The Beta‐Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants

Figures

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  FIGURE 1. Pharmacogenetic interactions and associations of time‐varying beta‐blocker exposure with all‐cause mortality stratified by the GRK4 genotypes and haplotype in 454 African American HFrEF patients. Arg65Leu = rs2960306; Ala142Val = rs1024323; Ala486Val = rs1801058. BB = beta‐blocker. Underlined alleles decrease adrenergic activity (Table 1) and are therefore expected to decrease beta‐blocker‐associated survival benefit (i.e., have a higher hazard ratio [HR] than the alternate allele). Models were adjusted for beta‐blocker propensity score [29], MAGGIC (minus beta‐blocker as an input variable) [28], and proportion of YRI (Yoruba in Ibadan, Nigeria) ancestry [25]. “P cor.” refers to the p‐value after correction for multiple comparisons by the adaptive Hochberg method [30]. “n” refers to the number of patients in the corresponding analysis. p < 0.1 for interaction tests after correction for multiple comparisons was a priori defined as statistically significant. Bolded p‐values met this definition for statistical significance. The x‐axis is on logarithmic scale. Black squares indicate the HR, and horizontal black lines indicate the 95% confidence intervals. The vertical dotted black…

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  FIGURE 2. Pharmacogenetic interactions and associations of time‐varying beta‐blocker exposure with all‐cause mortality stratified by ADRB1 Ser49Gly and Arg389Gly genotypes and haplotype in 893 African American and White HFrEF patients. Ser49Gly = rs1801252 and Arg389Gly = rs1801253. BB = beta‐blocker. Underlined alleles decrease adrenergic activity (Table 1) and are therefore expected to decrease beta‐blocker‐associated survival benefit (i.e., have a higher hazard ratio [HR] than the alternate allele). Models were adjusted for beta‐blocker propensity score [29], MAGGIC (minus beta‐blocker as an input variable) [28], and proportion of YRI (Yoruba in Ibadan, Nigeria) ancestry [25]. “P cor.” refers to the p‐value after correction for multiple comparisons by the adaptive Hochberg method [30]. “n” refers to the number of patients in the corresponding analysis. p < 0.1 for interaction tests after correction for multiple comparisons was a priori defined as statistically significant. The x‐axis is on logarithmic scale. Black squares indicate the HR, and horizontal black lines indicate the 95% confidence intervals. The vertical dotted black line indicates HR = 1.

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  FIGURE 3. Pharmacogenetic interactions and associations of time‐varying beta‐blocker exposure with all‐cause mortality stratified by the ADRA2C Ins/Del322‐325 genotypes in 454 African American HFrEF patients. Rs7434630 (C > T) was used as a proxy for the ADRA2C Ins > Del322‐325 variant rs61767072. BB = beta‐blocker. Underlined alleles decrease adrenergic activity (Table 1) and are therefore expected to decrease beta‐blocker‐associated survival benefit (i.e., have a higher hazard ratio [HR] than the alternate allele). Models were adjusted for beta‐blocker propensity score [29], MAGGIC (minus beta‐blocker as an input variable) [28], and proportion of YRI (Yoruba in Ibadan, Nigeria) ancestry [25]. “P cor.” refers to the p‐value after correction for multiple comparisons by the adaptive Hochberg method [30]. “n” refers to the number of patients in the corresponding analysis. p < 0.1 for interaction tests after correction for multiple comparisons was a priori defined as statistically significant. The x‐axis is on logarithmic scale. Black squares indicate the HR, and horizontal black lines indicate the 95% confidence intervals. The vertical dotted black line indicates HR = 1.