The impact of ADRB2 polymorphisms on immune responses and norepinephrine-induced immunosuppression

Rationale: To evaluate whether common nonsynonymous variants [single-nucleotide polymorphisms (SNPs) or SNP haplotypes] in the beta 2-adrenergic receptor render subjects more susceptible to norepinephrine-induced immunosuppression and whether they are associated with dysregulated ex vivo and in vivo inflammatory responses. Methods: Peripheral blood mononuclear cells from healthy volunteers (main cohort: n = 106, secondary cohort: n = 408) were ex vivo stimulated with various stimuli and production of cytokines was assessed. Additionally, ex vivo modulation of cytokine production by norepinephrine was evaluated in the main cohort. Volunteers from the main cohort also underwent experimental endotoxemia (administration of 1 ng/kg lipopolysaccharide), during which in vivo plasma cytokine concentrations and clinical inflammatory parameters were measured. Subjects were genotyped, common SNPs in the ADRB2 gene were extracted (rs1042711, rs1042713, and rs1042714), and the presence of haplotypes was identified (CysGlyGln, CysArgGln, and ArgGlyGlu). Results: In both cohorts, presence of ADRB2 SNPs or haplotypes was not associated with altered ex vivo cytokine responses. Norepinephrine attenuated production of the proinflammatory cytokines TNF and IL-6 [-26% (-22% to -30%) and -14% (-9% to -18%), respectively, both P < 0.0001] and enhanced release of the anti-inflammatory IL-10 [+9% (+3% to +15%), P = 0.003]. These effects were not modulated by the presence of ADRB2 SNPs or haplotypes (all P values > 0.37). In addition, no influence of SNPs or haplotypes on in vivo cytokine concentrations or clinical inflammatory parameters was observed (P values > 0.14). Conclusions: Common nonsynonymous variants in the ADRB2 gene influence neither ex vivo cytokine production or norepinephrine-mediated immunosuppression nor the systemic in vivo inflammatory response induced by lipopolysaccharide administration in healthy volunteers.

Automated summary

This study aimed to evaluate the association between common nonsynonymous variants in the beta 2-adrenergic receptor gene and norepinephrine-induced immunosuppression and dysregulated inflammatory responses. The results showed that these variants did not affect cytokine production, norepinephrine-mediated immunosuppression, or the systemic inflammatory response in healthy volunteers.