Clinical Studies
Associations of elevated Interleukin-6 and C-Reactive protein levels with mortality in the elderly,

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Abstract

PURPOSE: To investigate whether interleukin-6 and C-reactive protein levels predict all-cause and cause-specific mortality in a population-based sample of nondisabled older people.

SUBJECTS AND METHODS: A sample of 1,293 healthy, nondisabled participants in the Iowa 65+ Rural Health Study was followed prospectively for a mean of 4.6 years. Plasma interleukin-6 and C-reactive protein levels were measured in specimens obtained from 1987 to 1989.

RESULTS: Higher interleukin-6 levels were associated with a twofold greater risk of death [relative risk (RR) for the highest quartile (≥3.19 pg/mL) compared with the lowest quartile of 1.9 [95% confidence interval, CI, 1.2 to 3.1]). Higher C-reactive protein levels (≥2.78 mg/L) were also associated with increased risk (RR = 1.6; CI, 1.0 to 2.6). Subjects with elevation of both interleukin-6 and C-reactive protein levels were 2.6 times more likely (CI, 1.6 to 4.3) to die during follow-up than those with low levels of both measurements. Similar results were found for cardiovascular and noncardiovascular causes of death, as well as when subjects were stratified by sex, smoking status, and prior cardiovascular disease, and for both early (<2.3 years) and later follow-up. Results were independent of age, sex, body mass index, and history of smoking, diabetes, and cardiovascular disease, as well as known indicators of inflammation including fibrinogen and albumin levels and white blood cell count.

CONCLUSIONS: Higher circulating levels of interleukin-6 and C-reactive protein were associated with mortality in this population-based sample of healthy older persons. These measures may be useful for identification of high-risk subgroups for anti-inflammatory interventions.

Section snippets

Subjects

Study subjects were participants in the Iowa 65+ Rural Health Study, one of four sites of the Established Populations for Epidemiologic Studies of the Elderly (18). In 1982, 3,673 persons (80% of those eligible) living in two Iowa counties participated in a comprehensive interview. Interviews were repeated annually for 7 years, and follow-up for mortality was continued until December 31, 1992. Blood was obtained from 1,940 participants who were reinterviewed between 1987 and 1989 at the seventh

Diseases and risk factors associated with Interleukin-6 and C-Reactive protein

The sample consisted of 279 men and 396 women, with a mean age of 77.8 ± 3.2 years. Twenty-nine percent were former or current cigarette smokers, and 18% reported cardiovascular disease or diabetes (Table 1). Less than 4% of the group had levels of C-reactive protein greater than the clinically relevant threshold of 10 mg/L. Male sex, cigarette smoking, greater body mass index, history of diabetes, and history of any cardiovascular disease were all associated with greater levels of

Discussion

In this population-based study, moderately high levels of interleukin-6 and C-reactive protein were associated with increased mortality. Joint elevation of interleukin-6 and C-reactive protein levels was associated with mortality in the overall sample, as well as in ever and never smokers, and those with and without a history of cardiovascular disease. Our findings extend the results of previous studies of the associations between acute phase proteins and cardiovascular disease 1, 2, 3, 4, 5, 6

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    Supported in part by National Institute on Aging Contract AG-0-2106. This paper was finalized when Drs. Ferrucci and Corti were Visiting Scientists in the Epidemiology, Demography and Biometry Program at the National Institute on Aging.

    Access the “Journal Club” discussion of this paper at http:/www.elsevier.com/locate/ajmselect/

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