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ORIGINAL ARTICLE
Year : 2014  |  Volume : 62  |  Issue : 2  |  Page : 183-188

Association of genetic polymorphisms at beta-adrenergic receptor with risk of intracerebral hemorrhagic stroke in North Indian population: A case control study


1 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Neurobiochemistry, All India Institute of Medical Sciences, New Delhi, India

Date of Submission16-Jan-2014
Date of Decision07-Feb-2014
Date of Acceptance06-Apr-2014
Date of Web Publication14-May-2014

Correspondence Address:
Kameshwar Prasad
Department of Neurology, Clinical Epidemiology Unit, Room No. 704, Neurosciences Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.132383

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 » Abstract 

Background: Stroke is a multifactorial, polygenic disorder, influenced by both environmental and genetic factors. Aim: The purpose of this study was to determine the association of beta-1 and beta-2 adrenergic receptor (AR) polymorphisms with intracerebral hemorrhagic stroke (ICH) in a North Indian population. Materials and Methods: One hundred and six patients with intracerebral hemorrhage (ICH) and 106 age- and sex- matched controls were recruited. Genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RFLP results of three samples of each genotype were confirmed by DNA sequencing. Results: Mean age of cases and controls were 53.47 ± 14 and 52.92 ± 13.4, respectively. Significant association between Ser49Gly polymorphism of beta-1 AR and ICH in patients who had onset of disease at a later stage of life (>50 years) under a dominant model of inheritance (OR, 3.6; 95% 1.4 to 9.7) was observed. Under the dominant model of inheritance, Gln27Glu polymorphism of beta-2 AR was associated with risk of ICH (OR, 3.2; 95% CI, 1.7 to 5.8) and significant association persisted even after adjustment for demographic and other risk factor variables (OR, 2.9; 95% CI, 1.04 to 8; P = 0.04). Age-stratified analysis showed an independent significant association of Gln27Glu polymorphism of beta-2 AR with risk of ICH in patients those had onset of disease at young age (<50 years) under a dominant model of inheritance (OR, 3.5; 95% CI, 1.1 to 11). Conclusion: The present study provides the first preliminary evidence that Gln27Glu polymorphism of beta-2 AR may contribute modest effect in increase in risk of ICH in North Indian Population. Large prospective studies with large sample size are required to confirm these findings.


Keywords: Beta-adrenergic receptor polymorphism, hemorrhagic stroke, intracerebral hemorrhage, North India, North Indian population


How to cite this article:
Kumar A, Prasad K, Tripathi M, Padma Srivastava MV, Vivekanadhan S. Association of genetic polymorphisms at beta-adrenergic receptor with risk of intracerebral hemorrhagic stroke in North Indian population: A case control study. Neurol India 2014;62:183-8

How to cite this URL:
Kumar A, Prasad K, Tripathi M, Padma Srivastava MV, Vivekanadhan S. Association of genetic polymorphisms at beta-adrenergic receptor with risk of intracerebral hemorrhagic stroke in North Indian population: A case control study. Neurol India [serial online] 2014 [cited 2021 May 15];62:183-8. Available from: https://www.neurologyindia.com/text.asp?2014/62/2/183/132383



 » Introduction Top


Stroke is the second most common cause of death after ischemic heart disease. [1] It is a multifactorial, polygenic disorder, influenced by both environmental and genetic factors. Animal model studies, twin and family-based association studies have suggested the substantial genetic component of stroke. [2] Around 10% of hemorrhagic stroke patients have a family history of stroke, [3] which suggests a substantial genetic contribution to hemorrhagic stroke. The beta-adrenergic receptor (AR), a member of the G protein-coupled receptors, mediates the catecholamine-induced activation of adenylate cyclase through activation of G protein and thereby plays an important role in regulation of various cellular functions, for example, smooth muscle relaxation. Beta-adrenergic receptors play an important role in modulating a variety of target cell response to catecholamine. The level of circulating catecholamine often increases after hemorrhage. [4] In addition, the contractile response of human cerebral arteries to norepinephrine is larger than responses in other species. [5] Thus, neurogenic factors in controlling brain circulation would play an important role in pathological conditions such as hemorrhage. There is evidence of existence of beta-1 and beta-2 ARs in the human brain. [6] Four of functional polymorphisms (Ser49Gly and Arg389Gly location of beta-1 and Arg16Gly and Gln27Glu location of beta-2 AR polymorphism) have been studied consistently in several cardiovascular and non-cardiovascular diseases. [7],[8] The Arg389Gly polymorphism of beta-1 AR results in impaired coupling to G stimulatory (Gs) component of G-protein and, therefore, show less response to agonist, and the Ser49Gly variant of beta-1 AR show increased desensitization after exposure to agonist in vitro. [9] An enhanced agonist-mediated receptor down-regulation for the Gly16 variant of Arg16Gly of beta-2 AR and a resistance to down-regulation for the Glu27 variant of Gln27Glu polymorphism of beta-2 AR has been observed. [10] These are well studied polymorphisms that result in functional changes in receptor function in both in-vitro and in vivo studies; therefore, polymorphisms in beta-1 and beta-2 AR may influence the certain intermediate mechanism for the predisposition of cardiovascular and cerebrovascular diseases could be hypothesized. In this regard, this polymorphism is directly implicated in several cardiovascular and non-cardiovascular diseases, though with some controversy including hypertension, [11],[12] diabetes, [13] and myocardial infarction. [14] The association of these polymorphisms with ICH has not been determined yet up to the best of our knowledge. The present study was the first study to determine whether these polymorphisms can predict the risk of ICH.


 » Materials and Methods Top


In this study, 106 patients with ICH and 106 age- and sex- matched control subjects were enrolled from the ward and outpatient department of Neurology, All India Institute of Medical sciences (AIIMS), New Delhi, India from the period of February 2010 to April 2012. All subjects underwent standardized clinical evaluations. The study was approved by the local institutional ethics committee. Informed consent was obtained from each patient/control or from the relatives or a legal authorized representative in the case of critically disabled patients. Inclusion and exclusion criteria for cases and controls [15] and definition of variables are same as in the published study. [16]

Genotyping

The polymorphisms of beta-adrenergic receptor were genotyped by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). [17] RFLP results of three samples of each genotype were confirmed by DNA sequencing [Figure 1] and [Figure 2].
Figure 1: DNA sequencing chromatogram for determination of polymorphisms at Ser49Gly and Arg389Gly positions of beta-1 adrenergic receptor

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Figure 2: DNA sequencing chromatogram for determination of polymorphisms at Arg16Gly and Gln27Glu positions of beta-2 adrenergic receptor

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Statistical analyses

The conditional logistic regression model was used to estimate odds ratio (OR) and 95% confidence intervals (CIs) for association of beta-1 and beta-2 receptor polymorphisms with ICH. Due to significant differences in demographic and risk factor variables between cases and control participants, a multivariable conditional logistic regression analysis was performed that included the beta-1 and beta-2 AR polymorphism and potential confounders. Tests were considered significant at P < 0.05. Chi-square test was used to determine the frequency distribution of genotypes were in accordance with Hardy-Weinberg equilibrium (HWE). Data was analyzed using the SPSS statistical package, version 17.0 (SPSS, Chicago, IL, USA).


 » Results Top


One hundred six cases and 106 age- and sex- matched control subjects were recruited. Sixty nine were males, and 37 were females. The mean age of patients at the time of stroke onset was 53.47 ΁ 14 and at the time of recruitment of controls was 52.92 ΁ 13.1. Conditional logistic regression analysis of demographic and risk factor variables of ICH are given in [Table 1]. There was no significant association between Ser49Gly variant of beta-1 AR and risk of ICH [Table 2]. Analysis stratified by age showed significant association between Ser49Gly polymorphism of beta-1 AR and ICH in patients who had onset of disease at a later stage of life (>50 years) under a dominant model of inheritance (OR, 3.6; 95% 1.4 to 9.7) [Table 3]. There was no significant association between Arg389Gly variants of beta-1 AR and risk of ICH [Table 2] and [Table 3]. There was no significant association between Arg16Gly variant of beta-2 AR and risk of ICH [Table 2] and [Table 4]. Glu27Glu genotype of beta-2 AR was associated with an increase in risk of ICH under a recessive model of inheritance (OR, 3.8; 95% CI, 1.6 to 8.8) [Table 2]. However, the association became non-significant when demographic and other risk factor variables were controlled. Under the dominant model of inheritance, Gln27Glu polymorphism of beta-2 AR was associated with risk of ICH (OR, 3.2; 95% CI, 1.7 to 5.8), and significant association persisted even after adjustment for demographic and other risk factor variables (OR, 2.9; 95% CI, 1.04 to 8; P = 0.04) [Table 2]. Analysis stratified by hypertension showed significant independent association between Glu27Gln polymorphism of beta-2 AR and ICH in both hypertensive and non-hypertensive group [Table 4]. Age-stratified analysis showed an independent significant association of Gln27Glu polymorphism of beta-2 AR with risk of ICH in patients those had onset of disease at young stage under a dominant model of inheritance (OR, 3.5; 95% CI, 1.1 to 11) [Table 4]. There were no deviations of the genotype frequencies from those predicted by the Hardy-Weinberg equilibrium for any of polymorphism.
Table 1: Conditional logistic regression analysis of demographic and risk factor variables

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Table 2: Conditional logistic regression analysis of association of beta-1 and beta-2 AR polymorphisms with ICH

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Table 3: Analysis stratified by hypertension and age for association of polymorphism at beta-1 adrenergic receptor gene with ICH

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Table 4: Analysis stratified by hypertension and age for association of polymorphism at beta-2 adrenergic receptor gene with hemorrhagic stroke

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 » Discussion Top


In the present study, we investigated the association of beta-1 AR (Ser49Gly and Arg389Gly) polymorphism and beta-2 AR (Arg16Gly and Gln27Glu) polymorphisms with ICH. A common functional Gln27Glu polymorphism of beta-2 AR was found to be associated with more than two-fold increase in risk of ICH.

Examining the association between Ser49Gly polymorphism of beta-1 AR and ICH suggest that substitution of Glycine for Serine at the 49 th position of the amino acid chain was significantly associated with ICH in those subjects who had late onset (>50 years) of the disease under the dominant model of inheritance in multivariate analysis. This finding suggests that age differences may also contribute to the disparity of genetic association of Ser49Gly polymorphism of beta-1 AR with ICH. The present study suggests that those people who are older and carrying Gly49 variant of beta-1 AR may have a higher risk for ICH compared to control subjects.

In case of Arg389Gly polymorphism of beta-1 AR and Arg16Gly polymorphism of beta-2 AR, none of the data and subgroup analysis showed the associations of this polymorphism with ICH, suggesting that Arg16Gly and Arg389Gly polymorphisms might not have a role in the pathophysiology of ICH in North Indian population.

A common functional variation in the Gln27Glu polymorphism of beta-2 adrenergic receptor was found to be significantly associated with risk of ICH in the present study. In case of Gln27Glu polymorphism of the beta-2 AR, substitution of Glutamine (Gln) by Glutamic acid (Glu) leads to resistance to down-regulation of beta adrenergic receptor, thereby could lead to up-regulation of expression of beta-adrenergic receptor gene and consequently may lead to higher activity of circulatory catecholamine. Level of circulatory catecholamine often increases after hemorrhage. [4] Beta-adrenergic receptor plays an important role in the angiostatic factor production from choroidal endothelial or smooth muscle cells in order to maintain the normal vascular architecture. [17] Beta-2 adrenergic receptor plays an important role in controlling vascular tone and in the process of vascular remodeling. [18] Adrenergic receptor polymorphisms have been associated with risk of cardiac injury and dysfunction after hemorrhage. [19] We have now shown that those subjects who are carrier of Glu27Glu genotype of beta-2 AR may have 2.9 times greater risk of ICH in a North Indian population, with Glu27 allele of beta-2 AR representing a risk factor for this condition compared to control subjects under the dominant model of inheritance after adjusting for possible confounders. Interestingly, age-stratified analysis suggests that this functional variant was associated with subjects who had onset of stroke at a young age. This finding may suggest the possibility of the gene environment interaction of Gln27Glu polymorphism of beta-2 adrenergic receptor with the pathophysiology of ICH that had onset of disease at an early stage of life.

These data have important implications for risk prediction of ICH. Identifying subjects at higher risk of ICH would open the prospect of implementing the best preventive strategies in high-risk individuals. Other risk factors, intermediates, and combined data on genetic variation for these intermediates could be used to construct precise risk prediction model.

A number of limitations in this study should be discussed. The sample size of the present study (106 case and 106 control participants) might not be large enough to detect small effect of low penetrance SNPs. Each susceptible polymorphism may only contribute to mild effect, thus the analysis of single SNP could be misleading by unstudied polymorphism that influences the phenotype. The combine effect of multiple genetic variants of gene or multiple genes may provide more reliable information for genetic contribution to risk of ICH. We cannot completely exclude the effects of residual confounding attributable to the measurement error in the assessment of confounding factors. In the present study, the numbers of male patients were more than double the number of female patients, which substantiates that results of this study may be applied to male stroke populations.

In conclusion, the present study provides the first preliminary evidence that common variant of beta-adrenergic receptor (Gln27Glu polymorphism of beta-2 AR) may contribute modest effect in increase in risk of ICH in North Indian Population. Prospective studies with large sample size are required to confirm these findings.

 
 » References Top

1.World Health Organisation.int [internet]. WHO media centre [updated July 2013]. Available from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html. [Last accessed on 2014 Jan 15].  Back to cited text no. 1
    
2.Hassan A, Markus HS. Genetics and ischaemic stroke. Brain 2000;123:1784-12.  Back to cited text no. 2
    
3.Alberts MJ, McCarron MO, Hoffmann KL, Graffagnino C. Familial clustering of intracerebral hemorrhage: A prospective study in North Carolina. Neuroepidemiology 2002;21:18-21.  Back to cited text no. 3
    
4.Neil-Dwyer G, Cruickshank J, Stott A, Brice J. The urinary catecholamine and plasma cortisol levels in patients with subarachnoid haemorrhage. J Neurol Sci 1974;22:375-82.  Back to cited text no. 4
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5.Usui H, Fujiwara M, Tsukahara T, Taniguchi T, Kurahashi K. Differences in contractile responses to electrical stimulation and alpha-adrenergic binding sites in isolated cerebral arteries of humans, cows, dogs, and monkeys. J Cardiovasc Pharmacol 1985;7 Suppl 3:S47-52.  Back to cited text no. 5
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6.Tsukahara T, Taniguchi T, Shimohama S, Fujiwara M, Handa H. Characterization of beta adrenergic receptors in human cerebral arteries and alteration of the receptors after subarachnoid hemorrhage. Stroke 1986;17:202-7.  Back to cited text no. 6
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7.Yilmaz A, Kaya MG, Merdanoglu U, Ergun MA, Cengel A, Menevse S. Association of beta-1 and beta-2 adrenergic receptor gene polymorphisms with myocardial infarction. J Clin Lab Anal 2009;23:237-43.  Back to cited text no. 7
    
8.Iwamoto Y, Ohishi M, Yuan M, Tatara Y, Kato N, Takeya Y, et al. β-Adrenergic receptor gene polymorphism is a genetic risk factor for cardiovascular disease: A cohort study with hypertensive patients. Hypertens Res 2011;34:573-7.  Back to cited text no. 8
    
9.Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 1999;274:12670-4.  Back to cited text no. 9
    
10.Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994;33:9414-9.  Back to cited text no. 10
    
11.Ge D, Huang J, He J, Li B, Duan X, Chen R, et al. Beta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese. Ann Hum Genet 2005;69:36-44.  Back to cited text no. 11
    
12.Tang Z, Li X, Liao D. Associations of polymorphisms in the β2-adrenergic receptor gene with essential hypertension in Han Chinese population. Mol Biol Rep 2012;39:9339-45.  Back to cited text no. 12
    
13.Kawamura T, Egusa G, Fujikawa R, Okubo M. Gln27Glu variant of the beta2-adrenergic receptor gene is not associated with obesity and diabetes in Japanese-Americans. Metabolism 2001;50:443-6.  Back to cited text no. 13
    
14.Zee RY, Cook NR, Cheng S, Erlich HA, Lindpaintner K, Ridker PM. Multi-locus candidate gene polymorphisms and risk of myocardial infarction: A population-based, prospective genetic analysis. J Thromb Haemost 2006;4:341-8.  Back to cited text no. 14
    
15.Kumar A, Sagar R, Kumar P, Sahu JK, Grover A, Srivastava AK, et al. Identification of genetic contribution to ischemic stroke by screening of single nucleotide polymorphisms in stroke patients by using a case control study design. BMC Neurol 2013;13:136.  Back to cited text no. 15
    
16.Kumar A, Vivekanandhan S, Srivastava A, Tripathi M, Padma Srivastava MV, Saini N, et al. Association between angiotensin converting enzyme gene insertion/deletion polymorphism and ischemic stroke in north Indian population: A case-control study and meta-analysis. Neurol Res 2014;1743132814Y0000000335.  Back to cited text no. 16
    
17.Lima JJ, Feng H, Duckworth L, Wang J, Sylvester JE, Kissoon N, et al. Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations. Metabolism 2007;56:757-65.  Back to cited text no. 17
    
18.Steinle JJ, Smith PG. Role of adrenergic receptors in vascular remodelling of the rat choroid. Br J Pharmacol 2002;136:730-4.  Back to cited text no. 18
    
19.Zaroff JG, Pawlikowska L, Miss JC, Yarlagadda S, Ha C, Achrol A, et al. Adrenoceptor polymorphisms and the risk of cardiac injury and dysfunction after subarachnoid hemorrhage. Stroke 2006;37:1680-5.  Back to cited text no. 19
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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