Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome

J Pediatr. 2020 Jul;222:213-220.e5. doi: 10.1016/j.jpeds.2020.03.064.

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.

Keywords: angiotensin II receptor blocker; aortic root dissection; beta-adrenergic receptor blocker; personalized medicine; pharmacogenetics; pharmacogenomics.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adrenergic beta-1 Receptor Antagonists / therapeutic use
  • Adult
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Atenolol / therapeutic use*
  • Child
  • Child, Preschool
  • Cytochrome P-450 CYP2C9 / biosynthesis
  • Cytochrome P-450 CYP2C9 / genetics*
  • DNA / genetics
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation*
  • Genotype
  • Humans
  • Infant
  • Losartan / therapeutic use*
  • Male
  • Marfan Syndrome / drug therapy*
  • Marfan Syndrome / genetics
  • Marfan Syndrome / metabolism
  • Receptors, Adrenergic, beta-1 / biosynthesis
  • Receptors, Adrenergic, beta-1 / genetics*
  • Retrospective Studies
  • Young Adult

Substances

  • ADRB1 protein, human
  • Adrenergic beta-1 Receptor Antagonists
  • Angiotensin II Type 1 Receptor Blockers
  • Receptors, Adrenergic, beta-1
  • Atenolol
  • DNA
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Losartan