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. 2009 Feb;19(2):161-9.
doi: 10.1097/FPC.0b013e32831e030e.

Pharmacogenetic association of the APOA1/C3/A4/A5 gene cluster and lipid responses to fenofibrate: the genetics of lipid-lowering drugs and diet network study

Yongjun Liu  1 , Jose M Ordovas, Guimin Gao, Michael Province, Robert J Straka, Michael Y Tsai, Chao-Qiang Lai, Kui Zhang, Ingrid Borecki, James E Hixson, David B Allison, Donna K Arnett
Affiliations

Pharmacogenetic association of the APOA1/C3/A4/A5 gene cluster and lipid responses to fenofibrate: the genetics of lipid-lowering drugs and diet network study

Yongjun Liu et al. Pharmacogenet Genomics. 2009 Feb.

Abstract

Background: The apolipoproteins (APOA1/C3/A4/A5) are key components in modulating lipoprotein metabolism. It is unknown whether variants at the APOA1/C3/A4/A5 gene cluster are associated with lipid response to pharmacologic intervention.

Methods and results: Plasma triglycerides (TGs) and high-density lipoprotein (HDL) levels were measured in 861 Genetics of Lipid-Lowering Drugs and Diet Network study participants who underwent a 3-week fenofibrate trial. We examined 18 common single nucleotide polymorphisms (SNPs) spanning the APOA1/C3/A4/A5 genes to investigate the effects of variants at the gene cluster on lipid response to fenofibrate treatment. We found that the minor alleles of the SNPs rs3135506 (APOA5_S19W), rs5104 (APOA4_N147S), rs4520 (APOC3_G34G), and rs5128 (APOC3_3U386) were associated with enhanced TG response to fenofibrate treatment (P= 0.0004-0.018). The minor allele of SNP rs2854117 (APOC3_M482) was associated with reduced rather than enhanced TG response (P= 0.026). The SNP rs3135506 (APOA5_S19W) was associated with HDL response, with minor allele related to reduced HDL response to fenofibrate (P= 0.002). Association analyses on haplotype provided corroborative evidence to single SNP association analyses. The common haplotypes H2, H3, and H5 were significantly associated with reduced TG response to fenofibrate.

Conclusion: The genetic variants at APOA1/C3/A4/A5 gene cluster may be useful markers to predict response of lipid-lowering therapy with fenofibrate. Further studies to replicate/confirm our findings are warranted.

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Figures

Fig. 1
Fig. 1
Linkage disequilibrium structure and haplotype blocks of the APOA1/C3/A4/A5 gene cluster.
Fig. 2
Fig. 2
(a) Phenotypic changes with APOA5_S19W genotypes. Changes (mean ± SE) of high-density lipoprotein (HDL) cholesterol and triglyceride (TG) (y-axis) were growth curve slopes estimated from the mixed models. (b) Absolute changes of TG and HDL with APOA5_S19W genotypes.
See this image and copyright information in PMC

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