G16R single nucleotide polymorphism but not haplotypes of the β2-adrenergic receptor gene alters cardiac output in humans

Variation in genes encoding the,beta(2)-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence (Q) over dot (cardiac output). The 46G > A (G16R) SNP (single nucleotide polymorphism) has been associated with beta(2)-mediated vasodilation, but the effect of ADRB2 haplotypes on (Q) over dot has not been studied. Five SNPs within ADRB2 (46G > A, 79C> G, 491C > T, 523C > A and 1053G > C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise. Only the G16R polymorphism was associated with (Q) over dot. In carriers of the Arg(16) allele, (Q) over dot(rest) (resting (Q) over dot) was 0.4 [95% Cl (confidence interval), 0.0-0.7] l/min lower than in G16G homozygotes (P=0.048). During exercise, the increase in (Q) over dot was by 4.7 (95% Cl, 4.3-5.2) l/min per litre increase in pulmonary (V) over doto(2) (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0-0.9) l/min lower in Arg(16) carriers (P=0.035). A similar effect size was observed for the Arg(16) haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in (Q) over dot was 0.5 (Cl, 0.0 1.0) l/mm greater in ACE I/I carriers compared with I/D and D/D subjects (P=0.054). In conclusion, the ADRB2 Arg(16) allele in humans is associated with a lower (Q) over dot both at rest and during exercise, overriding the effects of haplotypes.