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

Abstract

Background and aims: 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.

Methods and results: 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.

Conclusions: 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.

Keywords: Adiponectin; Fenofibrate; Genetics.

Figure 1

Manhattan plot of genome-wide results of testing for association between SNPs and baseline adiponectin levels. The X-axes display the chromosome on which the SNP is located, the Y-axes display −log₁₀(P-value). The top horizontal line marks the genome-wide significance level (P-value= 5×10⁻⁸).

Figure 1

Manhattan plot of genome-wide results of testing for association between SNPs and baseline adiponectin levels. The X-axes display the chromosome on which the SNP is located, the Y-axes display −log₁₀(P-value). The top horizontal line marks the genome-wide significance level (P-value= 5×10⁻⁸).

Figure 2

Manhattan plot of genome-wide results of testing for association between SNPs and adiponectin response to fenofibrate treatment. The X-axes display the chromosome on which the SNP is located, the Y-axes display −log₁₀(P-value). The top horizontal line marks the genome-wide significance level (P-value= 5×10⁻⁸).

Figure 2

Manhattan plot of genome-wide results of testing for association between SNPs and adiponectin response to fenofibrate treatment. The X-axes display the chromosome on which the SNP is located, the Y-axes display −log₁₀(P-value). The top horizontal line marks the genome-wide significance level (P-value= 5×10⁻⁸).