期刊
DIABETES
卷 69, 期 4, 页码 771-783出版社
AMER DIABETES ASSOC
DOI: 10.2337/db19-0973
关键词
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资金
- National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) [HL110400, HL110380]
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH [DK36836]
- National Center for Advancing Translational Sciences (NCATS), NIH [UL1TR001111]
- NHLBI [HL110418, N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, Y1HC-9035, Y1-HC-1010]
- William Randolph Hearst Fellowship by the Hearst Foundation
- FONDAZIONE S.I.S.A.
- Italian Ministry of Health
- Italian Ministry of University and Research (PRIN 2015)
- Fondazione Roma (Biomedical Research: Non-Communicable Diseases 2013 grant)
- McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care
- Intramural Research Program of the National Institute of Environmental Health Sciences, NIH
- NIH [R01 NR013396]
- NIH: Washington University School of Medicine Specialized Centers of Clinically Oriented Research (SCCOR) [P50 HL077113]
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute on Aging
- National Eye Institute
- Centers for Disease Control and Prevention
- General Clinical Research Centers
- Clinical and Translational Science Awards
- Office of the Director of the NIH
- National Cancer Institute
- National Human Genome Research Institute
- National Institute on Drug Abuse
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- NATIONAL EYE INSTITUTE [ZIAEY000410] Funding Source: NIH RePORTER
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-alpha), 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 x 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.
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