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β₂-Adrenergic Receptor Gene Polymorphism Is Associated with Mortality in Septic Shock

¹ University of British Columbia Critical Care Research Laboratories, Heart + Lung Institute, St. Paul's Hospital, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Keith R. Walley, M.D., Critical Care Research Laboratories, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. E-mail: keith.walley{at}hli.ubc.ca

Rationale: The CysGlyGln haplotype of the β₂-adrenergic receptor gene (ADRB2) is functional and associated with altered responses to adrenergic agonists in patients with asthma. Whether this functional haplotype alters outcome in patients receiving adrenergic agonists in septic shock is unknown.

Objectives: To determine whether genetic variation of ADRB2 influences outcome in septic shock.

Methods: Two cohorts of patients with septic shock were studied: a single center (St. Paul's Hospital [SPH]) cohort (n = 589) and the Vasopressin and Septic Shock Trial (VASST) cohort (n = 616). The A allele of the rs1042717 G/A polymorphism is in complete linkage disequilibrium with the CysGlyGln haplotype of ADRB2; therefore, rs1042717 was genotyped. Modulation by norepinephrine and salbutamol of IL-6 production by stimulated in vitro lymphoblastoid cells was measured by genotype.

Measurements and Main Results: Patients who had the AA genotype of rs1042717 displayed increased 28-day mortality in SPH (adjusted hazard ratio, 2.23; 95% confidence interval, 1.33–3.72; P = 0.0022), and this result was replicated in VASST (adjusted hazard ratio 2.82; 95% confidence interval, 1.56–5.09; P = 0.0006). This genotypic effect was eliminated in patients treated with acute low-dose corticosteroids. In all patients, the AA genotype was associated with more organ dysfunction. Patients with the AA genotype had a higher heart rate (SPH; P < 0.05; VASST; P < 0.05) and required a higher norepinephrine dose over Days 1 through 3 (VASST; P < 0.05). The AA genotype was associated with decreased norepinephrine and salbutamol inhibition of IL-6 production by stimulated lymphoblastoid cells in vitro (P < 0.05).

Conclusions: The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

Key Words: single nucleotide polymorphisms • septic shock • genetic association study • lymphoblastoid cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Adrenergic agonist therapy is a cornerstone of cardiovascular management of septic shock. The β2-adrenergic receptor (ADRB2) is involved in regulation of the cardiopulmonary system and exerts antiinflammatory effects. Functional effects of several single-nucleotide polymorphisms of the ADRB2 gene have been demonstrated in vitro and in vivo. What This Study Adds to the Field The AA genotype of ADRB2 gene polymorphism rs1042717, marking the CysGlyGln haplotype of ADRB2, was associated with increased mortality, more organ dysfunction, and a higher heart rate and a higher dose of norepinephrine infusion in septic patients with shock. The same genotype demonstrated reduced antiinflammatory effects as measured by norepinephrine or salbutamol inhibition of IL-6 production in in vitro stimulated lymphoblastoid cells.