title: A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.
abstract: Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent (n=1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 (ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: β±SE=0.05±0.02, P=0.008; in non-Hispanic whites: 0.06±0.02, P=0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.
authors.affiliation: Department of Medicine, University of Texas Medical Branch, Galveston, Texas; lmbelalc@utmb.edu.
authors.forename: L Maria
authors.initials: LM
authors.lastname: Belalcazar
authors.affiliation: Department of Biostatistics, Brown University, Providence, Rhode Island;
authors.forename: George D
authors.initials: GD
authors.lastname: Papandonatos
authors.affiliation: Weight Control and Diabetes Research Center, Department of Psychiatry and Human Behavior, The Miriam Hospital and Brown Medical School, Providence, Rhode Island;
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: McCaffery
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.affiliation: Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina;
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Pajewski
authors.affiliation: Department of Biostatistics, Brown University, Providence, Rhode Island;
authors.forename: Bahar
authors.initials: B
authors.lastname: Erar
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest University Health Sciences, Winston-Salem, North Carolina;
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Allred
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
authors.affiliation: Department of Biochemistry and Center for Genomics and Personalized Medicine Research, Wake Forest University Health Sciences, Winston-Salem, North Carolina;
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: Ariel
authors.initials: A
authors.lastname: Brautbar
authors.affiliation: Department of Medicine, Columbia University, St. Luke's-Roosevelt Hospital, New York, New York;
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Pi-Sunyer
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Cardiovascular Disease Prevention, Methodist De Bakey Heart and Vascular Center, Houston, Texas; and.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: MCRI Center for Translational Genomics, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Huggins
mesh_terms: D052242:Adiponectin / Q000235:genetics*; D050154:Adiposity / Q000235:genetics; D000368:Aged; D057167:Claudins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics*; D010809:Physical Fitness; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C473255:CLDN7 protein, human; D057167:Claudins
keywords: DERP6; Elongator; Look AHEAD; adipose tissue; epithelial permeability; exercise; lifestyle intervention; mediation; p53; r3507506; sirtuin; tight junction; weight loss