Levels of total and high-density lipoprotein (HDL) cholesterol and triglycerides were measured using stan- dard laboratory methods; LDL cholesterol levels were cal- culated. C-reactive protein was measured with a highly sensitive method using a latex-enhanced immunoephe- lometric assay on a BN II analyser (Dade Behring, Lied- erbach, Germany). Interleukin 6 was determined by a commercially available immulite assay (Diagnostic Prod- ucts Corporation, Los Angeles, California), using ali- quots of undiluted sera tested against an absolute inter- leukin 6 standard preparation. Based on these standard curves, the concentrations of interleukin 6 were calcu- lated by the software provided. Cortisol was measured using a radioimmunoassay (Diagnostic System Labora- tories, Webster, Texas).

RESULTS

Lower extremity function or physical performance was assessed with measurements of standing balance, walking speed, and ability to rise from a chair (13). A summary performance scale, which ranged from 0 (worst) to 12 (best), was created by summing these scores. Satisfaction in performing activities of daily living was assessed by using a self-administered questionnaire (14). All items are evaluated on a 4-point scale; higher scores denote greater impairment.

Of the 402 men, 21 (5%) were heterozygous for the ER22/ 23EK polymorphism. No homozygotes were found. There were no significant differences in age, smoking sta- tus, measures of body composition, or lipids between the carriers and noncarriers (Table).

Mortality

Of the 381 noncarriers, 73 (19%) died during the 4 years of follow-up, while none of the 21 ER22/23EK carriers > = ( had died (Figure, P 0.03). Causes of mortality included     cardiovascular disease (40%, n 29), cancer (11%, n oa a 8), pneumonia (7%, n 5), cerebrovascular accident = (5%, n 4), miscellaneous (cachexia, infections, pulmo-    nary emphysema: 7%, n 5), and unknown (30%, n 22). Men with lower C-reactive protein levels (less than the median) had significantly better survival (13% [27/ 201] died) than those with higher C-reactive protein lev-  els (24% [47/201] died; hazard ratio 1.8; 95% confi- dence interval: 1.1 to 2.9). Additional analyses that adjusted for genotype, diabetes, or general health status (as physical performance, activities of daily life scores, and morbidity data) did not change these results.

At baseline, a 21-item medical history was obtained by a structured questionnaire, according to the following groups: musculoskeletal impairments (including arthri- tis and fractures); cardiovascular impairments (including symptoms or treatment of angina pectoris, heart failure, hypertension, arrythmia, myocardial infarction, cerebro- vascular accident, and shortness of breath); prostate problems (hyperplasia and cancer); other malignancies; endocrine disorders (diabetes mellitus and thyroid dis- ease); and other conditions (dizziness and disturbed vi- sion that impair mobility). A physical examination was performed. None of the participants was being treated for systemic infectious, inflammatory, or malignant disor- ders at the time of enrollment.

Anthropometric, Metabolic, and Parameters in ER22/23EK Carriers and Noncarriers

Glucocorticoid receptor genotypes were determined by restriction fragment length polymorphism analysis (15). For confirmation, we reanalyzed all 21 heterozygous samples and 10 wild-type samples, and found identical genotypes.

ER22/23EK carriers had significantly lower C-reactive protein levels than noncarriers (Table). Lean body mass tended to be higher in ER22/23EK carriers compared with noncarriers; however, this did not reach statistical significance after correction for height. C-reactive pro- tein levels correlated significantly with body mass index (r = ( 0.16, P  0.002), total fat mass (r  0.15, P  0.003), = | wee and trunk fat mass (r 0.16, P 0.001), but not with  aM?> = | lean body mass (r 0.02, P 0.63). Early morning cor- tisol levels did not correlate with C-reactive protein levels    (r 0.04, P 0.48) or genotype (P 0.81).

Data were analyzed using SPSS for Windows, release 10.1 (SPSS, Chicago, Illinois). Differences between the ER22/ 23EK carriers and the noncarriers were adjusted for age and, if necessary, for body mass index or smoking and tested by analysis of covariance using the general linear model procedure. Bonferroni post hoc tests were used to adjust for multiple comparisons. If dependent variables

Table 1. Baseline Characteristics of Noncarriers and Carriers of the ER22/23EK Polymorphism among 402 Elderly Men*

Noncarriers ER22/23EK Carriers     Characteristic (n 381) (n 21) P I+ Number (%), Mean SD, or Median (Interquartile Range)    Age (years) 77.7 3.6 78.3 3.6 0.46 Smokers 65 (17) 5 (24) 0.43 Body mass index (kg/m2) 25.6  4.3 25.9 Aasy+: 3.1 0.75 Lean mass (kg) 51.7    5.6 52.8  5.2 0.18† Fat mass (kg) 21.1  5.7 21.2  6.6 0.89†   I+ Trunk fat mass (kg) 10.6 2.6 10.6 2.9 0.98 Systolic blood pressure (mm Hg) 56   24 158  29 0.67‡ Diastolic blood pressure (mm Hg) 84  11 86  13 0.49‡ Total cholesterol (mmol/L)§ 5.8  1.1 5.4  1.0 0.14‡ LDL cholesterol (mmol/L)§ 3.8 Bt | 1.0 3.5 ye 0.9 0.22‡ HDL cholesterol (mmol/L)§ 1.3 I+ 0.4 1.3 I+ 0.3 0.36‡ Triglycerides (mmol/L)§ 1.4  0.8 1.3 I+ 0.7 0.75‡ C-reactive protein (mg/L)§ 4.0  9.1 2.0  2.6 0.01  _ Interleukin 6 (pg/mL) 19.1 11.1 19.9 9.2 0.47 Diabetes 30 (8) 3 (14) 0.31 Activities of daily life (points) 9 (8–12) 9 (8–11) 0.88 Physical performance (points) 9 (7–10) 9 (7–11) 0.54 Number of chronic diseases 3 (1–5) 3 (1–5) 0.78