Variants Identified in a GWAS Meta-Analysis for Blood Lipids Are Associated with the Lipid Response to Fenofibrate

被引：29

作者：

Aslibekyan, Stella ^{[1
]}

Goodarzi, Mark O. ^{[3
,4
]}

Frazier-Wood, Alexis C. ^{[1
,2
]}

Yan, Xiaofei ^{[4
]}

Irvin, Marguerite R. ^{[1
]}

Kim, Eric ^{[4
]}

Tiwari, Hemant K. ^{[2
]}

Guo, Xiuqing ^{[4
]}

Straka, Robert J. ^{[5
]}

Taylor, Kent D. ^{[4
]}

Tsai, Michael Y. ^{[6
]}

Hopkins, Paul N. ^{[8
]}

Korenman, Stanley G. ^{[9
]}

Borecki, Ingrid B. ^{[7
]}

Chen, Yii-Der I. ^{[4
]}

Ordovas, Jose M. ^{[10
,11
,12
]}

Rotter, Jerome I. ^{[4
]}

Arnett, Donna K. ^{[1
]}

机构：

[1] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA

[2] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA

[3] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA

[4] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[5] Univ Minnesota, Coll Pharm, Expt & Clin Pharmacol Dept, Sch Publ Hlth, Minneapolis, MN 55455 USA

[6] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[7] Washington Univ, Dept Genet, St Louis, MO 63110 USA

[8] Univ Utah, Sch Med, Salt Lake City, UT USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[10] Ctr Nacl Invest Cardiovasc, Dept Epidemiol Atherothrombosis & Imaging, Madrid, Spain

[11] Inst Madrilen Estudios Avanzados Alimentac, Madrid, Spain

[12] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA

来源：

PLOS ONE | 2012年 / 7卷 / 10期

关键词：

CHOLESTERYL ESTER TRANSFER; GENOME-WIDE ASSOCIATION; DIET NETWORK; APOLIPOPROTEIN-E; LOWERING DRUGS; GENETICS; POLYMORPHISM; THERAPY; HDL; PHARMACOGENOMICS;

D O I：

10.1371/journal.pone.0048663

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value <= 0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n = 267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. Finally, we present strong evidence for epistasis (P-value for interaction = 0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.

引用

页数：6

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