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

Alexis C. Frazier-Wood, Stella Aslibekyan, Ingrid B. Borecki, Paul N. Hopkins, Chao Qiang Lai, Jose M. Ordovas, Robert J. Straka, Hemant K. Tiwari, Donna K. Arnett

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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 and 8×10). 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.

Original languageEnglish (US)
Pages (from-to)750-757
Number of pages8
JournalPharmacogenetics and genomics
Volume22
Issue number10
DOIs
StatePublished - Oct 2012

Keywords

  • AHCYL2
  • CD36
  • PPARc
  • fenofibrate
  • inflammation
  • insulin resistance
  • insulin signaling
  • lipoprotein diameter
  • methylation
  • subclass

Fingerprint Dive into the research topics of 'Genome-wide association study indicates variants associated with insulin signaling and inflammation mediate lipoprotein responses to fenofibrate'. Together they form a unique fingerprint.

Cite this