Essential hypertension and Arg16Gly polymorphism of β₂-adrenergic receptor gene

Czech version

Authors: M. Jáchymová ¹; K. Horký ²; A. Jindra ¹; J. Peleška ³; J. Bultas ²; A. Linhart ²; Z. Hlubocká ²; S. Heller ²; M. Pavlikova ³
Authors‘ workplace: Laboratoř molekulární kardiologie Ústavu klinické biochemie a laboratorní diagnostiky 1. lékařské fakulty UK a VFN, Praha, přednosta prof. MUDr. Tomáš Zima, DrSc. ¹; II. interní klinika kardiologie a angiologie 1. lékařské fakulty UK a VFN, Praha, přednosta prof. MUDr. Michael Aschermann, DrSc., FESC ²; EuroMISE Centrum, Praha, přednostka prof. RNDr. Jana Zvárová, DrSc. ³
Published in: Vnitř Lék 2005; 51(9): 945-949
Category: Original Contributions

Overview

Study objective:
Sympathetic-adrenal activity plays important role in multifactorial pathogenesis of essential hypertension. Tissue effect of catecholamines is mediated by adrenergic receptors. Vasodilatation action of β₂-adrenergic receptors participates in BP regulation. Variations in their structure may lead to the limitation of vasodilatation efficiency and thereby to genesis of hypertension. Consequently polymorphism of β₂-adrenergic receptor gene seems to be a promising candidate gene for an analysis of its association with essential hypertension.

Patients’ population and methods:
In this study we investigated the effect of association of Arg16Gly polymorphism of β₂-adrenergic receptor gene with the incidence and degree of hypertension. We compared frequency of individual genotypes (GG, AG, AA) and alleles (G and A) in 3 groups of middle-aged individuals: a) a control group with normal BP ≤ 140/90 mm Hg (N, n = 122), b) patients with hypertension well-controlled with antihypertension treatment (KH, n = 156) and c) a group of hypertonic patients resistant to the combination of the three antihypertensives (RH, n = 73). We determined Arg16Gly polymorphism of β₂-adrenergic receptor gene by the PCR method on leukocyte DNA with subsequent incubation with restriction enzyme Ncol. We separated resulting fragments by means of electrophoresis on 3% Metaphore agarose gel stained with ethidium bromide. Kruskal-Wallis test (ANOVA), Fisher exact test, χ2 test and linear association test were used for statistical comparison of genotypes and alleles distribution between individual groups.

Results:
We did not find significant differences in representation of number of genotypes and allele frequency between individual monitored groups. However after pooling of KH and RH groups in one group (n = 229 patients) significant difference was found in allele frequency in pooled group of hypertonic patients versus normotonic patients (χ2 = 4.5, p = 0.035). This observation was in accord with the linear association test between the degree of hypertension and allele A incidence (5% significance level) with a shift to lower representation of allele A in higher degrees of hypertension (RH). During the evaluation of mean BP values the tendency to lower values of systolic and also diastolic BP was found, starting from GG genotype, over GA to AA genotype.

Conclusions:
Our recent observations support the hypothesis that genetic variation of β₂-adrenergic receptor gene (Arg16Gly polymorphism) can participate in affecting of BP level in combination with other factors and thus it can contribute to a genesis of the essential hypertension.

Key words:
essential hypertension – polymorphism – β₂-adrenergic receptor – pathogenetic participation

Sources

1. Arner P. Control of lipolysis and its relevance to development of obesity in man. Diab Met Rev 1988; 4: 507-515.

2. Bengtsson K, Orho-Melander M, Melander O et al. β2-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes. Hypertension 2001; 37: 1303-1308.

3. Busjahn A, Li GH, Faulhaber HD et al. β2-adrenergic receptor gene-variations, blood pressure, and heart size in normal twins. Hypertension 2000; 35: 555-560.

4. Dishy V, Sofowora GG, Xie HG et al. The effect of common polymorphisms of the β2- adrenergic receptor on agonist mediated vascular desensitization. N Engl J Med 2001; 345: 1030-1035.

5. Gratze G, Fortin J, Labugger R et al. β2-adrenergic receptor variants affects resting blood pressure and agonist-induced vasodilatation in young adult Caucasians. Hypertension 1999; 33: 1425-1430.

6. Heckbert SR, Hindorff LA, Edwards KL et al. β2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation 2003; 107: 2021-2024.

7. Hoit BD, Suresh DP, Craft L et al. β2-adrenergic receptor polymorphism at amino acid 16 differentially influence agonist stimulated blood pressure and peripheral blood flow in normal individuals. Am Heart J 2000; 139: 537-542.

8. Horký K. Genetické aspekty hypertenze. In: Souček M et al. Klinická patofyziologie hypertenze. Praha: Grada Publishing 2002: 17-20.

9. Iacarino G, Lanni F, Cipolleta E et al. The Glu27 allel of the beta2 adrenergic receptor increases the risk of cardiac hypertrophy in hypertension. J Hypertens 2004; 22: 2117-2122.

10. Jachymova M, Horky K, Bultas J et al. Association of the Glu298Asp polymorphisms in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy. Bioch Biophys Res Comm 2001; 284: 426-430.

11. Jia H, Sharma P, Hopper R et al. β2 adrenoceptor gene polymorphisms and blood pressure variations in East Anglian Caucasians. J Hypertens 2000; 18: 687-693.

12. Jindra A, Horky K, Peleska J et al. Association analysis of Arg16Gly polymorphism of the beta2-adrenergic receptor gene in offspring from hypertensive and normotensive families. Blood Pressure 2002; 11: 213-217.

13. Julius S. The evidence for a pathophysiologic significance of the sympathetic overactivity in hypertension. Clin Exp Hypertens 1996; 18: 305-321.

14. Kotanko P, Binder A, Tasker J et al. Essential hypertension in African Carribeans associates with a variant of the β2-adrenoceptor. Hypertension 1997; 30: 773-776.

15. Lafontan M, Barbe P, Galitzky J et al. Adrenergic regulation of adipocyte metabolism. Hum Reprod 1997; 12(Suppl I): 6-20.

16. Lee YW, Oh VMS, Garcia E et al. Haplotypes of the beta2-adrenergic receptor gene are associated with essential hypertension in a Singaporean Chinese population. J Hypertens 2004; 22: 211-2116.

17. Linhart A, Jindra A, Golan L et al. Associations between tyrosine hydoxylase polymorphisms and left ventricular structure in young normotensive men. Brit J Biochem Science 2002; 59: 90-94.

18. McGraw DW, Forbes SL, Kramer LA et al. Polymorphisms of the 5´ leader cistron of the human β2-adrenergic receptor regulate receptor expression. J Clin Invest 1998; 102: 1927-1932.

19. Pereira AC, Floriano MS, Mota GF et al. β2-adrenoceptor functional gene variants, obesity, and blood pressure levels interactions in general population. Hypertension 2003; 42: 685-692.

20. Reihsaus E, Innis M, MacIntyre N et al. Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8: 334-339.

21. Snieder H, Dong Y, Barbeau P et al. β2-adrenergic receptor gene and resting hemodynamics in European and African American youth. Am J Hypertens 2002; 15: 973-979.

22. Timmermann B, Mo R, Luft FC et al. β2-adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study. Kidney Int 1998; 53: 1455-1460.

23. Tomaszewski M, Brain NJR, Charchar FJ et al. Essential hypertension and β2-adrenergic receptor gene. Linkage and association analysis. Hypertension 2002; 40: 286-291.

24. Xie HG, Stein M, Kim RB et al. Human beta2-adrenergic receptor polymorphisms: no association with essential hypertension in black or white Americans. Clin Pharmacol Ther 2000; 67: 670-675.