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

Variation in genes encoding the β₂-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q̇ (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with β₂-mediated vasodilation, but the effect of ADRB2 haplotypes on Q̇ 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 Q̇. In carriers of the Arg¹⁶ allele, Q̇_rest (resting Q̇) was 0.4 [95% CI (confidence interval), 0.0–0.7] l/min lower than in G16G homozygotes (P=0.048). During exercise, the increase in Q̇ was by 4.7 (95% CI, 4.3–5.2) l/min per litre increase in pulmonary V̇O₂ (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0–0.9) l/min lower in Arg¹⁶ carriers (P=0.035). A similar effect size was observed for the Arg¹⁶ haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in Q̇ was 0.5 (CI, 0.0 –1.0) l/min greater in ACE I/I carriers compared with I/D and D/D subjects (P=0.054). In conclusion, the ADRB2 Arg¹⁶ allele in humans is associated with a lower Q̇ both at rest and during exercise, overriding the effects of haplotypes.