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(Circulation. 2004;109:607-612.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Relationship of Alcohol Intake With Inflammatory Markers and Plasminogen Activator Inhibitior-1 in Well-Functioning Older Adults

The Health, Aging, and Body Composition Study

Stefano Volpato, MD, MPH; Marco Pahor, MD; Luigi Ferrucci, MD, PhD; Eleanor M. Simonsick, PhD; Jack M. Guralnik, MD, PhD; Stephen B. Kritchevsky, PhD; Renato Fellin, MD, PhD; Tamara B. Harris, MD, MS

From the Department of Clinical and Experimental Medicine (S.V., R.F.), University of Ferrara, Italy; Laboratory of Epidemiology (S.V., J.M.G., T.B.H.), Demography and Biometry, National Institute on Aging, Bethesda, Md; Sticht Center on Aging (M.P., S.B.K.), Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC; Geriatric Department (L.F.), I Fraticini, Italian National Institute for Research and Care on Aging (INRCA), Florence, Italy; and Intramural Research Program (E.M.S.), National Institute on Aging, Baltimore, Md.

Correspondence to Stefano Volpato, MD, MPH, Department of Clinical and Experimental Medicine, University of Ferrara, Via Savonarola, 9, I-44100 Ferrara, Italy. E-mail vlt{at}unife.it

Received May 19, 2003; de novo received July 28, 2003; revision received October 20, 2003; accepted October 21, 2003.

	Abstract

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Background— Increased levels of acute-phase reactants predict the onset of poor health outcomes. A U-shaped association has been reported between alcohol intake and health outcomes, which suggests that alcohol intake may modify levels of acute-phase reactants. We investigated the relationship between weekly alcohol intake and interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor- (TNF-), and plasminogen activator inhibitor-1 (PAI-1).

Methods and Results— Data are from year 1 of the Health, Aging, and Body Composition study, a biracial cohort of 3075 well-functioning men and women aged 70 to 79 years, living in Memphis, Tenn, and Pittsburgh, Pa. The analysis included 2574 persons (51.2% women; 40.1% black) with complete data. After adjustment for age, race, smoking status, history of diabetes, history of cardiovascular disease, physical activity, high-density lipoprotein cholesterol, antiinflammatory medications, statins, and total fat mass, alcohol intake showed a J-shaped relationship with mean IL-6 (P for quadratic term <0.001) and CRP (P=0.014) levels. The association was consistent in both men and women. Compared with subjects who consumed 1 to 7 drinks per week, those who never drank had an increased likelihood of having high levels of both IL-6 and CRP, as did those who drank 8 or more drinks per week. We found no relationship between alcohol intake and levels of TNF- and PAI-1 (P=0.137 and 0.08, respectively).

Conclusions— In well-functioning older persons, light alcohol consumption is associated with lower levels of IL-6 and CRP. These results might suggest an additional biological explanation to the epidemiological link between moderate alcohol consumption and cardiovascular events.

Key Words: alcohol • inflammation • aging • epidemiology • interleukins

	Introduction

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There is strong evidence that increased levels of inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), predict the onset of poor health outcomes, particularly cardiovascular events and mortality, in middle-aged and older people.^1,2 Although the mechanisms that lead to increased plasma levels of these markers of inflammation have not been completely elucidated, many factors, including aging, infections, chronic conditions, body composition, and lifestyle habits, are likely to be involved in the regulation of proinflammatory cytokines and acute-phase proteins.³

Recent studies showed that moderate alcohol intake is associated with lower levels of some acute-phase markers, including fibrinogen and CRP.^4–6 Although several cytokines and exogenous agents can influence hepatic production of acute-phase reactants, IL-6 is the most potent stimulant of acute-phase proteins by hepatocytes. IL-6 is produced by a variety of cell types in different physiological and pathological states.⁷ It has been suggested that ethanol might modulate IL-6 production and clearance at several sites, including adipose tissue. In addition, ethanol might modulate the effect of IL-6 on the stimulation of acute-phase protein production from hepatocytes.⁸ Nevertheless, data on the relationship between alcohol intake and circulating IL-6 levels are scant.

Using data from a large biracial cohort of well-functioning older adults, we investigated the association of alcohol intake with 3 inflammatory markers, IL-6, tumor necrosis factor- (TNF-), and CRP. In addition, we assessed the relationship with plasminogen activator inhibitor-1 (PAI-1), a modulator of fibrinolytic activity that is correlated with several markers of inflammation.⁹

	Methods

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Sample
Data are from 3075 well-functioning white and black men and women aged 70 to 79 years who were participating in the Health, Aging, and Body Composition (Health ABC) study, a prospective cohort study. The cohort included 847 white women, 723 black women, 927 white men, and 544 black men from 2 field centers (Pittsburgh and Memphis). Recruitment was undertaken from a random sample of white Medicare beneficiaries and all age-eligible black community residents in designated zip codes surrounding the field centers. To be eligible for the study, participants had to report no difficulty in walking 1/4 of a mile, in climbing 10 steps, or in activities of daily living. Subjects provided informed consent after the study’s approval by the Institutional Review Boards of the University of Pittsburgh and the University of Tennessee, Memphis. Of the initial 3075, 501 subjects had no valid data on IL-6 (136), TNF- (203), CRP (38), PAI-1 (65), or total fat (113). Data presented here are from the baseline examination and include 2574 subjects (51.2% women) with complete information on main variables of interest. Participants excluded (n=501) from the analysis were more likely to be black but were not different in age or gender.

Measures
Alcohol Intake
Information on alcoholic beverage consumption was assessed by means of a questionnaire administered at the baseline interview. The interviewer first explained to the participant that alcoholic beverages included any kind of drink containing alcohol, including beer, ale, wine, liquors, gin, rum, vodka, and cocktails or other mixed drinks. The interviewer also explained that 1 drink was considered to be equal to 12 ounces of beer (1 can), 5 ounces of wine (a full glass), or a drink containing a "shot," a "jigger," or a "finger" of liquor. After that, the participant was asked to report how many drinks he/she had in a typical week, during the past 12 months. The participant was also asked if he/she ever drank more than what he/she was drinking in the past 12 months. No information was collected on specific beverages. Using this information, average weekly alcohol intake was categorized as follows: never, former, occasional (<1 drink per week), 1 to 7 drinks per week, 8 to 14 drinks per week, and >14 drinks per week. These categories were chosen according to national dietary guidelines that recommend that women have no more than 1 drink per day and men no more than 2 drinks per day.¹⁰ The last category was created to include the small percentage of subjects who drank more than 14 drinks per week.

Biochemical Measures
Blood samples were collected at the clinic the morning after an overnight fast of at least 8 hours. Cytokines were measured in duplicate by an ELISA kit from R&D Systems. The detectable limit for IL-6 (by HS600 Quantikine kit) was 0.10 pg/mL, and for TNF- (by HSTA50 kit), it was 0.18 pg/mL. Serum levels of CRP were also measured in duplicate by ELISA based on purified protein and polyclonal anti-CRP antibodies (Calbiochem). The CRP assay was standardized according to the World Health Organization First International Reference Standard, with a sensitivity of 0.08 µg/mL. Assays of blind duplicates collected for 150 participants yielded an average interassay coefficient of variation of 10.3% for IL-6, 8.0% for CRP, and 15.8% for TNF-. PAI-1 was measured with an in-house 2-site immunoassay that is sensitive to free PAI-1 but not to PAI-1 complexed with tissue plasminogen activator.¹¹ The analytical coefficient of variation for this assay is 3.5%. The expected normal range is 5 to 66 ng/mL. Total cholesterol, HDL cholesterol (HDL-C), and triglyceride levels were measured on a Vitros 950 analyzer (Johnson & Johnson), and LDL cholesterol level was calculated with the Friedewald equation.

Other Covariates
Other variables gathered included race, level of education, smoking history (never, former, or current smoker), and medication use. Physical activity of the past 7 days was assessed. Time spent on climbing stairs, walking for exercise or other purposes, aerobics, weight or circuit training, high-intensity exercise activities, and moderate-intensity exercise activities was obtained, as well as information on the intensity level. A metabolic equivalent value was assigned to each activity/intensity combination.¹² For each participant, the scores of all performed activities were summed and multiplied by body weight to create an overall physical activity score in kilocalories per week. Participants were categorized as physically inactive if they spent fewer than 200 kcal/week.¹³ Current use of antiinflammatory drugs (nonsteroidal, salicylates, and other antiinflammatory drugs) and statins was determined from drug data coded with the Iowa Drug Information System (IDIS) ingredient codes.¹⁴ Prevalence of chronic conditions was determined by self-reported physician-diagnosed disease information, clinic data, and medication use. Body mass index (BMI) was computed as weight (kilograms) divided by the square of height (meters) using objective measures. Total body fat (kg) was determined with fan-beam DXA (Hologic QDR4500, software version 8.21), whereas visceral fat area (cm²) was computed from a CT image obtained at L4-L5.

Analysis
General and health-related characteristics were compared across categories of alcohol consumption with the ² test used for categorical characteristics and ANOVA for continuous variables. IL-6, CRP, TNF-, and PAI-1 values were log-transformed to achieve an approximately normal distribution. These continuous variables were used as dependent variables in linear regression models in which the categories of alcohol were introduced as an ordinal variable. Multinomial regression models, with alcohol intake categories included as linear and quadratic terms, were used to assess the presence of a nonlinear relationship between alcohol intake and the dependent variables. We also combined the level of IL-6 and CRP to create a combined measure of inflammation with higher specificity. High IL-6 and CRP levels were defined as the highest tertiles for the study population (IL-6 >2.82 pg/mL; CRP >3.1 mg/L). The likelihood of having high levels of both IL-6 and CRP according to alcohol intake was estimated by means of multivariate logistic regression analysis. All multivariate models were adjusted for age, race, gender, education, smoking, diabetes, cardiovascular disease, total fat mass, physical activity, HDL-C, medication use, and site. To better understand the different effects of other lifestyle-related factors on the relationship between alcohol intake and inflammatory markers, 3 different logistic models were built: (1) unadjusted; (2) adjusted for demographics, smoking, and physical activity level; and (3) additional adjustment for all health-related factors.

	Results

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Almost 50% of the participants did not drink alcohol during the previous 12 months, but of these, 44% had consumed some amount of alcohol in the past. Among drinkers, most of the participants drank either occasionally or 1 to 7 drinks per week. Only 2.8% of this cohort reported consuming more than 14 drinks per week, with men accounting for 84.5% of this subgroup (Table 1). Women were more likely to be never-drinkers. Black participants reported a lower consumption of alcohol than white subjects. Cigarette smoking showed a positive relationship with the number of drinks consumed. Daily alcohol intake was inversely associated with BMI and total fat mass, but there was no relationship with visceral fat area.

View this table: [in this window] [in a new window]   TABLE 1. Selected General Characteristics According to Average Weekly Alcohol Intake

The Figure shows the crude association of weekly alcohol intake with IL-6, CRP, TNF-, and PAI-1. We found a J-shaped relationship between the number of drinks and mean IL-6 and CRP levels, with minimum levels in subjects who had 1 to 7 drinks per week. Of note, former drinkers tended to have greater values of IL-6 and CRP than subjects who never drank. These nonlinear relationships were confirmed in polynomial regression analyses, adjusted for potential confounders (Table 2). For both IL-6 and CRP, the inclusion of alcohol intake as a quadratic term significantly improved the goodness of fit of the models (probability value for the likelihood ratio test <0.001 for IL-6 and 0.014 for CRP). The results were consistent after exclusion of former drinkers. Weekly alcohol intake was not associated with TNF- or PAI-1 concentration.

View larger version (16K): [in this window] [in a new window]   Median IL-6 (pg/mL), CRP (mg/L), TNF- (pg/mL), and PAI-1 (ng/mL) plasma levels according to average weekly alcohol intake.

View this table: [in this window] [in a new window]   TABLE 2. Adjusted Means* for IL-6, CRP, TNF-, and PAI-1 According to Average Weekly Alcohol Intake

Table 3 reports the results of multivariate analyses stratified by gender and race. The J-shaped relationship between alcohol intake and IL-6 was significant in both men and women (P for quadratic terms <0.01). The same type of relationship was found for CRP; nevertheless, such an association was statistically significant only among women (P<0.01), with the coefficient for the interaction term being marginally significant (P=0.069). Consistent results were found after stratification for race.

View this table: [in this window] [in a new window]   TABLE 3. Adjusted Means* for IL-6 and CRP According to Alcohol Intake, Stratified by Gender and Race

Subjects who were drinking 1 to 7 drinks per week had a lower probability (15%) of having high levels of both IL-6 and CRP than subjects who never drank any alcoholic beverage (20.1%) and subjects who had >7 drinks per week (8 to 14, 27%; >14, 28.2%; Table 4). After adjustment for demographic and lifestyle-related variables, and compared with subjects who were drinking 1 to 7 drinks per week, participants who never drank had a 42% (95% CI 3% to 96%) increased risk of being in the top third of the IL-6 and CRP distribution. The estimate was somewhat reduced after additional adjustment for other confounders and potential mediators, including HDL -C and measures of body composition (25%; 95% CI -10% to 74%).

View this table: [in this window] [in a new window]   TABLE 4. Crude Rates and Adjusted ORs for the Likelihood of Having High Levels of IL-6 and CRP by Categories of Alcohol Intake

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this cohort of well-functioning older subjects, weekly alcohol intake had a J-shaped association with IL-6 and CRP levels. Participants who reported light alcohol intake had lower levels of both IL-6 and CRP than subjects who never drank alcohol and those who were drinking greater amounts of alcoholic beverages. This association was not affected by controlling for potential confounders, including a number of social and lifestyle indicators, and was consistent in both men and women. The findings were confirmed when IL-6 and CRP levels were combined to obtain a more specific indicator of inflammatory status. No association was found with TNF- and PAI-1 levels.

Moderate alcohol intake has been associated with decreased risk of a number of adverse health outcomes, including all-cause mortality, cardiovascular diseases, insulin resistance and diabetes, and dementia, all conditions for which inflammation has been proposed as a key pathogenic component.^15,16 Although other mechanisms are likely to be involved, the relationship between alcohol intake and the level of inflammatory markers would offer an additional biologically plausible explanation. Indeed, recent epidemiological^5,6 and experimental¹⁷ studies reported an association between moderate alcohol intake and lower levels of CRP in a sample of middle-aged men and women. For example, using data from the Third National Health and Nutritional Examination, Stewart and colleagues¹⁸ demonstrated that moderate alcohol drinkers (11 to 30 drinks per month) had a 26% decreased probability of having a high level of CRP. The present results are in line with this observation and extend earlier findings to older subjects, and for the first time, they demonstrate at a population level the association between alcohol intake and IL-6 levels. IL-6, which is a major determinant of acute-phase protein production, has been proposed as the key factor linking inflammation, obesity, stress, and coronary heart disease.¹⁹ Therefore, the present results might provide new insight to support a biological relation between alcohol intake and the risk for cardiovascular disease.

Increased levels of IL-6 and other inflammatory cytokines are clearly involved in the early stage of many liver diseases, including alcoholic steatohepatitis, therefore providing a biological support to the association between heavy alcohol intake and increased levels of IL-6 and CRP.²⁰ On the other hand, which mechanism could explain the lower levels of inflammation markers detected in subjects with light alcohol intake compared with nondrinkers? It has been suggested that a beneficial effect of ethanol on IL-6 levels could be the link. Two potential mechanisms have been proposed. First, experimental studies suggest that alcohol intake enhances the uptake and metabolism of IL-6, but not TNF-, by isolated and perfused rat liver.²¹ Second, acetate, the main circulating metabolite of ethanol, might downregulate TNF- and IL-6 secretion from adipocytes.⁸ From this point of view, it is interesting to note that the present results were consistent in subjects with low and high levels of visceral fat area (data not shown).

There is a close relationship between circulating levels of CRP, IL-6, and TNF-¹⁹; TNF- modulates the expression of PAI-1 by hepatocytes, endothelial cells, and adipose tissue.²² Therefore, we hypothesized a relationship of alcohol intake with TNF- and PAI-1. Indeed, a J-shaped relationship between alcohol intake and PAI-1 plasma level would have provided an additional biological explanation to the association between ethanol intake and risk of cardiovascular events, because reduction of PAI-1 levels is associated with enhanced fibrinolysis.²³ Nevertheless, although previous studies demonstrated the beneficial effect of moderate alcohol consumption on hemostatic factors, the present results did not show any relationship with PAI-1. This is in agreement with previous reports showing little or no association between alcohol intake and PAI-1²⁴ and may indicate that proinflammatory cytokines are not involved in the known relation between ethanol and hemostatic factors.⁴

The present study has several limitations. Alcohol intake was assessed by means of a standardized self-report questionnaire. Compared with prospective assessment of daily food records (ie, 7-day food record), this method is more prone to misreporting and misclassification of alcohol consumption. This methodological issue is important because nondifferential misclassification may have diluted the true association between alcohol intake and the biomarkers used in the present study. The questionnaire used for this study did not collect information on use of specific alcoholic beverages. As a consequence, we were not able to investigate any potential differential effect across types of alcoholic beverages. However, a recent work suggests that the protective effect of alcohol intake is consistent across different types of beverages.²⁵ An advantage of our approach is the possibility of discriminating between abstainers and ex-drinkers. This is important because ex-drinkers are more likely to have clinical and subclinical conditions that could spuriously increase cytokine levels in the nondrinker group. Alcohol intake is associated with several other lifestyle and clinical characteristics. Therefore, although the analysis considered a number of potential confounders, a residual confounding effect cannot be completely ruled out. Finally, this is a cross-sectional study, and therefore a causal relationship cannot be established.

In conclusion, our data confirm that light alcohol intake may have an antiinflammatory effect. Alcohol intake may have an antiinflammatory effect that may reflect a direct effect of ethanol on IL-6 metabolism. These findings might provide an additional biological explanation to the many epidemiological works that show a protective effect of light to moderate alcohol intake on several health outcomes.

	Acknowledgments

 
This work was supported through the National Institute on Aging, contract numbers N01-AG-6-2106, N01-AG-6-2102, and N01-AG-6-2103; the American Heart Association (grant No. 9970066N); and the Ministero dell’Universitá e della Ricerca Scientifica e Tecnologica, Italy. Dr Pahor was supported by grant P60 AG 10484-07.

	References

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