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

Author
item FRAZIER-WOOD, ALEXIS - University Of Alabama
item ASLIBEKYAN, STELLA - University Of Alabama
item BORECKI, INGRID - Washington University
item HOPKINS, PAUL - University Of Utah
item Lai, Chao Qiang
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item STRAKA, ROBERT - University Of Minnesota
item TIWARI, HEMANT - University Of Alabama
item ARNETT, DONNA - University Of Alabama

Submitted to: Pharmacogenetics and Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/16/2012
Publication Date: 10/1/2012
Citation: Frazier-Wood, A.C., Aslibekyan, S., Borecki, I.B., Hopkins, P.N., Lai, C., Ordovas, J.M., Straka, R.J., Tiwari, H.K., Arnett, D.K. 2012. Genome-wide association study indicates variants associated with insulin signaling and inflammation mediate lipoprotein responses to fenofibrate. Pharmacogenetics and Genomics. 22(10):750-757.

Interpretive Summary: Lipoproteins are spherical particles that carry lipids, particularly cholesterol and triglyceride, in the plasma. There is a well-established association between dyslipidemias, or disorders of lipoprotein metabolism, and coronary heart disease (CHD): elevated levels of blood cholesterol, especially low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C) which increases risk for CHD. Moreover, it is known that some lipoprotein subfractions are more atherogenic than others. Therefore examination of specific lipoprotein subclasses and their modulation by diet and other therapeutic agents could contribute to an improved understanding of the dynamic interaction between, dietary factors, lipid metabolism and CHD. Specifically, 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), a measure of diabetes risk. Fenofibrate, a compound that mimics some of the actions of omega-3 fatty acids, reduces IR and shifts lipoprotein diameter towards a healthier profile. However, individual responses to fenofibrate vary suggesting that some individuals will benefit less than others from this therapy. In order to gain further understanding about the genetic basis of this variability in response, we conducted a genome-wide association study to identify genetic differences that could contribute to such differences. For this purpose we used a gene chip able to detect over one million common single nucleotide polymorphisms (SNPs) through the whole genome. We carried out this analysis in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network. Our results have identified two new genes potentially involved in lipoprotein metabolism and response to fenofibrates. Thus SNPs in AHCYL2 and CD36 genes reached significance with VLDL and HDL diameter responses to fenofibrate. In conclusion, we report novel associations between lipoprotein diameter responses to fenofibrate and the AHCYL2 and CD36 genes. This knowledge should contribute to a better evaluation of individual risk and better prevention and therapy for diabetes and, in general, for coronary heart disease.

Technical Abstract: 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. 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. 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. 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.