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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION, OBESITY, CARDIOVASCULAR HEALTH AND GENOMICS

Location: Human Nutrition Research Center on Aging

Title: Preliminary evidence of genetic determinants of adiponectin response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

Authors
item Aslibekyan, Stella -
item An, P -
item Frazier-Wood, Alexis -
item Kabagambe, E -
item Irvin, M -
item Straka, Robert -
item Tiwari, Hemant -
item Tsa, Michael -
item Hopkins, Paul -
item Borecki, I -
item Ordovas, Jose -
item Arnett, Donna -

Submitted to: Nutrition, Metabolism and Cardiovascular Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 27, 2012
Publication Date: November 12, 2012
Citation: Aslibekyan, S., An, P., Frazier-Wood, A.C., Kabagambe, E.K., Irvin, M.R., Straka, R.J., Tiwari, H.K., Tsa, M.Y., Hopkins, P.N., Borecki, I.B., Ordovas, J.M., Arnett, D.K. 2012. Preliminary evidence of genetic determinants of adiponectin response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network. Nutrition, Metabolism and Cardiovascular Diseases. DOI: 10.1016/j.numecd.2012.07.010.

Interpretive Summary: Contrary to traditional thinking, fat tissue is not just a storage mechanism, but rather a metabolically active organ that synthesizes and releases highly active compounds. Adiponectin is a protein secreted by fat tissue that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate (a drug that mimics some of the activities of omega-3 fatty acids) therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. Therefore, we carried out a genome-wide association study to characterize the variable effects of fenofibrate on circulating adiponectin in participants of the Genetics of Lipid Lowering Drugs and Diet Network which had 793 participants before and after a 3-week daily treatment with 160 mg of fenofibrate. We observed a statistically significant association between a polymorphism (a variation in a particular DNA sequence) known as rs2384207 in a region of Chromosome 12 (12q24) that has been previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Moreover, we found evidence for other previously reported genomic regions linked to adiponectin levels. Therefore, we present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at without and in response to fenofibrate therapy. Our findings provide support for additional investigation of the 12q24 region to reveal the biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.

Technical Abstract: Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P = 5 × 10(-8)) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.

Last Modified: 8/27/2014
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