A single nucleotide polymorphism within the RXRA gene predicts a favorable response to exercise in heart failure.
Bryson T, Debbs JC, She R, Gui H, Luzum JA, Zeld N, Brawner CA, Keteyian SJ, Ehrman JK, Williams LK, and Lanfear DE. A single nucleotide polymorphism within the rxra gene predicts a favorable response to exercise in heart failure. Journal of the American College of Cardiology 2020; 75(11):1012.
J Am Coll Cardiol
Background Heart failure (HF) is a morbid condition associated with impaired exercise capacity. Exercise training is an effective strategy to improve functional capacity and quality of life. However, response to exercise training is highly variable and whether there are genetic factors that may impact response to exercise is unknown. We sought to identify genetic variants in patients with HF participating in cardiac rehabilitation (CR) that are associated with improvement in exercise capacity. Methods The study was conducted at Henry Ford Hospital in Detroit, MI. Patients enrolled in our genomic HF registry who had participated in CR at any time were selected (n=211). The primary endpoint was the change in metabolic equivalents of task (ΔMET) during CR, from week 1 to the last week of CR. All patients were genotyped using the Axiom biobank genotyping array with imputation using 1000 genomes reference panels (filter at R2 = 0.5 in both European and African ancestry). Genome-wide association testing was performed in linear models of ΔMET adjusted for baseline peak VO2, sex, age, and the first principal component (to control for race/population stratification). p<5×10−8 was considered statistically significant. Results The study cohort consisted of 135 African ancestry and 76 European ancestry patients and 36.5% were women. One SNP, rs11103633, met genome-wide significance (p = 8.86 × 10−12). Each additional allele was associated with 2.4 MET greater improvement (std err. = 0.331, p = 8.859 × 10−12). This SNP, in the retinoid x receptor A gene (RXRA), encodes an orphan nuclear receptor belonging to the steroid super-family and acts in a variety of cellular processes. In cardiac and skeletal muscle, RXRA, is the necessary binding partner of PPARA, a key regulator of mitochondrial proliferation and fatty acid oxidation. Conclusion A genetic variant in the RXRA gene appears to impact the beneficial effect of exercise training in HF patients and could act via influencing cellular energetic capacity. This finding could lead to targeted exercise therapy or to novel pharmacologic methods of improving exercise response in HF patients. External validation and investigation of possible mechanisms are needed.