beta2-Adrenergic receptor gene polymorphism is associated with mortality in septic shock.
BACKGROUND
The CysGlyGln haplotype of the beta(2)-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.


OBJECTIVE
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.


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.
Nakada
Taka-Aki
TA
Critical Care Research Laboratories, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Russell
James A
JA
Boyd
John H
JH
Aguirre-Hernandez
Rosalia
R
Thain
Katherine R
KR
Thair
Simone A
SA
Nakada
Emiri
E
McConechy
Melissa
M
Walley
Keith R
KR
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000483:Alleles; D001955:British Columbia; D002478:Cells, Cultured / Q000187:drug effects; D002648:Child; D015331:Cohort Studies; D004311:Double-Blind Method; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009638:Norepinephrine / Q000627:therapeutic use; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012307:Risk Factors; D012772:Shock, Septic / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D014662:Vasoconstrictor Agents / Q000627:therapeutic use; D014667:Vasopressins / Q000627:therapeutic use; D000093242:Interleukin-6 Inhibitors
D000316:Adrenergic alpha-Agonists; D009638:Norepinephrine; D018343:Receptors, Adrenergic, beta-2; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D000093242:Interleukin-6 Inhibitors