title: 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.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Liu
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Guimin
authors.initials: G
authors.lastname: Gao
authors.forename: Michael
authors.initials: M
authors.lastname: Province
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Straka
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tsai
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Lai
authors.forename: Kui
authors.initials: K
authors.lastname: Zhang
authors.forename: Ingrid
authors.initials: I
authors.lastname: Borecki
authors.forename: James E
authors.initials: JE
authors.lastname: Hixson
authors.forename: David B
authors.initials: DB
authors.lastname: Allison
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000235:genetics; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III / Q000235:genetics; D001053:Apolipoproteins / Q000235:genetics*; D001054:Apolipoproteins A / Q000235:genetics; D004032:Diet; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy* / Q000235:genetics*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C505693:APOA1 protein, human; C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D001054:Apolipoproteins A; D000960:Hypolipidemic Agents; C022205:apolipoprotein A-IV; D011345:Fenofibrate