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Glucocorticoid Receptor Gene and Risk of Cardiovascular Disease
Erica L. T. van den Akker, MD;
Jan W. Koper, PhD;
Elisabeth F. C. van Rossum, MD, PhD;
Marieke J. H. Dekker, MD;
Henk Russcher, PhD;
Frank H. de Jong, PhD;
Andre G. Uitterlinden, PhD;
Albert Hofman, PhD;
Huibert A. Pols, MD, PhD;
Jacqueline C. M. Witteman, PhD;
Steven W. J. Lamberts, MD, PhD
Arch Intern Med. 2008;168(1):33-39.
Background Genetic variants in immunomodulating genes have been suggested to contribute to the risk of cardiovascular disease. Glucocorticoids are important regulators of inflammatory processes and the immune system. Our aim was to determine the contribution of genetic glucocorticoid receptor variants, with different cortisol sensitivities, to the risk of cardiovascular disease.
Methods The study was conducted in a large (n = 7983) population-based, prospective cohort of the Rotterdam Study. The mean duration of follow-up was 8.9 years. Measures of cardiovascular disease were incident myocardial infarction, coronary heart disease, high-sensitivity C-reactive protein level, interleukin 6 level, and arteria carotis intima-media thickness.
Results Persons homozygous for haplotype 3, which is a common variant of the glucocorticoid receptor gene, had a more than 2-fold increased risk of myocardial infarction (hazard ratio, 2.1; 95% confidence interval, 1.13-4.07) and an almost 3-fold increased risk of coronary heart disease (hazard ratio, 2.6; 95% confidence interval, 1.40-4.81) compared with nonhomozygous persons. In addition, their C-reactive protein and interleukin 6 levels were higher, and carotis intima-media thickness was greater. No associations were found for the other haplotypes.
Conclusions The glucocorticoid receptor gene haplotype 3 is a common genetic variant and is related to a more active proinflammatory system. This haplotype is associated with the risk of cardiovascular disease and its parameters. These results should be regarded as hypothesis generating until they have been replicated in other studies. Our findings suggest that genetically determined cortisol sensitivity is involved in the pathogenesis of cardiovascular disease and might identify a subgroup at risk.
Author Affiliations: Departments of Internal Medicine (Drs van den Akker, Koper, van Rossum, Dekker, Russcher, de Jong, Uitterlinden, Pols, and Lamberts), Pediatrics (Dr van den Akker), and Epidemiology & Biostatistics (Drs Uitterlinden, Hofman, Pols, and Witteman), Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
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