A genome-wide study of lipid response to fenofibrate in Caucasians: A combined analysis of the GOLDN and ACCORD studies

Marguerite R. Irvin, Daniel M. Rotroff, Stella Aslibekyan, Degui Zhi, Bertha Hidalgo, Alison Motsinger-Reif, Skylar Marvel, Vinodh Srinivasasainagendra, Steven A. Claas, John B. Buse, Robert J. Straka, Jose M. Ordovas, Ingrid B. Borecki, Xiuqing Guo, Ida Y D Chen, Jerome I. Rotter, Michael J. Wagner, Donna K. Arnett

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients. Methods We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans). Results A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5×10 -8). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P<0.05). Conclusion Future research should evaluate the usefulness of this locus to refine clinical strategies for lipid-lowering treatments.

Original languageEnglish (US)
Pages (from-to)324-333
Number of pages10
JournalPharmacogenetics and genomics
Volume26
Issue number7
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
GOLDN was supported by the National Heart, Lung, and Blood Institute (NHLBI) R01HL091357. ACCORD was supported by Contract Nos. N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA #Y1-HC-9035, and IAA #Y1-HC-1010, and grant RO1 HL110380 from the NHLBI, with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). HyperTG was supported by NHLBI R01HL076771, with additional support from NCATS UL1TR000124 and NIDDK DK063491.

Publisher Copyright:
© 2016 Wolters Kluwer Health, Inc.

Keywords

  • cholesterol
  • dyslipidemia
  • fenofibrate
  • genome-wide association study
  • lipid
  • lipoprotein
  • triglyceride

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