Russian Medical Review
* Impact factor according to the SCIENCE INDEX 2020
O.O. Kuznetsova1,2, S.Yu. Nikulina1, A.A. Chernova1, V.N. Maximov3, G.V. Matyushin1
1Krasnoyarsk State Medical University named after Prof. Voino-Yasenetsky, Krasnoyarsk, Russian Federation
2Federal Center for Cardiovascular Surgery, Krasnoyarsk, Russian Federation
3Institute of Internal and Preventive Medicine, the branch of Federal Publicly Funded
Scientific Institution Federal Research Center of Cytology and Genetics, the Siberian
Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
Aim: to identify patterns of development of idiopathic dilated cardiomyopathy (IDC) and ischemic cardiomyopathy (ICM) by studying the rs 1801252 (Ser49Gly) polymorphic variant of the ADRB1 gene.
Patients and Methods: a cohort of 221 patients (mean age — 55.30±9.69 years) was examined. All respondents underwent a standard set of laboratory and instrumental examinations, including coronary angiography. The first group included 111 patients with IDC, 99 of them (89.2%) were men, who were excluded from probable factors of dilated cardiomyopathy. The second group included 110 patients with IDC, including 100 (91.5%) men who had reliable signs of CHD. The control group included 221 people (mean age — 53.6±4.8 years) without signs of cardiovascular diseases. A molecular genetic study of the rs 1801252 (Ser49Gly) polymorphism of the ADRB1 gene was performed in all patients and in the control group.
Results: among patients with IDC of both gender, 70.3% were carriers of the common homozygous A145A genotype, 27.0% of the heterozygous A145G genotype, and 2.7% of the rare homozygous G145G genotype. In the control group, there was also a predominant number of patients who carried the homozygous genotype for the common A145A allele — 71.9%. Carriers of the heterozygous A145G genotype were 25.3%, and the homozygous G145G genotype for a rare allele — 2.7%. The analysis of the genotypes frequency distribution of the polymorphic locus rs 1801252 (Ser49Gly) of the ADRB1 gene in patients with IDC and in the control group showed no differences. In the group of patients with ICM, the frequency of the common homozygous A145A genotype was 68.2%, there were fewer patients with the heterozygous A145G genotype — 29.1%, and the rare homozygous G145G genotype was detected in 2.7% of cases. There was no association with the ICM 1801252 (Ser49Gly) polymorphism of the ADRB1 gene in the group of patients with ICM, since the results of comparison with the control group data showed no statistically significant differences. At the same time, there were differences in the frequency of alleles of the polymorphic locus rs1801252 (Ser49Gly) of the ADRB1 gene: in male patients with IDC and ICM, the 145A allele was statistically significantly more common (p=0.0001) than in the control group.
Conclusion: the data obtained suggest that the carrier of the 145A allele of the ADRB1 gene may serve as an additional risk factor for the development of dilated cardiomyopathy.
Keywords: dilated cardiomyopathy, ischemic cardiomyopathy, genetic polymorphism, β-1-adrenergic receptor gene, heart failure, genetic predisposition.
For citation: Kuznetsova O.O., Nikulina S.Yu., Chernova A.A. et al. β-1-adrenoreceptor gene polymorphism role in the development of dilated cardiomyopathy. Russian Medical Inquiry. 2020;4(7):394–398. DOI: 10.32364/2587-6821-2020-4-7-394-398.
Dilated cardiomyopathy (DCM) is a rare heart condition characterized by the dilation of the left ventricle and systolic dysfunction which result in heart failure and sudden cardiac death . Published data demonstrate that the prevalence of DCM is 5-10 per 100,000 [2, 3]. DCM is an inherited disease predominantly referred to as monogenic disorders. The understanding of the molecular pathogenesis of inherited cardiac diseases has significantly improved due to the advances in molecular genetics. Moreover, genetic testing is becoming more available as a component of diagnostic and prognostic tools .
Several factors (i.e., viral infections, autoimmune disorders) have been recognized as root causes of DCM. However, many cases are now described as idiopathic DCM . Recent studies demonstrate that inherited DCM occurs in almost 60% of patients. More than 60 genes related to this disease were identified owing to the technological progress in genetic testing. These genes encode a broad spectrum of myocyte proteins (mainly sarcomeric and desmosomal proteins). Meanwhile, pathophysiological mechanisms are yet to be explored . Among these genes, β1-adrenoreceptor gene, ADRB1, is important. This gene is located on chromosome 10 (10q24-q26). The ADRB1 gene (1,434 bp) is lacking introns and encodes a protein consisting of 477 amino acids .
It was demonstrated that in patients with heart failure, ADRB1 gene polymorphism (base pair substitution at position 49) is related to survival. The studies on the effect of single nucleotide polymorphism (SNP) on the congestive heart failure were performed. Some studies on codon 49 of ADRB1 gene suggested that Gly49 polymorphic allele is related to DCM while others did not [7, 8]. Another study has demonstrated that the rate of hospital admissions and mortality rate among DCM patients with Gly49 polymorphic allele is involved in myocardial protection in DCM . Finally, a Japanese study did not reveal any associations between gene polymorphism and DCM .
One study evaluated the relation between ADRB1 Ser49Gly (rs1801252) and Arg389Gly (rs1801253) and left ventricular ejection fraction recovery in DCM patients. It was shown that homozygous ADRB1 Ser 49Ser genotype is associated with significantly better left ventricular ejection fraction recovery than Gly49 genotype .
Considering that ADRB1 is the major regulator of heart rhythm, it can be assumed that specific ADRB1 SNPs will provide a clinically relevant effect on heart rate (HR). In Japanese and Chinese populations, heterozygous Ser49Gly polymorphism affects resting HR irrespective of other factors. Patients with homozygous (Gly49) genotype experience HR reduction by 5 bpm compared to patients with homozygous (Ser49) genotype .
ADRB1 has a direct impact on cardiac output and exercise tolerance. The evaluation of exercise tolerance in patients with idiopathic or ischemic cardiomyopathy has demonstrated that patients with homozygous Gly389 polymorphism are much weaker than patients with Arg389. DCM patients with Arg389 polymorphism waiting for a heart transplant are characterized by the significant increase in oxygen consumption and physical activity period than patients with Gly389 polymorphism .
Hence, there are reasons to expect that knowing ADRB1 gene polymorphism pattern in early diagnosed various cardiomyopathies will have an impact on the risk of sudden cardiac death.
To recognize the patterns of the development of idiopathic DCM and ischemic cardiomyopathy (ICM) by examining rs1801252 (Ser49Gly) ADRB1 gene polymorphism.
Patients and Methods
A prospective study included the residents of the Krasnoyarsk Region (both men and women) older than 18 years. The study was approved by the local ethics committee of the Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University. All patients have given the informed consent to participate in the study.
221 patients with DCM and ICM were examined. Mean age was 55.30 ± 9.69 (20-70) years. In DCM group (n = 111), 99 patients (89,2%) were men. Mean age of DCM patients was 51.73 ± 9.74 years. In ICM group (n = 110), 100 patients (91.5%) were men. Mean age of ICM patients was 58.68 ± 8.38 years. Control group included 221 individuals (199 men, mean age 53.6 ± 4.8 years) without any signs of cardiovascular diseases as demonstrated by medical exams.
All study participants underwent standard laboratory and instrumental tests including coronary angiography. In suspected myocarditis, cardiac magnetic resonance imaging was performed. Patients without a clear cause of the enlargement of heart chambers were included in group 1. Patients with the signs of coronary heart disease were included in group 2.
All patients underwent molecular genetic testing to detect the genotypes of rs1801252 (Ser49Gly) ADRB1 gene polymorphisms. After phenol chloroform DNA extraction, polymerase chain reaction was performed for rs1801252 (Ser49Gly) ADRB1 polymorphism genotyping. Finally, restriction fragment length polymorphism was analyzed .
In addition, when analyzing the frequencies of ADRB1 alleles and genotypes, we used an over-dominant model that compares two homozygous genotypes together (MM + mm) versus a heterozygous genotype (Mm). We compared the frequency of AG genotype and the cumulative frequency of AA and GG genotypes between study groups (i.e., DCM and ICM) and the control group.
Statistical analysis was performed using Statistica v. 7.0 software. The significance of intergroup differences and the conformity of genotype frequencies with the Hardy-Weinberg principle were evaluated using chi-square test (χ2). The strength of the associations of the genotypic characteristics of the genes investigated and the risk of unfavorable outcome was calculated by odds ratio (OR) and its 95% confidence interval (CI). OR = 1 stands for the lack of associations while OR > 1 stands for a positive association between the allele/genotype and the disease and OR < 1 stands for a negative association between the allele/genotype and the disease.
Results and discussion
The distribution of genotype prevalence among DCM patients was as follows: 70.3% of patients were the carriers of common homozygous genotype (A145A), 27.0% were the carriers of heterozygous genotype (A145G), and 2.7% were the carriers of rare homozygous genotype (G145G). In the control group, most individuals (71.9%) were the carriers of common homozygous genotype (A145A) while 25.3% were the carriers of heterozygous genotype and 2.7% were the carriers of rare homozygous genotype (G145G). The analysis of the distribution of the prevalence of rs1801252 (Ser49Gly) polymorphic locus of ADRB1 gene did not reveal any differences between DCM patients and healthy individuals.
69.7% of DCM male patients carried common homozygous genotype A145A, 28.3% carried heterozygous genotype A145G, and 2.0% carried rare homozygous genotype G145G. The carriers of common homozygous genotype A145A also prevailed in the control group (72.9%; see Table 1).
No significant differences in rs1801252 (Ser49Gly) polymorphic alleles of ADRB1 gene were identified between DCM patients and the controls. Meanwhile, when comparing the prevalence of rs1801252 (Ser49Gly) alleles of ADRВ1 gene, 145А allele was shown to be significantly more common in DCM male patients compared to male controls (83.8% vs. 59.3%, respectively, р = 0.0001).
Among DCM patients, 68,2%, 29.1%, and 2.7% carried common homozygous genotype (A145A), heterozygous genotype (A145G), and rare homozygous genotype G145G, respectively. Among the controls, 71.9%, 25.3%, and 2.7% carried common homozygous genotype (A145A), heterozygous genotype (A145G), and rare homozygous genotype G145G, respectively. In ICM group, no associations with rs1801252 (Ser49Gly) polymorphism of ADRB1 gene were identified as no significant differences between study group and the controls were reported.
Among ICM male patients, genotype prevalence was as follows (see Table 2). 67.0% carried common homozygous genotype (A145A), 30.0% carried heterozygous genotype (A145G), and 3.0% carried rare homozygous genotype (G145G). As to the controls, 72.9%, 24.6%, and 2.5% carried common homozygous genotype (A145A), heterozygous genotype (A145G), and rare homozygous genotype G145G, respectively. In ICM male patients, no associations with rs1801252 (Ser49Gly) polymorphism of ADRB1 gene were identified.
When comparing the prevalence of rs1801252 (Ser49Gly) alleles of ADRВ1 gene, 145А allele was shown to be significantly more common in ICM male patients compared to male controls (82.0% vs. 59.3%, respectively, р = 0.0001).
No significant differences in the prevalence of rs1801252 (Ser49Gly) alleles of ADRВ1 gene between DCM or ICM female patients and the controls were reported.
Our study on rs1801252 (Ser49Gly) ADRB1 gene polymorphism has revealed no significant differences in genotype prevalence between study group (DCM or ICM) and the controls. However, we have demonstrated the differences in the prevalence of rs1801252 (Ser49Gly) polymorphic allele of ADRВ1 gene between study group and the controls, i.e., 145А allele was much more common in male patients with DCM and ICM than in healthy men. Considering that these data were derived from the analysis of allele prevalence in male patients with DCM and ICM, we suggest that carrying 145А allele of ADRB1 gene is an additional risk factor for dilated cardiomyopathy. Further studies with large sample sizes are needed to confirm our findings.
A biological reason for using an over-dominant model implies that at least one variant allele (i.e., А145 allele) is enough for modifying the risk of the development of different cardiomyopathies. We failed to find any published data demonstrating the association between ADRB1 gene polymorphism and ICM or DCM.
The existence of genetic characteristics of various populations accounts for the importance of studying them. Molecular genetic testing for the predictors of the genetic predisposition to cardiomyopathies is a promising area of researches. Cardiologists should learn to integrate these novel knowledge into diagnostic protocols to improve the management of the families with inherited cardiomyopathies, in particular, to discuss with patients and their relatives the genetic aspects of these disorders (including their inheritance). This requires the basic understanding of the principles of genetic counseling which helps overcome the psychological, social, professional, ethic, and legal consequences of a genetic disorder.
Our findings on the molecular genetic pattern of different cardiomyopathies will contribute to the global databases on genome-wide association studies and the studies on the pathophysiological mechanisms of dilated cardiomyopathy.
About the authors:
Oksana O. Kuznetsova — Cand. of Sci. (Med.), Associate Professor of the Department of Cardiology, Functional, Clinical and Laboratory Diagnosis of the Institute of Continuing Education, Krasnoyarsk State Medical University named after Prof. Voino-Yasenetsky: 1, Partizana Zheleznyaka, Krasnoyarsk, 660022, Russian Federation; cardiologist, Federal Center for Cardiovascular Surgery: 45, Karaulnaya str., Krasnoyarsk, 660020, Russian Federation; ORCID iD 0000-0003-2247-4242.
Svetlana Yu. Nikulina — Dr. of Sci. (Med.), Professor, Head of the Department of Internal diseases No. 1, Krasnoyarsk State Medical University named after Prof. Voino-Yasenetsky: 1, Partisana Zheleznyaka str., Krasnoyarsk, 660022, Russian Federation; ORCID iD 0000-0002-6968-7627.
Anna A. Chernova — Dr. of Sci. (Med.), Associate Professor of the Department of Internal Diseases No. 1, Krasnoyarsk State Medical University named after Prof. Voino-Yasenetsky: 1, Partisana Zheleznyaka str., Krasnoyarsk, 660022, Russian Federation; ORCID iD 0000-0003-2977-1792.
Vladimir N. Maximov — Dr. of Sci. (Med.), Professor, Head of the Laboratory of Molecular Genetic Research of Therapeutic Diseases; Institute of Internal and Preventive Medicine, the branch of Federal Publicly Funded Scientific Institution Federal Research Center of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences: 175/1, B. Bogatkova str., Novosibirsk, 630089, Russian Federati on; ORCID iD 0000-0002-7165-4496.
Gennady V. Matyushin — Dr. of Sci. (Med.), Professor, Head of the Department of Cardiology, Functional and Clinical Laboratory Diagnostics, Krasnoyarsk State Medical University named after Prof. Voino-Yasenetsky: 1, Partisana Zheleznyaka str., Krasnoyars, 630022, Russian Federation; ORCID iD 0000-0002-0150-6092.
Contact information: Oksana O. Kuznetsova, e-mail: Isachenko102@inbox.ru. Financial Disclosure: no authors have a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 14.07.2020, revised 28.07.2020, accepted 11.08.2020.
2. Барт Б.Я., Беневская В.Ф. Дилатационная кардиомиопатия в практике терапевта и кардиолога (лекция). Терапевтический архив. 2004;79(1):12–17. [Bart B.Y., Benevskaya V.F. Dilated cardiomyopathy in therapeutic and cardiological practice (lecture). Therapeutic archive. 2004;79(1):12–17 (in Russ.)].
3. Sugrue D.D., Rodeheffer R.J., Codd M.B. et al. The clinical course of idiopathic dilated cardiomyopathy. A population-based study. Ann Intern Med. 1992;117(2):117–123. DOI: 10.7326/0003-4819-117-2-117.
4. Muir A.R., Menown I.B. Genetic biomarkers in cardiovascular disease. Biomark Med. 2013;7(4):497–499. DOI: 10.2217/bmm.13.82.
5. Startari U., Taylor M.R., Sinagra G. et al. Dilated cardiomyopathy: etiology, clinical criteria for diagnosis and screening of the familial form. Ital Heart J Suppl. 2002;3(4):378–385.
6. Perez-Serra A., Toro R., Sarquella-Brugada G. et al. Genetic basis of dilated cardiomyopathy. Int J Cardiol. 2016;224:461–472. DOI: 10.1016/j.ijcard.2016.09.068.
7. Podlowski S., Wenzel K., Luther H.P. et al. Beta1-adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy? J Mol Med (Berl). 2000;78(2):87–93. DOI: 10.1007/s001090000080.
8. Small K., Mcgraw D., Liggett S. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol. 2003;43:381–411. DOI: 10.1146/annurev.pharmtox.43.100901.135823.
9. Börjesson M., Magnusson Y., Hjalmarson A. et al. A novel polymorphism in the gene coding for the beta — adrenergic receptor associated with survival in patients with heart failure. Eur Heart J. 2000;21(22):1853–1858. DOI: 10.1053/euhj.1999.1994.
10. Nonen S., Okamoto H., Akino M. et al. No positive association between adrenergic receptor variants of alpha2cDel322–325, beta1Ser49, beta1Arg389 and the risk for heart failure in the Japanese population. Br J Clin Pharmacol. 2005;60(4):414–417. DOI: 10.1111/j.1365-2125.2005.02447.x.
11. Luzum J.A., English J.D., Ahmad U.S. et al. Association of Genetic Polymorphisms in the Beta-1 Adrenergic Receptor with Recovery of Left Ventricular Ejection Fraction in Patients with Heart Failure. J Cardiovasc Transl Res. 2019;12(4):280–289. DOI: 10.1007/s12265-019-09866-5.
12. Ranade K., Jorgenson E., Sheu W.H. et al. A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet. 2002;70(4):935–942. DOI: 10.1086/339621.
13. Sandilands A.J., Parameshwar J., Large S. et al. Confirmation of a role for the 389R>G beta-1 adrenoceptor polymorphism on exercise capacity in heart failure. Heart. 2005;91(12):1613–1614. DOI: 10.1136/hrt.2004.047282.
14. Афанасьев С.А., Реброва Т.Ю., Муслимова Э.Ф. и др. Ассоциация полиморфных вариантов гена ADRB1 с сократительной дисфункцией миокарда и адренореактивностью эритроцитов у пациентов с нарушениями ритма. Российский кардиологический журнал. 2019;24(7):47–52. DOI: 10.15829/1560-4071-2019-7-47-52. [Afanasiev S.A., Rebrova T. Yu., Muslimova E.F. et al. Association of polymorphic variants of ADRB1 gene with contractile myocardial dysfunction and erythrocyte adrenoreactivity in patients with rhythm disorders. Russian Journal of Cardiology. 2019;24(7):47–52 (in Russ.)]. DOI: 10.15829/1560-4071-2019-7-47-52.
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