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


METHODS
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-α)] 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.


RESULTS
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 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). 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).


CONCLUSIONS
We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.
Departments of Epidemiology, School of Public Health, University of Alabama at Birmingham, Alabama, USA. saslibek@uab.edu
Stella
S
Aslibekyan
Edmond K
EK
Kabagambe
Marguerite R
MR
Irvin
Robert J
RJ
Straka
Ingrid B
IB
Borecki
Hemant K
HK
Tiwari
Michael Y
MY
Tsai
Paul N
PN
Hopkins
Jian
J
Shen
Chao-Qiang
CQ
Lai
Jose M
JM
Ordovas
Donna K
DK
Arnett
D000328:Adult; D002097:C-Reactive Protein / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007249:Inflammation / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000235:genetics*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000960:Hypolipidemic Agents; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D011345:Fenofibrate