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JAMA DOI:10.1001/jama.2014.6511

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.

Publication TypeJournal Article
Year of Publication2014
AuthorsEstrada, K, Aukrust, I, Bjørkhaug, L, Burtt, NP, Mercader, JM, García-Ortíz, H, Huerta-Chagoya, A, Moreno-Macías, H, Walford, G, Flannick, J, Williams, AL, Gómez-Vázquez, MJ, Fernandez-Lopez, JC, Martínez-Hernández, A, Jiménez-Morales, S, Centeno-Cruz, F, Mendoza-Caamal, E, Revilla-Monsalve, C, Islas-Andrade, S, Córdova, EJ, Soberón, X, González-Villalpando, ME, Henderson, E, Wilkens, LR, Le Marchand, L, Arellano-Campos, O, Ordóñez-Sánchez, ML, Rodríguez-Torres, M, Rodríguez-Guillén, R, Riba, L, Najmi, LA, Jacobs, SBR, Fennell, T, Gabriel, S, Fontanillas, P, Hanis, CL, Lehman, DM, Jenkinson, CP, Abboud, HE, Bell, GI, Cortés, ML, Boehnke, M, González-Villalpando, C, Orozco, L, Haiman, CA, Tusié-Luna, T, Aguilar-Salinas, CA, Altshuler, D, Njølstad, PR, Florez, JC, MacArthur, DG
Corporate AuthorsConsortium, SIGMATD2
JournalJAMA
Volume311
Issue22
Pages2305-14
Date Published2014 Jun 11
ISSN1538-3598
KeywordsAdult, Age of Onset, Aged, Diabetes Mellitus, Type 2, Female, Genotype, Hepatocyte Nuclear Factor 1-alpha, Hispanic Americans, Humans, Male, Mexico, Middle Aged, Mutation, Missense, Sequence Analysis, DNA, United States
Abstract

IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide.

OBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships.

DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays.

MAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function.

RESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19).

CONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

URLhttp://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.6511
DOI10.1001/jama.2014.6511
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24915262?dopt=Abstract

Alternate JournalJAMA
PubMed ID24915262
PubMed Central IDPMC4425850
Grant ListU01 DK085501 / DK / NIDDK NIH HHS / United States
U01DK085501 / DK / NIDDK NIH HHS / United States
UM1 CA164973 / CA / NCI NIH HHS / United States
R01 CA80205 / CA / NCI NIH HHS / United States
U01 DK057295 / DK / NIDDK NIH HHS / United States
R35CA53890 / CA / NCI NIH HHS / United States
U01DK085526 / DK / NIDDK NIH HHS / United States
R01DK053889 / DK / NIDDK NIH HHS / United States
R01 DK057295 / DK / NIDDK NIH HHS / United States
R01 CA144034 / CA / NCI NIH HHS / United States
R01 DK047482 / DK / NIDDK NIH HHS / United States
R01 DK033665 / DK / NIDDK NIH HHS / United States
CA164973 / CA / NCI NIH HHS / United States
R01 DK042273 / DK / NIDDK NIH HHS / United States
R35 CA053890 / CA / NCI NIH HHS / United States
R01 CA055069 / CA / NCI NIH HHS / United States
CA063464 / CA / NCI NIH HHS / United States
CA054281 / CA / NCI NIH HHS / United States
R01 CA063464 / CA / NCI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
P01 HL045522 / HL / NHLBI NIH HHS / United States
R01DK047482 / DK / NIDDK NIH HHS / United States
R01 CA054281 / CA / NCI NIH HHS / United States
U01 CA063464 / CA / NCI NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 CA080205 / CA / NCI NIH HHS / United States
R01HL24799 / HL / NHLBI NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
P01HL045522 / HL / NHLBI NIH HHS / United States
U01 CA164973 / CA / NCI NIH HHS / United States
R37 CA054281 / CA / NCI NIH HHS / United States
R01 DK053889 / DK / NIDDK NIH HHS / United States