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CLINICAL STUDY: RISK FACTORS

An insertion/deletion polymorphism in the _2b-adrenergic receptor gene is a novel genetic risk factor for acute coronary events

Amir Snapir, MD^*, Paula Heinonen, MD^*, Tomi-Pekka Tuomainen, MD, Pia Alhopuro, BM^*, Matti K. Karvonen, MD^*, Timo A. Lakka, MD, Kristiina Nyyssönen, PhD, Riitta Salonen, MD, Jussi Kauhanen, MD, Veli-Pekka Valkonen, BM, Ullamari Pesonen, PhD^*, Markku Koulu, MD^*, Mika Scheinin, MD^* and Jukka T. Salonen, MD

^* Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland
Research Institute of Public Health, University of Kuopio, Kuopio, Finland
Inner Savo Health Center, Suonenjoki, Finland

Manuscript received May 16, 2000; revised manuscript received December 18, 2000, accepted January 29, 2001.

Reprint requests and correspondence: Dr. Jukka T. Salonen, Research Institute of Public Health, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland
jukka.salonen{at}uku.fi

	Abstract

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OBJECTIVES

Our aim was to study whether an insertion/deletion (I/D) polymorphism in the _2B-adrenoceptor gene is associated with the risk for cardiovascular diseases.

BACKGROUND

₂-adrenoceptors mediate contraction of vascular smooth muscle and induce coronary vasoconstriction in humans. The ₂-adrenoceptor subtype B mediates vasoconstriction in mice. A variant of the human _2B-adrenoceptor gene that encodes a D of three residues in an intracellular acidic motif has been shown to confer decreased receptor desensitization. This receptor variant could, therefore, be involved in diseases associated with enhanced vasoconstriction.

METHODS

This study was part of a prospective population-based study investigating risk factors for cardiovascular diseases in a cohort of middle-aged men from eastern Finland. Nine hundred twelve men aged 46 to 64 years were followed for an average time of 4.5 years.

RESULTS

In this study population, 192 men (21%) had the D/D genotype; 256 (28%) had the I/I genotype, and 464 (51%) had a heterozygous genotype. In a Cox model adjusting for other coronary risk factors, men with the D/D genotype had 2.2 times (95% confidence interval: 1.1 to 4.4, p = 0.02) the risk to experience an acute coronary event (n = 15 for D/D, 10 for I/I and 12 for I/D) compared with men carrying either of the other two genotypes. The _2B-adrenoceptor genotype was not associated with hypertension in this study population.

CONCLUSIONS

The D/D genotype of the _2B-adrenoceptor is a novel genetic risk factor for acute coronary events, but not for hypertension.

Abbreviations and Acronyms   AMI = acute myocardial infarction   AR = adrenergic receptor   BMI = body mass index   BP = blood pressure   CHD = coronary heart disease   CI = confidence interval   D = deletion   ECG = electrocardiogram   I = insertion   KIHD = Kuopio Ischemic Heart Disease Risk Factor study   LDL = low density lipoprotein   PCR = polymerase chain reaction   RR = relative risk   WHO = World Health Organization

A variant form of the human _2B-AR gene was recently identified (12). The variant allele encodes a receptor protein with a deletion (D) of three glutamate residues in an acidic stretch of 18 amino acids (of which 15 are glutamates) located in the third intracellular loop of the receptor polypeptide. This long acidic stretch is a unique feature in the primary structure of _2B-AR in comparison with _2A-AR and _2C-AR. An amino acid sequence alignment of _2B-AR polypeptides of different mammals reveals that the acidic stretch is conserved in mammalian _2B-ARs and that the acidic stretch is long in humans in comparison with other species. This suggests that the motif is important for the functionality of the receptor and that the short form (D) probably represents the ancestral form and the long form (insertion [I]) could well represent a more recent allelic variant in humans. Removal of negatively charged amino acids from a synthetic peptide, part of the third intracellular loop of the _2A-AR, implied that they are necessary for receptor phosphorylation by ß-adrenoceptor kinase (13).

Jewell-Motz and Liggett (14) studied in vitro the functions of this acidic stretch using site-directed mutagenesis to delete, as well as to substitute, 16 amino acids of the stretch. The wild-type _2B-AR underwent approximately 52% functional desensitization in transfected cells while agonist-promoted desensitization was ablated in both mutated receptors. The mutated receptors underwent agonist-promoted phosphorylation at levels of only 45% to 50% relative to the wild-type _2B-AR. Using similar methods, the same group recently showed that the deletion variant, targeted by the current study, is sufficient to impair agonist-promoted receptor desensitization to a similar extent as D of the entire acidic stretch (15). Thus, the natural polymorphism determines the susceptibility of the receptor to modulation by a key mechanism of dynamic regulation.

Based on the coronary vasoconstrictive property of ₂-ARs in humans, the peripheral vasoconstrictive property of the _2B-AR subtype in mice and the significance of this acidic region for the desensitization of the receptor, we hypothesized that the naturally occurring D variant confers reduced receptor desensitization and, therefore, increased vasoconstriction in humans. This property could be associated with cardiovascular pathologies, such as acute coronary events and hypertension. To test this hypothesis, we carried out a prospective study in 912 middle-aged Finnish men.

	Methods

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Study population.   This study was carried out as part of the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), which is an ongoing prospective population-based study designed to investigate risk factors for cardiovascular diseases and related outcomes in men from eastern Finland (16). This area is known for its homogenous population (17) and high coronary morbidity and mortality rates (18). The KIHD study protocol was approved by the Research Ethics Committee of the University of Kuopio. The present study population is the second cohort of the KIHD study, examined in 1989 to 1993. The subject recruitment is detailed in Figure 1. This study, thus, contains data from a representative population sample of 912 men, aged 46 (n = 222), 52 (n = 230), 58 (n = 250) or 64 (n = 210) years at the beginning of the follow-up. All subjects gave their written informed consent. The average time of follow-up was 4.5 years (range 1 to 7.6 years). The follow-up was started from the day of drawing blood for DNA extraction and was ended (truncated) at the end of 1996.

View larger version (53K): [in this window] [in a new window]   Figure 1 Subject recruitment flowchart: the Kuopio Ischemic Heart Disease Risk Factor (KIHD) study. AMI = acute myocardial infarction; AR = adrenergic receptor; D = deletion; I = insertion.

Only first events were used in the analysis; a subject was excluded from further analysis when an acute coronary event had occurred.

Measurement of covariates and blood specimens.   The collection of blood specimens, the measurement of serum lipids and lipoproteins, plasma fibrinogen, blood glucose and serum insulin have been previously described (19,20). Detailed descriptions of the following have also been published earlier: blood pressure measurements (21), examination protocol (16), assessment method of medical history, use of medication, smoking, consumption of food and alcohol, intake of nutrients (19) and exercise test protocol (22).

Coronary heart disease (CHD) in the family was determined when either a parent or a sibling of a subject had a history of CHD, as assessed by a questionnaire. A history of CHD was defined as a history of AMI or angina pectoris (23) or at least weekly use of nitroglycerin for chest pain.

Treatment for hypertension was assessed by a self-administered questionnaire where the subject was asked to report the regular use of any drug prescribed by a physician at the time of examination. The subject was defined as taking antihypertensive medication if he reported regular use of an antihypertensive drug as classified by WHO’s Anatomical Therapeutic Chemical (ATC) code (24). Diagnosis of hypertension was made when a subject had a systolic blood pressure (BP) 165 mm Hg or diastolic BP 95 or was treated for hypertension.

DNA extraction and analysis.   DNA for genotyping was extracted from peripheral blood using standard methods. The _2B-AR I/D genotypes were determined by separating polymerase chain reaction (PCR) amplified DNA fragments with electrophoresis. Based on the nature of the I/D variant, identification of the long and short alleles was achieved by their different electrophoretic migration rates due to their 9 base pair (bp) size difference. A few samples of each genotype were sequenced to confirm the identification of the genotype based on the electrophoresis.

The region of interest was amplified using a sense primer 5'-AGG-GTG-TTT-GTG-GGG-CAT-CT-3' and an antisense primer 5'-CAA-GCT-GAG-GCC-GGA-GAC-ACT-3' (Oligold, Eurogentec, Seraing, Belgium), yielding a product size of 112 bp for the long allele (I) and 103 bp for the short allele (D). Polymerase chain reaction amplification was conducted in a 10 µL volume containing approximately 100 ng genomic DNA, 1x buffer G (Invitrogen, San Diego, California), 0.8 mM dNTPs, 0.3 µM of each primer and 0.25 U of AmpliTaq DNA polymerase (Perkin Elmer Cetus, Norwalk, Connecticut). Samples were amplified with a GeneAmp PCR System 9600 (Perkin Elmer Cetus). After initial denaturation at 94°C for 2 min, the samples were amplified over 35 cycles. Polymerase chain reaction amplification conditions were 96°C (40 s), 69°C (30 s) and 72°C (30 s) followed by final extension at 72°C for 6 min.

After amplification, samples were loaded onto 4% MetaPhor agarose gel (FMC BioProducts, Rockland, Maine) with ethidium bromide staining. The different alleles were identified based on their different electrophoretic migration rates (Fig. 2).

View larger version (59K): [in this window] [in a new window]   Figure 2 Electrophoretic separation of the polymerase chain reaction products. The insertion (I) and deletion (D) alleles were identified based on their different migration rates. bp = base pair.

The genotyping result of each subject was I/I (which is a homozygous form of the published _2B-AR sequence [25]), D/D (which is a homozygous form of the recently discovered variant) or I/D.

Statistical analysis.   Statistical computations were performed with SPSS/Win version 8.0.1 software (SPSS Inc., Chicago, Illinois). Chi-square tests were used for analysis of discrete variables (two-sided Fisher exact significance test was used in 2 x 2 tables). One-way analysis of variance or Student t test was used for continuous variables (presented as mean ± SD). To assess the possible association of the ₂-AR I/D polymorphism with the risk for an acute coronary event, univariate Cox regression analysis was performed, first for all three genotype groups and next for comparison of the D/D genotype with the two others combined, now assuming a recessive mode of inheritance.

Multivariate Cox regression analysis was performed to assess the impact of possible confounding and modifying factors on the observed association. Variables that were associated (p < 0.10 in the above analyses) with the _2B-AR I/D genotype were entered into a multivariate Cox regression model. The same procedure was performed for all variables that were previously identified as risk factors for CHD in this study population. The variables identified in these two models were entered together with all established major risk factors for CHD (26) into a new multivariate Cox regression model.

	Results

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Results from the entire cohort.   Of the 912 subjects, 192 (21%) had the D/D genotype; 256 (28%) had the I/I genotype, and 464 (51%) were heterozygous. This genotype distribution is in Hardy-Weinberg equilibrium (p = 0.46). Thirty-seven acute coronary events occurred during the follow-up time: 15 in the D/D genotype group (7.8%), 12 in the I/D group (2.6%) and 10 in the I/I group (3.9%). Of these 37 acute coronary events, 18 were classified as definite AMI, 12 as possible AMI and 7 as prolonged chest pain (Table 1).

Analysis using a model of recessive inheritance.   In a univariate Cox regression model, the D/D genotype was associated with an acute coronary event risk of 2.5 (95% CI = 1.3 to 4.8, p = 0.006) relative to the I/D and the I/I groups combined. A Kaplan-Meier survival function of event-free time (Fig. 3) illustrates the consistently increased incidence of acute coronary events in the D/D group compared with the combined I/D and I/I group. Applying the same Cox regression analysis only to the definite or possible AMI events, excluding the prolonged chest pain category, revealed a risk of 3.7 (95% CI = 1.8 to 7.5, p = 0.0006) for the D/D group relative to the two others combined. When the Cox analysis for all events (including prolonged chest pain) was performed on the data from a subpopulation of men with no history of CHD at study outset (n = 787; 25 events), an RR of 2.3 (95% CI = 1.0 to 5.2, p = 0.04) for an acute coronary event was found for the D/D genotype group.

View larger version (20K): [in this window] [in a new window]   Figure 3 Event-free Kaplan-Meier survival function for acute coronary events. D = deletion; I = insertion.

In a Cox proportional hazards’ model adjusting for age, serum LDL and high density lipoprotein cholesterol levels, smoking, hypertension, BMI, diabetes and family history of CHD, the RR associated with the D/D genotype was 2.2 (95% CI = 1.1 to 4.4, p = 0.02). The RR was 3.2 (95% CI = 1.5 to 6.7, p = 0.002) when the analysis was performed using only the definite and the probable AMI events (n = 30). When only men with no history of CHD were included in the analysis, the adjusted RR associated with the D/D genotype was 2.2 (95% CI = 1.0 to 5.0, p = 0.06) (Table 2).

_2B-AR genotype and hypertension.

View this table: [in this window] [in a new window]   Table 3 Prevalence of Treatment for Hypertension and the Level of Blood Pressure in the 2B-AR Genotypes

	Discussion

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Our hypothesis that the D variant of the _2B-AR gene confers increased vasoconstriction is based on two premises: the impaired desensitization associated with the D variant and the role of the _2B-AR in vasoconstriction. The functional significance of this I/D polymorphism of the _2B-AR gene has recently been investigated in an in vitro cell culture model. The results indicated that the D variant conferred clearly impaired receptor desensitization properties under prolonged agonist activation compared with the I form (15). The assumption that the _2B-AR is critically involved in the regulation of vasoconstriction cannot be directly tested in in vivo studies in humans, as subtype-selective _2B-AR drugs are not available. Studies in gene-targeted mice have clearly documented a prominent role for the _2B-AR in vasoconstriction (1). Despite that the perception of the _2B-AR subtype as an important mediator of vasoconstriction is based on studies in mice only, the similarity of the blood pressure responses to ₂-AR agonists in humans and laboratory rodents (1) suggests that the _2B-AR, rather than the _2A-AR or the _2C-AR, is the subtype that mediates vasoconstriction in humans also.

Augmentation in the constrictive properties of coronary arteries may be involved in the increased incidence of acute coronary events indirectly as the cause for intimal tearing leading to AMI or directly as in a coronary artery spasm (27,28). Increased vasoconstriction could lead to the observed higher prevalence of ischemic findings and incidence of coronary events in the D/D group by at least two additional mechanisms: 1) decreased coronary blood flow due to increased vasoconstriction of small coronary arteries, and 2) increased total peripheral resistance that leads to increase cardiac work load and increased oxygen demand.

The _2B-AR I/D genotype emerges in this study as an independent risk factor for acute coronary events, but the statistical association is not proof of causality. To examine the possibility that the D allele is a genetic marker for acute coronary events rather than a causative factor, we searched the literature for known genetic risk factors for CHD and their chromosomal localization. All other known genetic markers of CHD risk are located on different chromosomes than the _2B-AR gene (chromosome 2), favoring a causal relationship. Nevertheless, since the mechanism suggested for explaining this association has not been rigorously proven in vivo, it remains a real possibility that this I/D polymorphism is a genetic marker, rather than a causative factor, for acute coronary events.

_2B-AR polymorphism and hypertension.   There was no evidence for an association between the _2B-AR D variant and hypertension in our study. A similar result was reported by Baldwin et al. (29) in a study of 155 hypertensive sibling pairs. Therefore, it is possible that this variant truly has no effect on systemic BP or that its effect on BP is too small to be detected using the approaches employed by Baldwin et al. (29) or by us.

Study limitations.   The lack of a proven in vivo mechanism is a weakness of this study. The suggested mechanism of increased vasoconstriction mediated by _2B-AR due to decreased desensitization is based on the role of _2B-AR in peripheral vasoconstriction in transgenic mice (1) and an in vitro desensitization study on the D variant expressed in transfected cells (15). We hypothesized that deletion of three amino acids in this stretch can cause the same effect in humans in vivo. The large differences between the studies’ conditions—the species and tissue differences and the nature of the outcome measures—weaken the plausibility of the suggested mechanism and necessitate further studies on the physiological effects of this D variant on the human cardiovascular system.

Conclusions.   Taken together, the known biological properties of the _2B-AR in mice, the impaired desensitization properties of the D variant in vitro and the employed prospective study design suggest that the D variant of the _2B-AR gene is a causal risk factor for acute coronary events in Finnish men. To confirm the causality, the association of the D/D genotype with acute coronary events needs to be tested in other well-designed genetic epidemiological studies, and its physiological in vivo effects need to be identified.

	Acknowledgments

 
The authors thank Kari Seppänen, MSc, for supervising a part of the chemical analyses, Esko Taskinen, MD, and Juha Venäläinen, MD, for supervising exercise tests, Jaakko Tuomilehto, MD, PhD, and Kalevi Pyörälä, MD, PhD, for the access to the FINMONICA coronary register data and Kimmo Ronkainen, MA, for data management.

	Footnotes

 
Support for this study was provided by the European Commission (BMH4-CT98-373), Turku University Hospital and by research grants from the National Heart, Lung and Blood Institute of the U.S. (grant HL 44199 to Dr. George A. Kaplan) and the Academy of Finland (grants 41471, 1041086 and 2041022 to Dr. Jukka T. Salonen). Dr. Heinonen was supported by the Research and Science Foundation of Farmos and the Yrjö Jahnsson Foundation.

	References

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