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

Mario Luca Morieri, Hetal S Shah, Jennifer Sjaarda, Petra A Lenzini, Hannah Campbell, Alison A Motsinger-Reif, He Gao, Laura Lovato, Sabrina Prudente, Assunta Pandolfi, Marcus G Pezzolesi, Ronald J Sigal, Guillaume Paré, Santica M Marcovina, Daniel M Rotroff, Elisabetta Patorno, Luana Mercuri, Vincenzo Trischitta, Emily Y Chew, Peter Kraft, John B Buse, Michael J Wagner, Sharon Cresci, Hertzel C Gerstein, Henry N Ginsberg, Josyf C Mychaleckyj, Alessandro Doria, Mario Luca Morieri, Hetal S Shah, Jennifer Sjaarda, Petra A Lenzini, Hannah Campbell, Alison A Motsinger-Reif, He Gao, Laura Lovato, Sabrina Prudente, Assunta Pandolfi, Marcus G Pezzolesi, Ronald J Sigal, Guillaume Paré, Santica M Marcovina, Daniel M Rotroff, Elisabetta Patorno, Luana Mercuri, Vincenzo Trischitta, Emily Y Chew, Peter Kraft, John B Buse, Michael J Wagner, Sharon Cresci, Hertzel C Gerstein, Henry N Ginsberg, Josyf C Mychaleckyj, Alessandro Doria

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 (P interaction = 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.

© 2020 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Regional plot of the PPARA gene region. Each point represents one SNP. The base pair position on chromosome (chr) 22 (from 46.5 to 46.7 Mb) is on the x-axis, and the negative log transformation of the P value for interaction between each SNP and fenofibrate on the primary outcome is on the y-axis. The significance threshold (P = 6.2 × 10−4) after adjustment for multiple comparisons is indicated by the dashed line. Colors indicate the amount of linkage disequilibrium between plotted SNPs and rs6008845 (specific information of top SNPs can be found in Supplementary Table 2). Plots were generated using LocusZoom v1.1 (Abecasis Laboratory, University of Michigan School of Public Health).
Figure 2
Figure 2
rs6008845 association with primary outcome stratified by fenofibrate treatment in discovery and validation cohorts of subjects with type 2 diabetes and high cardiovascular risk. Note: the association between rs6008845 and the primary outcome is depicted as the effect per each T allele copy.
Figure 3
Figure 3
Fenofibrate cardiovascular effectiveness according to rs6008845 genotypes. Top panel: among all self-reported white subjects randomized to fenofibrate or placebo in the ACCORD-Lipid study. Middle and bottom panels: in the same population according to absence or presence of atherogenic dyslipidemia at baseline (a few subjects, N = 15, were not included due to missing data on lipid profile at baseline).
Figure 4
Figure 4
Effects of fenofibrate on changes in lipid levels among self-reported whites in ACCORD-Lipid, stratified by rs6008845 genotypes. Error bars represent SEs. One SD is equal to 5.4 mg/dL for HDL-c, 87.1 mg/dL for triglycerides, 35.2 mg/dL for total cholesterol, and 29.8 mg/dL for LDL cholesterol. To convert cholesterol values to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. Chol, cholesterol.
Figure 5
Figure 5
Fenofibrate effects on chemokine levels according to rs6008845 genotypes among self-reported whites from the ACCORD-MIND biomarker study. Error bars represent SEs.

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