Abstract P190: Genome-wide Association Study Suggests that Inflammation and Insulin Regulation Pathways May Mediate Lipoprotein Diameter Response to Fenofibrate
Authors: Alexis C Wood, Stella Aslibekyan, Robert J Strake, Ingrid B Borecki, Hemant K Tiwari, Michael Y Tsai, Paul N Hopkins, Jose M Ordovas, Edmond K Kabagambe, Donna K Arnett
Journal: Circulation (2012)

Shifts in lipoprotein diameter occur in insulin resistant (IR) patients - a known risk factor for cardiovascular disease. Fenofibrate modulates lipoprotein markers in a manner which is expected to reduce the risk of adverse cardiovascular events. However inter-individual variability in response to fenofibrate is very high. We aimed to examine phenotype-variant associations with shifts in lipoprotein diameter, for each of the three fractions of lipoprotein, in response to a three-week fenofibrate trial. Participants formed the general population sample from that Genetics of Lipid Lowering Drugs and Diet Network (n=817; mean age of 48.8 ± 16.2 y). Very-low, low- and high- density lipoprotein diameters were measured using NMR spectroscopy before and after a 3-week fenofibrate treatment (160mg/day). Lipoprotein diameter change, for each fraction, was calculated using growth curve models which modeled compliance with the fenofibrate protocol. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and lipoprotein diameter change were assessed using mixed linear models, adjusted for age, sex, study center, and family. A Bonferroni correction for multiple testing was used, with genome wide levels of significance set at P &lt;1.97*10 -08 . Given power problems inherent in using change scores, suggestive levels of significance were set at P &lt;1.97 * 10 -06 where there were more than five hits at this level within a 500kb region. The AHCLY2 ( P &lt;3.95*10 -08 ) gene was significantly associated with very-low density lipoprotein diameter. 14 genes reached suggestive levels of significance ( Table 1 ). We conclude that genes previously associated with inflammation ( LPAR1 , GRP110 ) and insulin ( PION , EIF2AK3 , CHRM3 , WNT ) may mediate lipoprotein diameter response to fenofibrate. Upon replication in clinical populations, this may help understand the co-occurrence of IR, inflammation and cardiovascular disease as well the mechanisms of action and therapeutic potential of fenofibrate's role in patients with IR. Table 1 Significant, and suggestive genotype-phenotype associations from a genome-wide study investigating genetic associations with VLDL, LDL and HDL diameter changes in response to fenofibrate Gene Response phenotype 1 P-value 2 Previous associations 3 AHCLY2 VLDL 3.95*10 -09 Produces an enzyme necessary for methylation DOCK4 VLDL 1.39*10 -07 - PPARG HDL 2.87*10 -07 Increases expression of ABCA1; target of thiazolidinediones used to treat insulin resistance ACCSL HDL 5.18*10 -07 - TFAP2A HDL 5.26*10 -07 cardiomyopathy PPTC7 HDL 6.40*10 -07 - NSUN3 HDL 6.45*10 -07 - RPLP1 HDL 6.47*10 -07 - ORK2 HDL 9.10*10 -07 Olfactory receptor G-protein coupled gene LPAR1 HDL 9.10*10 -07 inflammation, adipogenesis GPR110 VLDL 2.97*10 -06 G-protein coupled gene, inflammation EIF2AK3 VLDL 7.02*10 -06 insulin secretion, type 2 diabetes CHRM3 HDL 3.63*10 -06 insulin secretion, type 2 diabetes PLD1 VLDL 6.75*10 -06 insulin secretion and lipid droplet formation TINK VLDL 6.75*10 -06 wnt signaling, type 2 diabetes Abbreviations: VLDL: very-low density lipoprotein; LDL: low-density lipoprotein, HDL: High density lipoprotein 1 Diameter change 2 Smallest p-value for a single phenotype-variant association within the gene 3 PubMed searches for the genes where within the gene single nucleotide polymorphisms were associated at ( P &lt;1.97 * 10 -06 ).