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JAMA. 2014 Jun 11;311(22):2305-14. doi: 10.1001/jama.2014.6511.

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

Author information

1
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston3Department of Medicine, Harvard Medical School, Boston, Massachusetts.
2
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway6Department of Biomedicine, University of Bergen, Bergen, Norway.
3
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway5Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
4
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
5
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts7Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston8Joint BSC-CRG-IRB Research Prog.
6
Instituto Nacional de Medicina Genómica, Tlalpan, Mexico City, Mexico.
7
Instituto de Investigaciones Biomédicas, UNAM Unidad de Biología Molecular y Medicina Genómica, UNAM/INCMNSZ, Coyoacán, Mexico City, Mexico.
8
Universidad Autónoma Metropolitana, Tlalpan, Mexico City, Mexico.
9
Department of Medicine, Harvard Medical School, Boston, Massachusetts7Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston.
10
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts13Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts.
11
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts14Department of Biological Sciences, Columbia University, New York, New York.
12
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Sección XVI, Tlalpan, Mexico City, Mexico.
13
Unidad de Investigación Médica en Enfermedades Metabólicas, CMN SXXI, Instituto Mexicano del Seguro Social, Mexico City.
14
Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, Mexico City, Mexico.
15
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
16
Epidemiology Program, University of Hawaii Cancer Center, Honolulu.
17
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway23Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
18
The Genomics Platform, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
19
Human Genetics Center, University of Texas Health Science Center at Houston.
20
Department of Medicine, University of Texas Health Science Center at San Antonio.
21
Department of Human Genetics, University of Chicago, Chicago, Illinois28Department of Medicine, University of Chicago, Chicago, Illinois.
22
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
23
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor.
24
Instituto de Investigaciones Biomédicas, UNAM Unidad de Biología Molecular y Medicina Genómica, UNAM/INCMNSZ, Coyoacán, Mexico City, Mexico17Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Sección XVI, Tlalpan, Mexico City, Mexico.
25
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts3Department of Medicine, Harvard Medical School, Boston, Massachusetts7Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit).
26
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts3Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Erratum in

  • JAMA. 2014 Nov 12:312(18):1932. Jiménez-Morales, Silvia[Added].

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.

PMID:
24915262
PMCID:
PMC4425850
DOI:
10.1001/jama.2014.6511
[Indexed for MEDLINE]
Free PMC Article

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