β-2 Adrenergic Receptor Gene Variations, Blood Pressure, and Heart Size in Normal Twins

Abstract

Abstract-Genetic variability, which influences cardiovascular phenotypes in normal persons, is likely to be relevant to cardiovascular disease. We studied normal monozygotic and dizygotic twins and found strong genetic influences on blood pressure and heart size. We then relied on the dizygotic twins and their parents to apply molecular genetic techniques. We performed a linkage analysis with markers close to the ␤-2 adrenergic receptor (AR) gene locus in the dizygotic twins and their parents and found strong evidence for linkage to the quantitative traits of blood pressure and heart size. We then used allele-specific polymerase chain reaction to genotype the subjects further. We performed an association analysis and found that 4 functionally relevant polymorphisms in the ␤-2 AR gene, namely Arg16/Gly, Gln27/Glu, Thr164/Ile, and a variant in the promoter region (Ϫ47C/T), were variably associated with blood pressure and heart size differences but were in linkage dysequilibrium with each other. A subsequent conditional analysis suggested that the Arg16/Gly polymorphism exerted the predominant effect. These findings underscore the importance of the ␤-2 AR gene to blood pressure regulation, heart size, and probably to the development of hypertension. We suggest that a combined linkage and association approach will elucidate the genetic variability influencing blood pressure and other cardiovascular phenotypes. (Hypertension. 2000;35:555-560.)Key Words: receptors, adrenergic, beta Ⅲ genetics Ⅲ hypertension, genetic Ⅲ twins Ⅲ blood pressure T he ␤-2 adrenergic receptor (␤-2 AR) has been implicated in the pathogenesis of hypertension, both on the basis of studies suggesting altered ␤-2-mediated vasodilation 1 and on the basis of molecular genetic association studies. 2,3 Recently, Kotanko et al 4 found an association between the Arg16/Gly polymorphism in the ␤-2 AR gene and hypertension in an African Caribbean population. They showed that the Gly16 allele was more common in hypertensive subjects than in normotensive African Caribbean control subjects. Since the Gly16 allele indicates an increased propensity for downregulation of the receptor, 5 the authors raised the possibility that an impaired vasodilation in peripheral arteries in response to ␤-2 AR agonists may play a role in the hypertension of individuals carrying the Gly16 allele. We subsequently examined the firstborn normotensive adult children of couples documented to be normotensive or hypertensive in the Bergen Blood Pressure Study. 6 Offspring of 2 hypertensive parents had higher blood pressures and a preponderance of the Arg16 allele compared with offspring of 2 normotensive parents. To further examine the genetic variability at the ␤-2 AR locus and its relevance for the cardiovascular system in northern Europeans, we performed a combined linkage and association study in normotensive twin subjects. We used allele-specific polymerase chain reaction (PCR), which allowed us to examine other polymorphisms in the ␤-2 AR gene. MethodsWe recruited 166 pairs of t...

Studies of the associations between functional β2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects

“…In studies of quantitative traits the Gly allele carriers had increased systolic blood pressure and the Glu allele carriers of the Gln27Glu variant had an increase in systolic blood pressure. These associations were weak and when considering adjustment for multiple testing these associations become insignificant; however, both observations are consistent with earlier findings [10,15].…”

“…The same ambiguity is observed when the two variants are examined in relation to hypertension [9,10,[12][13][14][15] and type 2 diabetes [2,5,9,14,[16][17][18].…”

Genetics of arterial hypertension and hypotension

“…The β2AR polymorphisms accounted for ∼2% of the observed variation in blood pressure (Bray et al 2000). While results of some groups confirmed the association between the 16Gly allele and blood pressure (Kotanko et al 1997;Rosmond et al 2000;Gratze et al 1999), others found opposite effects, i.e., an association between the 16Arg allele and hypertension (Busjahn et al 2000;Bengtsson et al 2001a,b;Timmermann et al 1998) or no effects at all (Herrmann et al 2002;Kato et al 2001;Xie et al 2000; for a recent meta-analysis see Hahntow et al 2006). Again, differing inclusion of haplotypes, variations in ethnicities and different study designs may contribute to these sobering results.…”

Genetic polymorphisms and heart failure

“…A study in normotensive twins indicated that all three polymorphisms might be associated with ventricular wall thickness. 92 However, other studies have failed to detect any association between the Arg16Gly and Gln27Glu polymorphisms and cardiac dimensions. [95][96][97] These studies did not investigate the role of the Thr164Ile variant.…”

“…90 There is marked linkage disequilibrium between these two polymorphisms. 92 The Gly16 receptor displays enhanced agonist-promoted downregulation, whereas the Glu27 form is resistant to downregulation. 90,93 Two studies have investigated the effect of ␤ 2 -adrenergic polymorphisms in heart failure.…”