A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network

Authors: ASLIBEKYAN, STELLA - University Of Alabama; KABAGAMBE, EDMOND - University Of Alabama; IRVIN, MARGUERITE - University Of Alabama; STRAKA, ROBERT - University Of Minnesota; BORECKI, INGRID - Washington University; TIWARI, HEMANT - University Of Alabama; TSAI, MICHAEL - University Of Minnesota; HOPKINS, PAUL - University Of Utah; SHEN, JIAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Lai, Chao Qiang; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ARNETT, DONNA - University Of Alabama

Submitted to: Pharmacogenetics and Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2011
Publication Date: 3/1/2012
Citation: Aslibekyan, S., Kabagambe, E.K., Irvin, M.R., Straka, R.J., Borecki, I.B., Tiwari, H.K., Tsai, M.Y., Hopkins, P.N., Shen, J., Lai, C., Ordovas, J.M., Arnett, D.K. 2012. A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network. Pharmacogenetics and Genomics. 22(3):191-197.

Interpretive Summary: Inflammation is a major mechanism by which the immune system protects the body from disease. However, when inflammation becomes chronic, often as a result of obesity, it contributes to many common diseases such as cardiovascular disease. We can detect chronic inflammation by measuring “inflammatory biomarkers” in the blood. Drugs which are used to reduce fats in the blood, such as fenofibrate, may also reduce inflammatory biomarkers, but whether or not the inflammatory markers are improved by fenofibrate treatment varies widely among different people. In the current study, we examined nearly a million genetic factors (variants) in a population of 1092 people, to determine whether any of these variants were related to differences in inflammatory biomarkers, both before and after treatment with fenofibrate. Results of the study showed us that a small number of genetic variants were associated with inflammatory biomarkers at baseline. Our results also suggested that one variant might be associated with response to the treatment. This study is an example of how genetic studies can be used to add to our understanding of what causes chronic inflammation, and how we might eventually tailor drug treatments based on individual genetic factors.

Technical Abstract: Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation. Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-Alpha)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect. Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10**-9 and rs12722605, P=5×10**-8). Associations of the MCP1-TNF-a pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10**-7, 5×10**-7, 6×10**-7, and 7×10**-7, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-Alpha pattern (P=3×10**-7). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10**-7). We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.