 11/9/2017
Volume : Pages
66 : 2903 - 2914
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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