PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid-Reference-Cited by-同舟云学术

PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid

Published:2020-01-23 Issue:4 Volume:69 Page:771-783
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Morieri Mario Luca¹²³^ORCID,Shah Hetal S.¹²^ORCID,Sjaarda Jennifer⁴,Lenzini Petra A.⁵,Campbell Hannah⁵⁶,Motsinger-Reif Alison A.⁷^ORCID,Gao He¹²,Lovato Laura⁸,Prudente Sabrina⁹^ORCID,Pandolfi Assunta¹⁰,Pezzolesi Marcus G.¹¹^ORCID,Sigal Ronald J.¹²^ORCID,Paré Guillaume⁴^ORCID,Marcovina Santica M.¹³,Rotroff Daniel M.¹⁴,Patorno Elisabetta¹⁵^ORCID,Mercuri Luana⁹,Trischitta Vincenzo⁹¹⁶^ORCID,Chew Emily Y.¹⁷,Kraft Peter¹⁸,Buse John B.¹⁹,Wagner Michael J.²⁰,Cresci Sharon⁵⁶,Gerstein Hertzel C.⁴^ORCID,Ginsberg Henry N.²¹^ORCID,Mychaleckyj Josyf C.²²,Doria Alessandro¹²^ORCID

Affiliation:

1. Research Division, Joslin Diabetes Center, Boston, MA

2. Department of Medicine, Harvard Medical School, Boston, MA

3. Department of Medicine, University of Padova, Padova, Italy

4. McMaster University and Population Health Research Institute, Hamilton, Ontario, Canada

5. Department of Genetics, Washington University School of Medicine, St. Louis, MO

6. Department of Medicine, Washington University School of Medicine, St. Louis, MO

7. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC

8. Wake Forest School of Medicine, Winston Salem, NC

9. Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

10. Department of Medical, Oral and Biotechnological Sciences, University “G. d'Annunzio,” Chieti, Italy

11. Division of Nephrology and Hypertension and Diabetes and Metabolism Center, University of Utah, Salt Lake City, UT

12. Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Cumming School of Medicine, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, Alberta, Canada

13. Department of Medicine, University of Washington, and Northwest Lipid Metabolism and Diabetes Research Laboratories, Seattle, WA

14. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH

15. Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA

16. Department of Experimental Medicine, “Sapienza” University, Rome, Italy

17. Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD

18. Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA

19. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC

20. Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC

21. Irving Institute for Clinical and Translational Research, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY

22. Center for Public Health Genomics, University of Virginia, Charlottesville, VA

Abstract

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (Pinteraction = 3.7 × 10−4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

Funder

National Heart, Lung, and Blood Institute

National Institute of Diabetes and Digestive and Kidney Diseases

National Center for Advancing Translational Sciences

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Link

https://journals.org/diabetes/diabetes/article-pdf/69/4/771/436137/db190973.pdf

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