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

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.

Figure 1.. Study cohorts.

This ancillary study included 161 (126 white, non-Hispanic) of the 303 participants of the main randomized trial who were assigned to atenolol, and 162 (124 white, non-Hispanic) of the 305 participants assigned to losartan. For atenolol the 161 enrolled included 13 Hispanic, 13 Black, and 9 of other race/ethnicity who were excluded from the primary analysis due to small group size; Similarly, the 162 enrolled in the Losartan group had 19 Hispanic, 10 Black, and 9 of other race/ethnicity who were excluded from the primary analysis.

Figure 3.. Predicted baseline-adjusted change in maximum aortic-root z-score over time for atenolol and losartan assignment by ADRB1-rs1801253 genotype.

The model-predicted aortic-root z-score is plotted on the y-axis and time since randomization on the x-axis. The atenolol group is shown in red and the losartan group in blue. Shading indicates 95% pointwise confidence bands. The genotype × treatment × time interaction p=0.002. The left panel shows individuals with CC genotype for ADRB1-rs1801253 (slope=−0.20±0.02 for atenolol and −0.07±0.02 for losartan, p<0.001 for difference in slope). The right panel shows individuals with the CG or GG genotype for ADRB1-rs1801253 (no significant difference in slope).