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 - Publisher Copyright:
© 2020 by the American Diabetes Association.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
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 -