Fenofibrate, a PPAR-α inhibitor used for treating dyslipidemia, has well-documented anti-inflammatory effects that vary between individuals. While DNA sequence variation explains some of the observed variability in response, epigenetic patterns present another promising avenue of inquiry due to the biological links between the PPAR-α pathway, homocysteine and S-adenosylmethionine – a source of methyl groups for the DNA methylation reaction.
[Photo: (left to right) Dr. Hemant Tiwari, Dr. Stella Aslibekyan, Dr. Bertha Hidalgo, and Dr. Marguerite Ryan Irvin]
The hypothesis was that DNA methylation variation at baseline is associated with the inflammatory response to a short-term fenofibrate treatment.
The research team conducted the first epigenome-wide study of inflammatory response to daily treatment with 160 mg of micronized fenofibrate over a 3-week period in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 750). Epigenome-wide DNA methylation was quantified on CD4+ T cells using the Illumina Infinium HumanMethylation450 array.
Multiple CpG sites were identified that were significantly associated with the changes in plasma concentrations of inflammatory cytokines such as high sensitivity CRP (hsCRP, 7 CpG sites), IL-2 soluble receptor (IL-2sR, one CpG site), and IL-6 (4 CpG sites). Top CpG sites mapped to KIAA1324L (p = 2.63E-10), SMPD3 (p = 2.14E-08), SYNPO2 (p = 5.00E-08), ILF3 (p = 1.04E-07), PRR3, GNL1 (p = 6.80E-09), FAM50B (p = 3.19E-08), RPTOR (p = 9.79e-07) and several intergenic regions (p < 1.03E-07). We also derived two inflammatory patterns using principal component analysis and uncovered additional epigenetic hits for each pattern before and after fenofibrate treatment.
This study provides preliminary evidence of a relationship between DNA methylation and inflammatory response to fenofibrate treatment.
University of Alabama at Birmingham School of Public Health authors include Dr. Bertha Hidalgo, assistant professor, Dr. Marguerite Ryan Irvin and Dr. Stella Aslibekyan, associate professors in the department of epidemiology, and Dr. Hemant Tiwari, professor in the department of biostatistics. UAB School of Medicine Dr. Nabiha Yusuf, assistant professor in the department of dermatology, was also an author.
The analysis was published in the August 24 issue of Pharmacogenomics.