A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes

作者：Belalcazar L Maria^*; Papandonatos George D; McCaffery Jeanne M; Peter Inga; Pajewski Nicholas M; Erar Bahar; Allred Nicholette D; Balasubramanyam Ashok; Bowden Donald W; Brautbar Ariel; Pi Sunyer F Xavier; Ballantyne Christie M; Huggins Gordon S

来源：Physiological Genomics, 2015, 47(6): 215-224.

DOI：10.1152/physiolgenomics.00109.2014

• adipose tissue
• lifestyle intervention
• exercise
• weight loss
• epithelial permeability
• tight junction
• mediation
• Look AHEAD
• r3507506
• Elongator
• p53
• sirtuin
• DERP6

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: beta +/- 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.

• 出版日期2015-6-1