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Genome-wide association study indicates variants associated with insulin signaling and inflammation mediate lipoprotein responses to fenofibrate

Frazier-Wood, Alexis C.a,b,c; Aslibekyan, Stellaa; Borecki, Ingrid B.d; Hopkins, Paul N.e; Lai, Chao-Qiangf; Ordovas, Jose M.f,h,i; Straka, Robert J.g; Tiwari, Hemant K.b; Arnett, Donna K.a

doi: 10.1097/FPC.0b013e328357f6af

Objective A shift towards overall larger very low-density lipoprotein (VLDL), and smaller low-density lipoprotein and high-density lipoprotein (HDL) diameters occurs in insulin resistance (IR), which reflects shifts in the distribution of the subfraction concentrations. Fenofibrate, indicated for hypertriglyceridemia, simultaneously reduces IR and shifts in lipoprotein diameter. Individual responses to fenofibrate vary, and we conducted a genome-wide association study to identify genetic differences that could contribute to such differences.

Methods Association analysis was conducted between single nucleotide polymorphisms (SNPs) on the Affymetrix 6.0 array and fasting particle diameter responses to a 12-week fenofibrate trial, in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network. Linear models were conducted, which adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. The top three SNPs associated with each fraction were examined subsequently for associations with changes in subfraction concentrations.

Results SNPs in AHCYL2 and CD36 genes reached, or closely approached, genome-wide levels of significance with VLDL and HDL diameter responses to fenofibrate, respectively (P=4×10−9 and 8×10−8). SNPs in AHCYL2 were associated with a decrease in the concentration of the large VLDL subfraction only (P=0.002). SNPs associated with HDL diameter change were not associated with a single subfraction concentration change (P>0.05) indicating small shifts across all subfractions.

Conclusion We report novel associations between lipoprotein diameter responses to fenofibrate and the AHCYL2 and CD36 genes. Previous associations of these genes with IR emphasize the role of IR in mediating lipoprotein response to fenofibrate.

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aDepartment of Epidemiology

bSection on Statistical Genetics, Department of Biostatistics, School of Public Health

cDepartment of Energetics, University of Alabama at Birmingham, Birmingham, Alabama

dDepartment of Genetics, Washington University School of Medicine, St Louis, Missouri

eDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah

fNutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts

gDepartment of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA

hThe Department of Epidemiology and Population Genetics, Centro Nacional Investigación Cardiovasculares (CNIC)

iIMDEA Food, Madrid, Spain

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Correspondence to Alexis C. Frazier-Wood, PhD, Department of Epidemiology, University of Alabama at Birmingham, RPHB 230P, Birmingham, Alabama 35294, USA Tel: +1 205 975 9198; fax: +1 205 934 8665; e-mail:

Received February 13, 2012

Accepted July 9, 2012

© 2012 Lippincott Williams & Wilkins, Inc.