title: Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.
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.
authors.affiliation: 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.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: 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.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: 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.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: 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.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: 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.
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.affiliation: 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.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchanan
authors.affiliation: Research and Evaluation Branch, Kaiser Permanente of Southern California, Pasadena, CA.
authors.forename: Anny H
authors.initials: AH
authors.lastname: Xiang
authors.affiliation: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.affiliation: 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.
authors.forename: Julie T
authors.initials: JT
authors.lastname: Ziegler
authors.affiliation: 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.
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Williams
authors.affiliation: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.affiliation: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Jinrui
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA.
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Mackay
authors.affiliation: 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.
authors.forename: Leora F
authors.initials: LF
authors.lastname: Henkin
authors.affiliation: Cedars-Sinai Diabetes & Obesity Research Institute, Los Angeles, CA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.affiliation: 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.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: James
authors.initials: J
authors.lastname: Gauderman
authors.affiliation: Department of Ophthalmology and Visual Science, University of Illinois at Chicago, Chicago, IL.
authors.forename: Rohit
authors.initials: R
authors.lastname: Varma
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Hanis
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Highland
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Howard Hughes Medical Institute, Chicago, IL Biological Sciences Department, Columbia University, New York, NY.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Williams
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Noel P
authors.initials: NP
authors.lastname: Burtt
authors.affiliation: Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.affiliation: Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Alicia
authors.initials: A
authors.lastname: Huerta-Chagoya
authors.affiliation: Centro de Estudios en Diabetes, Instituto Nacional de Salud Pública, Mexico City, Mexico.
authors.forename: Clicerio
authors.initials: C
authors.lastname: Gonzalez-Villalpando
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
authors.forename: Lorena
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authors.lastname: Orozco
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tsai
authors.affiliation: Collaborative Health Studies Coordinating Center, Department of Biostatistics, University of Washington, Seattle, WA.
authors.forename: W Craig
authors.initials: WC
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authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA.
authors.forename: Jie
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authors.affiliation: Division of Epidemiology, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Evanston, IL.
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authors.lastname: Rasmussen-Torvik
authors.affiliation: Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN.
authors.forename: James
authors.initials: J
authors.lastname: Pankow
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Beverly
authors.initials: B
authors.lastname: Snively
authors.affiliation: Ohio State University Medical Center, Columbus, OH.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Jackson
authors.affiliation: Department of Epidemiology, Brown University, Providence, RI.
authors.forename: Simin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medicine, Eastern Virginia Medical School, Norfolk, VA.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.affiliation: Department of Diabetes, Endocrinology & Metabolism, City of Hope, Duarte, CA.
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.affiliation: 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.
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Leslie J
authors.initials: LJ
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authors.affiliation: 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.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: 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.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.affiliation: 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.
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mesh_terms: D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D014644:Genetic Variation; D016678:Genome; D055106:Genome-Wide Association Study; D005838:Genotype; D006630:Hispanic or Latino; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D006801:Humans
chemical_list: D001786:Blood Glucose