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

• Published in: Physiological genomics 2015-06, Vol.47 (6), p.215-224
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adiponectin - genetics; Adiposity - genetics; Aged; Claudins - genetics; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Female; General Interest; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Life Style; Male; Middle Aged; Obesity - complications; Obesity - genetics; Physical Fitness; Polymorphism, Single Nucleotide - genetics
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00109.2014

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.