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.

CPT1A methylation is associated with plasma adiponectin

“…Specifically, we have performed look-up of methylation variants located in or near (+/−50 bp) the genes previously identified as implicated in adiponectin homeostasis in our study population: ADIPOQ , CDH13 , IL22RA1 , IL28RA , PCSK5 , SCUBE1 , and TMEM18 , as well as intergenic variants on chromosomes 12 and 20 (7, 17). We also interrogated methylation in the following adiponectin-related genes identified in two or more populations in the GWAS catalog: ARL15 , CMIP , FER , GPR109A , and PEPD (http://www.ebi.ac.uk/gwas/search?query=Adiponectinlevels).…”

Saturated Fat Intake Modulates the Association between an Obesity Genetic Risk Score and Body Mass Index in Two US Populations

“…The GRS, BMI (and waist circumference) and dietary variables were evaluated continuously and SFA intake was also evaluated categorically. A prior study 29 found no significant population structure in GOLDN, allowing this term to be omitted from the model as a potential confounder. To construct the categorical variable, SFA intakes expressed as percent total daily energy intake were classified into two groups (low or high) according to the median score of the population.…”

Review: adiponectin in retinopathy

“…Clinically, fenofibrate, together with other fibric acid derivatives such as bezafibrate, is correlated with increased circulating APN levels in patients with either dyslipidemia[94] or metabolic syndrome[95]. Although the response to fenofibrate-induced APN levels increases may be genetically dependent[96], clinically available fibric acid derivatives may be used to increase APN levels to benefit eye diseases.…”