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Diabetes DOI:10.2337/db17-0187

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

Publication TypeJournal Article
Year of Publication2017
AuthorsMercader, 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, MLuisa, Rodríguez-Guillén, R, Rodríguez-Torres, M, Segura-Kato, Y, García-Ortíz, 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, Cruz-Bautista, I, Muñoz-Hernández, L, Gómez-Velasco, D, Alvirde, U, Henderson, BE, Wilkens, LR, Le Marchand, L, Arellano-Campos, O, Riba, L, Harden, M, Gabriel, S, Abboud, HE, Cortés, ML, Revilla-Monsalve, C, Islas-Andrade, S, Soberón, X, Curran, JE, Jenkinson, CP, DeFronzo, RA, Lehman, DM, Hanis, CL, Bell, GI, Boehnke, M, Blangero, J, Duggirala, R, Saxena, R, Macarthur, D, Ferrer, J, McCarroll, SA, Torrents, D, Knowler, WC, Baier, LJ, Burtt, N, González-Villalpando, C, Haiman, CA, Aguilar-Salinas, CA, Tusié-Luna, T, Flannick, J, Jacobs, SBR, Orozco, L, Altshuler, D, Florez, JC
Corporate AuthorsDiabetes Prevention Program Research Group, Broad Genomics Platform, T2D-GENES Consortium, SIGMA T2D Genetics Consortium
JournalDiabetes
Volume66
Issue11
Pages2903-2914
Date Published2017 11
ISSN1939-327X
KeywordsAdipose Tissue, Cell Line, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Expression Regulation, Genetic Variation, Genotype, Humans, Insulin-Like Growth Factor II, Liver, Mexican Americans, Mexico, Protein Isoforms, RNA Splice Sites, Stem Cells
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.

DOI10.2337/db17-0187
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28838971?dopt=Abstract

Alternate JournalDiabetes
PubMed ID28838971
PubMed Central IDPMC5652606
Grant ListU01 DK048437 / DK / NIDDK NIH HHS / United States
U01 DK048407 / DK / NIDDK NIH HHS / United States
U01 DK048412 / DK / NIDDK NIH HHS / United States
U01 DK048375 / DK / NIDDK NIH HHS / United States
P60 DK020593 / DK / NIDDK NIH HHS / United States
U01 DK085524 / DK / NIDDK NIH HHS / United States
R01 DA006227 / DA / NIDA NIH HHS / United States
R01 MH101782 / MH / NIMH NIH HHS / United States
U01 DK048413 / DK / NIDDK NIH HHS / United States
R01 DK098032 / DK / NIDDK NIH HHS / United States
R01 MH101810 / MH / NIMH NIH HHS / United States
R01 MH101819 / MH / NIMH NIH HHS / United States
R01 DA033684 / DA / NIDA NIH HHS / United States
R01 DK072041 / DK / NIDDK NIH HHS / United States
F32 HG005944 / HG / NHGRI NIH HHS / United States
U2C DK059637 / DK / NIDDK NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 MH090936 / MH / NIMH NIH HHS / United States
MR/L02036X/1 / / Medical Research Council / United Kingdom
U01 DK048397 / DK / NIDDK NIH HHS / United States
U01 DK048381 / DK / NIDDK NIH HHS / United States
U01 DK048339 / DK / NIDDK NIH HHS / United States
R01 CA063464 / CA / NCI NIH HHS / United States
U01 DK048485 / DK / NIDDK NIH HHS / United States
U01 DK048443 / DK / NIDDK NIH HHS / United States
P30 DK020593 / DK / NIDDK NIH HHS / United States
U01 DK048380 / DK / NIDDK NIH HHS / United States
U01 DK048400 / DK / NIDDK NIH HHS / United States
R01 CA054281 / CA / NCI NIH HHS / United States
R01 MH090951 / MH / NIMH NIH HHS / United States
U01 CA063464 / CA / NCI NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 MH101820 / MH / NIMH NIH HHS / United States
R01 MH101825 / MH / NIMH NIH HHS / United States
R01 MH090948 / MH / NIMH NIH HHS / United States
R01 MH090941 / MH / NIMH NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
R01 MH101822 / MH / NIMH NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
R01 MH090937 / MH / NIMH NIH HHS / United States
U01 DK048404 / DK / NIDDK NIH HHS / United States
U01 DK048489 / DK / NIDDK NIH HHS / United States
R37 CA054281 / CA / NCI NIH HHS / United States
HHSN268201000029C / HL / NHLBI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States
U24 DK059637 / DK / NIDDK NIH HHS / United States