Genetic Polymorphisms: An Insertion/Deletion Polymorphism of the a2B-Adrenoceptor Gene as a Risk Factor for Acute Coronary Events

Abstract

BACKGROUND: We have recently identified a variant form of the human a_2B-adrenoreceptor (AR) gene. Based on the coronary vasoconstrictive property of a₂-adrenoreceptors in humans, we hypothesized that the naturally occurring D (deletion) variant confers reduced receptor desensitization and therefore increased vasoconstriction in humans. This property could be associated with cardiovascular pathologies such as acute myocardial infarction (AMI) and sudden cardiac death (SCD). To test this hypothesis, we carried out two separate clinical genetic studies in middle-aged Finnish men, reported in two separate original publications.

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METHODS: We examined a subset (912 men, aged 46 to 64 years) of the Kuopio Ischemic Heart Disease Risk Factor Study, an ongoing prospective population???based study investigating risk factors for cardiovascular diseases and related outcomes in men from eastern Finland (Prospective Follow-up study). Seven hundred out-of-hospital deaths of Finnish men in the Helsinki region were subjected to autopsy and formed the basis of the second, cross-sectional study investigating the associations between the a_2B-AR I/D polymorphism and coronary heart disease (Autopsy study). DNA for genotyping was extracted using standard methods. The a_2B-adrenoreceptor insertion/deletion (I/D) genotypes were determined using PCR-amplification and DNA electrophoresis.

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RESULTS: Of the 912 subjects, 192 (21%) had the D/D genotype, 256 (28%) had the I/I genotype, and 464 (51%) were heterozygous. 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%). Using a univariate analysis, the risk for an acute coronary event differed significantly between the three genotype groups (p = 0.017). The D/D genotype group had a 3-fold increased risk for an acute coronary event in comparison with the I/D group (95% CI = 1.4 ??? 6.5, p = 0.004), and a non-significantly increased risk of 1.9 relative to the I/I genotype group (95% CI = 0.8 - 4.1, p = 0.128). In a Cox proportional hazards??? model adjusting for several variables, the relative risk associated with the D/D genotype was 2.2 (95% CI = 1.1 ??? 4.4, p = 0.02).

In the autopsy cohort, a_2B-AR I/D genotyping was accomplished for 683 men (98%). Of these, 152 (22%) had the D/D genotype, 186 (27%) had the I/I genotype, and 345 (51%) were heterozygous. The D/D genotype was associated with an increased risk for SCD and prehospital fatal AMI, with adjusted odds ratios (OR) of 1.8 - 2.4 compared to the other two genotypes (p < 0.05).

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CONCLUSION: the D variant of the a_2B-AR gene is a causal risk factor for AMI and SCD in Finnish men. Further genetic epidemiological studies are still needed to confirm the causality and to test its generalization to other populations, and its physiological in vivo effects need to be identified.

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Key Words: a_2B-adrenoreceptor polymorphism; coronary heart disease; acute myocardial infarction; sudden cardiac death; genotyping; genetic studies