* All parameters were adjusted for age, and C-reactive protein and interleukin 6 values were logarithmically transformed for statistical analysis. † Lean mass and fat mass were also adjusted for height. ‡ Blood pressures and lipids were adjusted for body mass index. § To convert total, HDL, and LDL cholesterol levels from mmol/L to mg/dL, multiply by 38.67; for triglyceride levels, multiply by 89.15. To convert C-reactive protein levels from mg/L to mg/dL, divide by 10. HDL  high-density lipoprotein; LDL   low-density lipoprotein.

effects of glucocorticoids, and have lower fasting insulin and cholesterol levels (2). Perhaps the lower C-reactive protein levels we observed in ER22/23EK carriers are re- lated to, and possibly even due to, having less atheroscle- rosis.

We found no differences in body mass index, blood pressure, or levels of HDL cholesterol, triglycerides, or interleukin 6 between ER22/23EK carriers and noncarri- ers (Table).

Greater body mass index, and fat mass in particular, are related to higher levels of interleukin 6 and C-reactive protein (18–22). We found that C-reactive protein level correlated positively with body mass index and fat mass in these elderly men, but there was no association be- tween interleukin 6 and these parameters. We did not observe differences in body mass index or fat mass by genotype. ER22/23EK carriers had a slightly (but not sig- nificantly) higher lean body mass. We hypothesize that a greater lean body mass, which might also result in greater insulin sensitivity, may also be a factor in the better car- diovascular health status of ER22/23EK carriers, thereby contributing to lower C-reactive protein levels. In an- other 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 ten- dencies towards less fat mass. Muscle mass is an impor-

DISCUSSION

In this population-based study involving elderly men, we found that carriers of the ER22/23EK polymorphism of the glucorticoid 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 athero- sclerosis or whether it reflects the degree of vascular dam- age (17). We previously demonstrated that carriers of the ER22/23EK polymorphism are relatively resistant to the

80Cumulative Survival (%)Subjects at risk (N)—-— ER22/23EK carriers— Noncarriers 21381 21373Follow -up time (years )21 21358 33721307

Thus, the association between ER22/23EK polymor- phism and mortality might be due to factors other than C-reactive protein. We reported an association between the ER22/23EK polymorphism and greater insulin sensi- tivity, as well as lower total and LDL cholesterol levels in a population-based sample that had a mean age of 67 years. Although we observed a similar pattern in the present study, we did not find statistically significant differences in cholesterol levels, perhaps because the mean age in the current study was more than 10 years older; selection of surviving participants with relatively low cholesterol lev- els may have occurred.

In this study, and in our previous study (2), there was no correlation between ER22/23EK polymorphism and early morning cortisol levels. However, we previously re- ported that the carrier genotype is associated with glu- cocorticoid resistance, as manifest by a decreased re- sponse to the dexamethasone suppression test (2). These data suggest that there may be beneficial metabolic ef- fects, 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 pro- tein levels and better survival in elderly men.

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

tant determinant of insulin sensitivity and can thus con- tribute 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.

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