Liu Yongjun, Ordovas Jose M, Gao Guimin, Province Michael, Straka Robert J, Tsai Michael Y, Lai Chao-Qiang, Zhang Kui, Borecki Ingrid, Hixson James E, Allison David B, Arnett Donna K
Departments of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Pharmacogenet Genomics. 2009 Feb;19(2):161-9. doi: 10.1097/FPC.0b013e32831e030e.
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.
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.
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.
载脂蛋白（APOA1/C3/A4/A5）是调节脂蛋白代谢的关键成分。APOA1/C3/A4/A5基因簇的变异是否与药物干预后的血脂反应相关尚不清楚。
在861名参与降脂药物与饮食网络研究的受试者中测量了血浆甘油三酯（TG）和高密度脂蛋白（HDL）水平，这些受试者接受了为期3周的非诺贝特试验。我们检测了跨越APOA1/C3/A4/A5基因的18个常见单核苷酸多态性（SNP），以研究该基因簇变异对非诺贝特治疗血脂反应的影响。我们发现，SNP rs3135506（APOA5_S19W）、rs5104（APOA4_N147S）、rs4520（APOC3_G34G）和rs5128（APOC3_3U386）的次要等位基因与非诺贝特治疗后TG反应增强相关（P = 0.0004 - 0.018）。SNP rs2854117（APOC3_M482）的次要等位基因与TG反应降低而非增强相关（P = 0.026）。SNP rs3135506（APOA5_S19W）与HDL反应相关，次要等位基因与非诺贝特治疗后HDL反应降低相关（P = 0.002）。单倍型关联分析为单SNP关联分析提供了佐证。常见单倍型H2、H3和H5与非诺贝特治疗后TG反应降低显著相关。
APOA1/C3/A4/A5基因簇中的遗传变异可能是预测非诺贝特降脂治疗反应的有用标志物。有必要进行进一步研究以重复/证实我们的发现。
