Sara L Van Driest1, Lynn A Sleeper2, Bruce D Gelb3, Shaine A Morris4, Harry C Dietz5, Geoffrey A Forbus6, Elizabeth Goldmuntz7, Arvind Hoskoppal8, Jeanne James9, Teresa M Lee10, Jami C Levine2, Jennifer S Li11, Bart L Loeys12, Larry W Markham13, Josephina A N Meester12, Seema Mital14, Jonathan D Mosley15, Aaron K Olson16, Marjolijn Renard17, Christian M Shaffer15, Angela Sharkey18, Luciana Young19, Ronald V Lacro2, Dan M Roden20. 1. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. 2. Department of Cardiology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA. 3. Mindich Child Health and Development Institute, Departments of Pediatrics and Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY. 4. Division of Cardiology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX. 5. Institute of Genetic Medicine, Johns Hopkins University School of Medicine and Howard Hughes Medical Institute, Baltimore, MD. 6. Department of Pediatrics, Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, SC. 7. Division of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics University of Pennsylvania Perlman School of Medicine, Philadelphia, PA. 8. Departments of Pediatrics and Internal Medicine, University of Utah and Intermountain Healthcare, Salt Lake City, UT. 9. Department of Pediatrics, Section of Cardiology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI. 10. Department of Pediatrics, Columbia University Medical Center, New York, NY. 11. Department of Pediatrics, Division of Cardiology, Duke University Medical Center, Durham, NC. 12. Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium. 13. Department of Pediatrics, Division of Pediatric Cardiology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN. 14. Department of Pediatrics, Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 15. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. 16. Department of Pediatrics, Seattle Children's Hospital, Seattle, WA. 17. Center for Medical Genetics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. 18. Department of Pediatrics, Washington University, St. Louis, MO. 19. Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital, Chicago, IL. 20. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Departments of Pharmacology and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.
Abstract
OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
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