title: Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).
abstract: Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
authors.forename: Deidre A
authors.initials: DA
authors.lastname: Winnier
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
authors.forename: Marcel
authors.initials: M
authors.lastname: Fourcaudot
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
authors.forename: Luke
authors.initials: L
authors.lastname: Norton
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Abdul-Ghani
authors.affiliation: Division of Nephrology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
authors.forename: Shirley L
authors.initials: SL
authors.lastname: Hu
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Vidya S
authors.initials: VS
authors.lastname: Farook
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, United States of America.
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Coletta
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Satish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Sobha
authors.initials: S
authors.lastname: Puppala
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Geetha
authors.initials: G
authors.lastname: Chittoor
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.affiliation: Division of Endocrinology and Diabetes, Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
authors.forename: Rector
authors.initials: R
authors.lastname: Arya
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Carless
authors.affiliation: Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Lehman
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: Division of Orthopedics, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America; South Texas Veterans Health Care System, San Antonio, TX, United States of America.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Cromack
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America; South Texas Veterans Health Care System, San Antonio, TX, United States of America.
authors.forename: Devjit
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Duggirala
authors.affiliation: Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America; South Texas Veterans Health Care System, San Antonio, TX, United States of America.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America; Texas Biomedical Research Institute, San Antonio, TX, United States of America; South Texas Veterans Health Care System, San Antonio, TX, United States of America.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Jenkinson
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000428:Alcohol Drinking / Q000235:genetics; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics; D023281:Genomics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D017720:Molecular Epidemiology; D009765:Obesity / Q000453:epidemiology* / Q000235:genetics*; D011236:Prediabetic State / Q000453:epidemiology / Q000235:genetics; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism; D014481:United States / Q000453:epidemiology; D014493:United States Department of Veterans Affairs
chemical_list: C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase
references.citation: Forensic Sci Int. 2012 Mar 10;216(1-3):97-100
references.pmid: 21945304
references.citation: Alcohol. 1998 Feb;15(2):147-60
references.pmid: 9476961
references.citation: Alcohol Alcohol. 2001 Nov-Dec;36(6):608
references.pmid: 11704630
references.citation: Ann Epidemiol. 2010 Sep;20(9):670-5
references.pmid: 20696406
references.citation: Hum Hered. 2013;76(1):36-46
references.pmid: 24060607
references.citation: Diabetologia. 1983 Apr;24(4):272-7
references.pmid: 6862133
references.citation: J Proteome Res. 2008 Aug;7(8):3230-41
references.pmid: 18613714
references.citation: Diabetes Care. 1996 Aug;19(8):827-30
references.pmid: 8842599
references.citation: Cytotechnology. 2012 Oct;64(5):511-21
references.pmid: 22328147
references.citation: Diabetologia. 2004 May;47(5):816-20
references.pmid: 15105989
references.citation: J Biol Chem. 2005 Mar 18;280(11):10290-7
references.pmid: 15598661
references.citation: Nat Rev Genet. 2010 May;11(5):356-66
references.pmid: 20395969
references.citation: Gastroenterology. 2000 Nov;119(5):1340-7
references.pmid: 11054393
references.citation: Am J Hum Genet. 1998 May;62(5):1198-211
references.pmid: 9545414
references.citation: Nucleic Acids Res. 2011 Jul;39(Web Server issue):W307-15
references.pmid: 21646343
references.citation: Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):777-83
references.pmid: 10073986
references.citation: Am J Epidemiol. 1987 Oct;126(4):674-84
references.pmid: 3631057
references.citation: Diabetes Care. 1997 Jul;20(7):1183-97
references.pmid: 9203460
references.citation: Arch Intern Med. 1999 Jul 12;159(13):1450-6
references.pmid: 10399896
references.citation: J Am Coll Cardiol. 2011 Jun 21;57(25):2461-73
references.pmid: 21679848
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D797-802
references.pmid: 18948288
references.citation: Diabetologia. 1999 Feb;42(2):139-45
references.pmid: 10064092
references.citation: Physiol Rev. 1995 Jul;75(3):473-86
references.pmid: 7624391
references.citation: BMC Endocr Disord. 2011 Mar 22;11:7
references.pmid: 21426570
references.citation: J Anal Toxicol. 1983 Jul-Aug;7(4):193-7
references.pmid: 6101261
references.citation: Pharmacol Ther. 1990;45(1):69-83
references.pmid: 2405433
references.citation: Am J Hum Genet. 2003 Aug;73(2):323-35
references.pmid: 12851856
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references.pmid: 11682119
references.citation: Nature. 2005 Jul 21;436(7049):356-62
references.pmid: 16034410
references.citation: J Gerontol A Biol Sci Med Sci. 2013 Nov;68(11):1356-76
references.pmid: 23525482
references.citation: Am J Gastroenterol. 2001 Apr;96(4):1200-4
references.pmid: 11316170
references.citation: Am J Physiol Endocrinol Metab. 2008 May;294(5):E910-7
references.pmid: 18334611
references.citation: Am J Hum Genet. 1999 Apr;64(4):1127-40
references.pmid: 10090898
references.citation: J Clin Endocrinol Metab. 2004 Feb;89(2):463-78
references.pmid: 14764748
references.citation: Alcohol. 1988 May-Jun;5(3):263-5
references.pmid: 3415770
references.citation: Diabetes. 2006 Oct;55(10):2805-10
references.pmid: 17003346
references.citation: Obes Res. 2004 Mar;12(3):369-439
references.pmid: 15044658
references.citation: Nat Genet. 2006 Mar;38(3):320-3
references.pmid: 16415884
references.citation: Integr Comp Biol. 2004 Aug;44(4):284-9
references.pmid: 21676711
references.citation: Diabetes Care. 1999 Sep;22(9):1462-70
references.pmid: 10480510
references.citation: JAMA. 2012 Feb 1;307(5):491-7
references.pmid: 22253363
references.citation: PLoS One. 2012;7(7):e41175
references.pmid: 22859968
references.citation: Diabetes. 2009 Apr;58(4):773-95
references.pmid: 19336687
references.citation: Alcohol Clin Exp Res. 2011 Sep;35(9):1584-92
references.pmid: 21599713
references.citation: Biochem J. 1970 Jul;118(4):635-44
references.pmid: 5481498
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827
references.citation: J Chromatogr B Biomed Sci Appl. 1999 Apr 30;727(1-2):89-94
references.pmid: 10360426
references.citation: Nat Genet. 2007 Oct;39(10):1208-16
references.pmid: 17873875
references.citation: Diabetes. 1988 Jun;37(6):667-87
references.pmid: 3289989
references.citation: Nature. 2007 Feb 22;445(7130):881-5
references.pmid: 17293876
references.citation: Diabetes Care. 2003 Nov;26(11):3160-7
references.pmid: 14578255
references.citation: PLoS Genet. 2011 Mar;7(3):e1001333
references.pmid: 21437268
references.citation: Genet Epidemiol. 2001 Apr;20(3):373-82
references.pmid: 11255245
references.citation: J Diabetes Metab. 2012 Jun 23;3(198):
references.pmid: 23243555
references.citation: Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E537-46
references.pmid: 15126243
references.citation: Trends Genet. 2008 Dec;24(12):613-21
references.pmid: 18952314
references.citation: Diabetologia. 1981 Feb;20(2):87-93
references.pmid: 7193616
references.citation: Diabetes. 1988 Dec;37(12):1595-607
references.pmid: 3056758
references.citation: Hepatology. 2013 Feb;57(2):601-9
references.pmid: 23055155
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Curr Diab Rep. 2010 Dec;10(6):476-84
references.pmid: 20820957
references.citation: Diabetologia. 1992 Apr;35(4):389-97
references.pmid: 1516769
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3502-9
references.pmid: 16537441
references.citation: Am J Hum Genet. 2004 Dec;75(6):1094-105
references.pmid: 15514893