A PPARA genetic variant (rs6008845) influences the cardiovascular effectiveness of the PPAR-alpha agonist fenofibrate independent of changes in lipid profile. Here we investigated whether the same variant influences fenofibrate effectiveness on diabetic retinopathy (DR) . This was evaluated with regard to DR progression in 592 subjects with prior DR history from the ACCORD Eye Study, and with regard to other pre-specified diabetic eye outcomes in the ACCORD Lipid Study (n=3,650) . The effect of fenofibrate on 93 inflammatory biomarkers was studied in 320 rs6008845 T/T homozygotes from ACCORD Lipid and a large retina-eQTL dataset (GtExEye) was used to evaluate the association between rs6008845 and PPARA expression and derive a Genetic Score (eQtGS) of PPARA expression in the retina. rs6008845 modulated fenofibrate effectiveness on DR progression in a way similar to that previously reported for MACE, with the largest benefit being in rs6008845 T/T (OR 0.10, 95% C.I. 0.02-0.74) and the smallest (OR 0.54, 95% C.I. 0.21-1.42) in C/C homozygotes (p for interaction = 0.01) . The same synergism was found for severe vision loss (p=0.03) . The T allele was associated with higher PPARA retinal expression (P=4×10-38) in GtExEye, and ACCORD subjects with higher eQtGS for PPARA expression had better response to fenofibrate on DR progression (P=0.008) . Among T/T homozygotes, fenofibrate caused a marked increase in serum FGF21 (+0.87 S.D.; 95% C.I. 0.67-1.07, P=10×10-13) . Each S.D. increase in log2 FGF21 was associated with a 45% lower risk of severe vision loss (HR 0.55; 95%C.I. 0.34-0.91, p=0.01) , explaining 90% of fenofibrate benefit on this outcome in T/T subjects (p=0.03) .
In conclusion,fenofibrate effectiveness on DR depends on genetic variants affecting PPARA expression and is mediated by an increase in serum FGF21 - a metabolic and anti-inflammatory cytokine that may therefore be a therapeutic target to treat diabetic eye disease.
M.Morieri: Advisory Panel; Merck Sharp & Dohme Corp., Consultant; neopharmed gentili, SLAPharma, Other Relationship; Lilly, Novo Nordisk, Servier Laboratories. H.Shah: None. Y.Tang: None. C.Mendonca: None. J.Jobe: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation.
NHLBI HL110400 e HL153559-Italian Ministry of Health - Ricerca Finalizzata - GR-2019-12369702.