ER22/23EK carriers had slightly (but not significantly) higher lean body mass. A greater lean body mass, which might also result in greater insulin sensitivity, may be a factor in the better cardiovascular health status of ER22/23EK carriers, thereby contributing to lower C-reactive protein levels. In another study, we found associations of the ER22/23EK polymorphism with body composition in young adults, specifically in male carriers aged 36 years with an average of 5 kg more lean mass and in female carriers with tendencies towards less fat mass. Muscle mass is an important determinant of insulin sensitivity and can thus contribute to a better metabolic profile. We believe that body composition could play an important role in the relation of the ER22/23EK polymorphism with both survival and C-reactive protein levels.

In this population-based study involving elderly men, we found that carriers of the ER22/23EK polymorphism of the glucocorticoid receptor gene had better 4-year survival. This is in line with our previous findings (2), in which we observed that the proportion of ER22/23EK carriers was significantly greater in the older half of the study sample. The ER22/23EK carriers also had significantly lower C-reactive protein levels, but no association was found with anthropometric parameters or interleukin 6 levels. Since C-reactive protein level predicts total and cardiovascular mortality in the elderly (16), it might underlie the effect of the ER22/23EK polymorphism on survival. However, it is unclear whether C-reactive protein is a cause of atherosclerosis or whether it reflects the degree of vascular damage (17).

We previously demonstrated that carriers of the ER22/23EK polymorphism are relatively resistant to the effects of glucocorticoids, as manifest by a decreased response to the dexamethasone suppression test (2). These data suggest that there may be beneficial metabolic effects resulting in better survival due to subtle lifelong glucocorticoid resistance. In the present study, we found that the ER22/23EK polymorphism of the glucocorticoid receptor gene was associated with lower C-reactive protein levels and better survival in elderly men.

Figure. Kaplan-Meier survival curves by glucocorticoid receptor genotype. ER22/23EK carriers had significantly better survival than noncarriers. The solid line denotes noncarriers; the dotted line denotes ER22/23EK carriers.

REFERENCES:
1. Baxter JD, Rousseau GG. Glucocorticoid hormone action: an overview. Monogr Endocrinol. 1988;13:1-20.
2. van Rossum EF, Koper JW, Huizenga NA, et al. A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes. 2002;51:3128-3134.
3. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506-512.
4. Ridker PMBetween five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet. ;  :

Strandberg TE, Tilvis RS. C-reactive protein, cardiovascular risk factors, and mortality in a prospective study in the elderly. Arteriosclerosis Thrombosis and Vascular Biology. ;  :

Rattazzi M, Puato M, Faggin E, et al. C-reactive protein and interleukin in vascular disease: culprits or passive bystanders? Journal of Hypertension. ;  :

Frohlich M, Imhof A, Berg G, et al. Association between C-reactive protein and features of the metabolic syndrome: a population-based study. Diabetes Care. ;  :