Insertion/deletion polymorphism in α2-adrenergic receptor gene is a genetic risk factor for sudden cardiac death

doi:10.1016/j.ahj.2009.07.023

American Heart Journal

Volume 158, Issue 4, October 2009, Pages 615-621

https://doi.org/10.1016/j.ahj.2009.07.023 Get rights and content

Background

Adrenoceptors mediate contraction of vascular smooth muscle and induce coronary vasoconstriction in humans. A deletion variant of the human α_2B-adrenoreseptor of glutamic acid residues has been associated with impaired receptor desensitization. This receptor variant could, therefore, be involved in cardiovascular diseases associated with enhanced vasoconstriction. Our aim was to study whether an insertion/deletion (I/D) polymorphism in the α_2B-adrenoceptor gene is associated with the risk for sudden cardiac death.

Methods

This was a prospective population-based study investigating risk factors for cardiovascular diseases in middle-aged men from 42 to 60 years from eastern Finland. The study is based on 1,606 men with complete data on DNA observed for an average time of 17 years.

Results

In this study population, 338 men (21%) had the D/D genotype, 467 (29%) had the I/I genotype, and 801 (50%) had a heterozygous genotype. There were 76 sudden cardiac deaths during follow-up (0.81 deaths/1,000 persons per year). In a Cox model adjusting for other coronary risk factors (age, systolic blood pressure, smoking, diabetes, serum low-density lipoprotein and high-density lipoprotein cholesterol, body mass index, and exercise-induced myocardial ischemia), men with the D/D or I/D genotype had 1.97 times (95% CI 1.08-3.59, P = .026) higher risk to experience sudden cardiac death (20 events for D/D genotype, 13 events for I/I genotype, and 43 events for I/D genotype) compared with men carrying the I/I genotype. In addition, the α_2B-adrenoceptor D/D genotype was associated with the risk of coronary heart disease death and acute coronary events, after adjusting for risk factors.

Conclusions

The genetic polymorphism of the α_2B-adrenoreceptor is genetic risk predictor for sudden cardiac death.

Section snippets

Study population

This study was designed to investigate risk factors for CHD and related outcomes in a population-based sample of men. Subjects were randomly selected sample of 3,433 men aged 42 to 60 years who resided in the town of Kuopio or its surrounding rural communities; 198 were excluded because of death, serious disease, or migration. This area is known for its homogenous population and high coronary morbidity and mortality rates.¹³ Of the remainder, 2,682 (83%) participated in the study, and those

Characteristics

Of the all subjects, 338 men (21%) had the D/D genotype, 467 (29%) had the I/I genotype, and 801 (50%) had a heterozygous genotype. The distributions of common baseline characteristics are shown in Table I as well as the prevalence of conventional risk factors is presented in Table II according to genotype. The genotype groups were not different in known major risk factors for CHD. Only body mass index and blood pressure were significantly different (P < .05) between the 3 genotype groups. The

Discussion

This prospective cohort study indicates that there is a strong association between a D variant of the α_2B-AR gene and SCD in middle-aged men. Men with the D/D as well as D/I genotypes had 2-fold higher the risk of experiencing an SCD as compared with men with the I/I genotypes. The present long-term follow-up study demonstrates that _2B-AR gene predicts unexpected SCD, especially in men with prevalent CHD or previous MI.

Our results are consistent with previous findings showing an increased

Acknowledgements

We thank the staff of the Kuopio Research Institute of Exercise Medicine and the Research Institute of Public Health, and University of Kuopio, Kuopio, Finland, for data collection in the study.

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The 12Glu9 or I/D polymorphism is linked to the autonomic dysfunction and increased sympathetic nervous system activity (Papanas et al., 2007). These characteristics have been associated with adverse metabolic and vascular effects, including reduced basal metabolic rate (Heinonen et al., 1999), obesity (Siitonen et al., 2004), and earlier onset of diabetes (Papazoglou et al., 2006), acute coronary ischemia (Snapir et al., 2001), T2DM with neuropathy (Papanas et al., 2007), sudden cardiac death (Laukkanen et al., 2009), spontaneous abortions (Galazios et al., 2011), migraine (Ni et al., 2010), glucose 6 phosphate dehydrogenase (Alharbi et al., 2013), suicide (Fukutake et al., 2008), and hypertension with and without T2DM (Vasudevan et al., 2008). Several studies of subjects from different ethnic backgrounds have reported a positive or negative association between the ADRA2B gene variants in different diseases.
There are no earlier studies that reported the association of the 12Glu9 polymorphism in the alpha-2B adrenoceptor (ADRA2B) gene with gestational diabetes mellitus (GDM). We examined the potential association between the ADRA2B gene insertion/deletion (I/D) polymorphism in the Saudi population with GDM. Pregnant women with GDM have been reported to exhibit the same susceptibility as that observed in type 2 diabetes mellitus (T2DM). We have selected I/D polymorphism of the ADRA2B gene located in chromosome 2q11.1 that has been extensively related to T2DM and cardiovascular diseases. This case–control study was conducted with 200 GDM and 300 non-GDM pregnant women. Genotyping of I/D polymorphism was performed by conventional PCR method. Biochemical analyses were found to be significantly different between GDM and non-GDM subjects (p < 0.05). Genotype (ID + DD vs II, p = 0.0002) and allele (D vs I, p = 0.0002) frequencies of the 12Glu9 polymorphism were found to be statistically significant. However, a significant difference was found between allele and genotypes of I/D polymorphism of the ADRA2B gene or the clinical characteristics of the subjects. Our results obtained in this study indicate the ADRA2B gene in the Saudi women was associated with the development of GDM.
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Further studies linked α2BAR Del301-303 with increased risk of sudden cardiac death in a Caucasian population, with particular risk for men under age 50 (Snapir, Mikkelsson, Perola, Penttila, Scheinin, & Karhunen, 2003b). More recently, a separate group confirmed the α2BAR Del301-303 variant as a genetic risk factor for myocardial infarction and sudden cardiac death in middle-aged men (Laukkanen, Makikallio, Kauhanen, & Kurl, 2009). Hence, available evidence strongly links the α2BAR genotype with risk of acute heart disease, suggesting the receptor as a useful potential target for screening.
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: The US National Heart, Lung, and Blood Institute grant HL44199.

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Clinical InvestigationGeneticsInsertion/deletion polymorphism in α2-adrenergic receptor gene is a genetic risk factor for sudden cardiac death

Background

Methods

Results

Conclusions

Section snippets

Study population

Characteristics

Discussion

Acknowledgements

J Am Coll Cardiol

J Biol Chem

J Am Coll Cardiol

J Am Coll Cardiol

Sudden cardiac death

Circulation

Sudden death due to cardiac arrhythmias

N Engl J Med

How sudden is cardiac death

Circulation

Coronary risk factors and plaque morphology in men with coronary disease who died suddenly

N Engl J Med

Circadian variation in ischemic threshold: a mechanism underlying the circadian variation in ischemic events

Circulation

Role of alpha 2-adrenoceptors in normal and atherosclerotic human coronary circulation

Circulation

Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries

Circulation

Alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans

Circulation

Clinical Investigation
Genetics
Insertion/deletion polymorphism in α₂-adrenergic receptor gene is a genetic risk factor for sudden cardiac death