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-a), 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 5 3.7 3 1024). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N 5 585, P 5 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N 5 3059, P 5 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 5 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.
| Original language | English |
|---|---|
| Pages (from-to) | 771-783 |
| Number of pages | 13 |
| Journal | Diabetes |
| Volume | 69 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2020 |
Fingerprint
Dive into the research topics of 'PPARA polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes: Findings from accord-lipid'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
PPARA polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes : Findings from accord-lipid. / Morieri, Mario Luca; Shah, Hetal S.; Sjaarda, Jennifer et al.
In: Diabetes, Vol. 69, No. 4, 01.04.2020, p. 771-783.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - PPARA polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes
T2 - Findings from accord-lipid
AU - Morieri, Mario Luca
AU - Shah, Hetal S.
AU - Sjaarda, Jennifer
AU - Lenzini, Petra A.
AU - Campbell, Hannah
AU - Motsinger-Reif, Alison A.
AU - Gao, He
AU - Lovato, Laura
AU - Prudente, Sabrina
AU - Pandolfi, Assunta
AU - Pezzolesi, Marcus G.
AU - Sigal, Ronald J.
AU - Paré, Guillaume
AU - Marcovina, Santica M.
AU - Rotroff, Daniel M.
AU - Patorno, Elisabetta
AU - Mercuri, Luana
AU - Trischitta, Vincenzo
AU - Chew, Emily Y.
AU - Kraft, Peter
AU - Buse, John B.
AU - Wagner, Michael J.
AU - Cresci, Sharon
AU - Gerstein, Hertzel C.
AU - Ginsberg, Henry N.
AU - Mychaleckyj, Josyf C.
AU - Doria, Alessandro
N1 - Funding Information: The ACCORD genome-wide association analysis was supported by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), grants HL110400 (to A.D.) and HL110380 (to J.B.B.) and National Institute of Diabetes and Digestive and Kidney Diseases, NIH, grant DK36836 (Advanced Genomics and Genetics Core of the Diabetes Research Center at the Joslin Diabetes Center). The project described was also supported by the National Center for Advancing Translational Sciences (NCATS), NIH, through grant UL1TR001111 (to J.B.B.). H.N.G. was also supported by NHLBI grant HL110418. M.L.M. was supported by a William Randolph Hearst Fellowship provided by the Hearst Foundation and by a Research Fellowship provided by FONDAZIONE S.I.S.A. S.P. was supported by the Italian Ministry of Health (Ricerca Corrente 2018-2020). V.T. was supported by the Italian Ministry of Health (Ricerca Corrente 2015 and 2016), by the Italian Ministry of University and Research (PRIN 2015), and by Fondazione Roma (“Biomedical Research: Non-Communicable Diseases 2013 grant). H.C.G. is supported by the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. A.M.R. is supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. S.C., H.C., and P.A.L. efforts were in part supported by NIH grant R01 NR013396 (to S.C.). TRIUMPH was sponsored by the NIH: Washington University School of Medicine Specialized Centers of Clinically Oriented Research (SCCOR) grant P50 HL077113. ACCORD (ClinicalTrials.gov, clinical trial reg. no. NCT00000620) was supported by NHLBI contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, and IAA #Y1-HC-9035 and IAA #Y1-HC-1010. Other components of the NIH, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute, contributed funding. The Centers for Disease Control and Prevention funded substudies within ACCORD on cost-effectiveness and health-related quality of life. General Clinical Research Centers and Clinical and Translational Science Awards provided support at many sites. The GTEx project was supported by the Common Fund (https://commonfund.nih.gov/GTEx/index) of the Office of the Director of the NIH and by the National Cancer Institute, National Human Genome Research Institute, NHLBI, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke. In the ACCORD study, the following companies provided study medications, equipment, or supplies: Abbott Laboratories (Abbott Park, IL), Amylin Pharmaceutical (San Diego, CA), AstraZeneca (Wilmington, DE), Bayer HealthCare (Tarrytown, NY), Closer Healthcare (Tequesta, FL), GlaxoSmithKline (GSK) (Philadelphia, PA), King Pharmaceuticals (Bristol, TN), Merck & Co. (Whitehouse Station, NJ), Novartis Pharmaceuticals (East Hanover, NJ), Novo Nordisk (Princeton, NJ), Omron Healthcare (Schaumburg, IL), Sanofi U.S. (Bridgewater, NJ), Schering-Plough Corporation (Kenilworth, NJ), and Takeda Pharmaceuticals (Deerfield, IL). Funding Information: None of these companies had an interest in or bearing on the genome-wide analysis of the ACCORD data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders. Duality of Interest. ORIGIN (ClinicalTrials.gov, clinical trial reg. no. NCT00069784) was funded by Sanofi. M.L.M. received lecture fees from Servier and funding and research grant support from Amryt Pharma (outside of the submitted work). R.J.S. was supported by a Health Senior Scholar award from Alberta Innovates - Health Solutions. G.P. received research funding from Sanofi. E.P. received research funding from GSK and Boehringer Ingelheim (outside the submitted work). J.B.B.’s contracted consulting fees and travel support for contracted activities are paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, and Zafgen, and J.B.B. receives grant support from Novo Nordisk, Sanofi, Tolerion, and vTv Therapeutics; is a consultant to Cirius Therapeutics, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics, and Stability Health; and holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio, and Stability Health. H.C.G. has received research grant support from Sanofi, Lilly, AstraZeneca, and Merck; honoraria for speaking from Sanofi, Novo Nordisk, AstraZeneca, and Boehringer Ingelheim; and consulting fees from Sanofi, Lilly, AstraZeneca, Merck, Novo Nordisk, Abbot, Amgen, and Boehringer Ingelheim. H.N.G. is a consultant to Kowa and member of the PROMINENT trial steering committee. A.D. received research funding from Sanofi (outside the submitted work). No other potential conflicts of interest relevant to this article were reported. Author Contributions. M.L.M. designed the study; acquired, analyzed, and interpreted the data; and wrote the manuscript. H.S.S. designed the study; acquired, analyzed, and interpreted the data; and reviewed the manuscript. A.A.M.-R. and H.G. acquired and interpreted data and reviewed the manuscript. J.S., P.A.L., H.C., L.L., and G.P. acquired and analyzed data and reviewed the manuscript. S.P., A.P., M.G.P., D.M.R., E.P., L.M., and V.T. interpreted the data and reviewed the manuscript. R.J.S. and E.Y.C. designed the study and reviewed the manuscript. S.C. and H.C.G. designed the study, acquired and interpreted data, and reviewed the manuscript. S.M.M., J.B.B., and M.J.W. acquired and interpreted data and reviewed the manuscript. P.K. designed the study, interpreted the data, and reviewed the manuscript. H.N.G. designed the study, acquired and interpreted the data, and reviewed the manuscript. J.C.M. designed the study; acquired, analyzed, and interpreted the data; and reviewed the manuscript. A.D. designed the study; acquired, analyzed, and interpreted the data; and wrote the manuscript. A.D. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Preliminary data of this study were presented at the National Congress of the Italian Society for the Study of Atherosclerosis (SISA), Palermo, Sicily, 19–21 November 2017. Funding Information: Acknowledgments. The authors thank the investigators, staff, and participants of ACCORD for their support and contributions and for giving the authors access to this rich data set. The data used for the gene expression analyses described in this manuscript were obtained from the GTEx Portal on 3 March 2017 (release V6). Funding. The ACCORD genome-wide association analysis was supported by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), grants HL110400 (to A.D.) and HL110380 (to J.B.B.) and National Institute of Diabetes and Digestive and Kidney Diseases, NIH, grant DK36836 (Advanced Genomics and Genetics Core of the Diabetes Research Center at the Joslin Diabetes Center). The project described was also supported by the National Center for Advancing Translational Sciences (NCATS), NIH, through grant UL1TR001111 (to J.B.B.). H.N.G. was also supported by NHLBI grant HL110418. M.L.M. was supported by a William Randolph Hearst Fellowship provided by the Hearst Foundation and by a Research Fellowship provided by FONDAZIONE S.I.S.A. S.P. was supported by the Italian Ministry of Health (Ricerca Corrente 2018-2020). V.T. was supported by the Italian Ministry of Health (Ricerca Corrente 2015 and 2016), by the Italian Ministry of University and Research (PRIN 2015), and by Fondazione Roma (“Biomedical Research: Non-Communicable Diseases 2013 grant). H.C.G. is supported by the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. A.M.R. is supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. S.C., H.C., and P.A.L. efforts were in part supported by NIH grant R01 NR013396 (to S.C.). TRIUMPH was sponsored by the NIH: Washington University School of Medicine Specialized Centers of Clinically Oriented Research (SCCOR) grant P50 HL077113. ACCORD (ClinicalTrials.gov, clinical trial reg. no. NCT00000620) was supported by NHLBI contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, and IAA #Y1-HC-9035 and IAA #Y1-HC-1010. Other components of the NIH, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute, contributed funding. The Centers for Disease Control and Prevention funded substudies within ACCORD on cost-effectiveness and health-related quality of life. General Clinical Research Centers and Clinical and Translational Science Awards provided support at many sites. The GTEx project was supported by the Common Fund (https://commonfund.nih.gov/ GTEx/index) of the Office of the Director of the NIH and by the National Cancer Institute, National Human Genome Research Institute, NHLBI, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke. In the ACCORD study, the following companies provided study medications, equipment, or supplies: Abbott Laboratories (Abbott Park, IL), Amylin Pharmaceutical (San Diego, CA), AstraZeneca (Wilmington, DE), Bayer HealthCare (Tarrytown, NY), Closer Healthcare (Tequesta, FL), GlaxoSmith-Kline (GSK) (Philadelphia, PA), King Pharmaceuticals (Bristol, TN), Merck & Co. (Whitehouse Station, NJ), Novartis Pharmaceuticals (East Hanover, NJ), Novo Nordisk (Princeton, NJ), Omron Healthcare (Schaumburg, IL), Sanofi U.S. Publisher Copyright: © 2020 by the American Diabetes Association.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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-a), 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 5 3.7 3 1024). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N 5 585, P 5 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N 5 3059, P 5 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 5 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.
AB - 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-a), 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 5 3.7 3 1024). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N 5 585, P 5 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N 5 3059, P 5 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 5 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.
UR - http://www.scopus.com/inward/record.url?scp=85082148312&partnerID=8YFLogxK
U2 - 10.2337/db19-0973
DO - 10.2337/db19-0973
M3 - Article
C2 - 31974142
AN - SCOPUS:85082148312
VL - 69
SP - 771
EP - 783
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 4
ER -