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Diabetes. 2015 May;64(5):1853-66. doi: 10.2337/db14-0732. Epub 2014 Dec 18.

Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

Author information

1
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC.
2
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
3
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
4
Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA Diabetes & Obesity Research Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA.
5
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA.
6
Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO.
7
Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO.
8
Diabetes & Obesity Research Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA Department of Physiology and Biophysics, Keck School of Medicine of University of Southern California, Los Angeles, CA Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA.
9
Research and Evaluation Branch, Kaiser Permanente of Southern California, Pasadena, CA.
10
Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
11
Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA.
12
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
13
Cedars-Sinai Diabetes & Obesity Research Institute, Los Angeles, CA.
14
Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA Department of Ophthalmology and Visual Science, University of Illinois at Chicago, Chicago, IL.
15
Department of Ophthalmology and Visual Science, University of Illinois at Chicago, Chicago, IL.
16
Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX.
17
Department of Human Genetics, University of Chicago, Chicago, IL.
18
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Howard Hughes Medical Institute, Chicago, IL Biological Sciences Department, Columbia University, New York, NY.
19
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
20
Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
21
Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico Universidad Nacional Autónoma de México, Mexico City, Mexico.
22
Centro de Estudios en Diabetes, Instituto Nacional de Salud Pública, Mexico City, Mexico.
23
Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
24
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.
25
Collaborative Health Studies Coordinating Center, Department of Biostatistics, University of Washington, Seattle, WA.
26
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA.
27
Division of Epidemiology, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Evanston, IL.
28
Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN.
29
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
30
Ohio State University Medical Center, Columbus, OH.
31
Department of Epidemiology, Brown University, Providence, RI.
32
Department of Medicine, Eastern Virginia Medical School, Norfolk, VA.
33
Department of Diabetes, Endocrinology & Metabolism, City of Hope, Duarte, CA.
34
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC Section on Endocrinology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
35
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
36
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA jrotter@labiomed.org.
37
Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA Diabetes & Obesity Research Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA Department of Physiology and Biophysics, Keck School of Medicine of University of Southern California, Los Angeles, CA rwatanab@usc.edu.
38
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC lwgnkcht@wakehealth.edu.

Abstract

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

PMID:
25524916
PMCID:
PMC4407862
DOI:
10.2337/db14-0732
[Indexed for MEDLINE]
Free PMC Article

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