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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2559-2566
Copyright © 2007 by The Endocrine Society

Alcohol Consumption and Lipoprotein Subclasses in Older Adults

Kenneth J. Mukamal, Rachel H. Mackey, Lewis H. Kuller, Russell P. Tracy, Richard A. Kronmal, Murray A. Mittleman and David S. Siscovick

Divisions of General Medicine and Primary Care (K.J.M.) and Cardiology (M.A.M.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215; Department of Epidemiology (R.H.M., L.H.K.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Department of Pathology (R.P.T.), University of Vermont, Burlington, Vermont 05405; Department of Epidemiology (M.A.M.), Harvard School of Public Health, Boston, Massachusetts 02115; and Departments of Biostatistics (R.A.K.), Epidemiology (D.S.S.), and Medicine (D.S.S.), University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: Kenneth J. Mukamal, M.D., M.P.H., M.A., Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RO-114, Boston, Massachusetts 02215. E-mail: kmukamal{at}pidmc.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Limited evidence suggests that alcohol intake may be associated with lipoprotein subclass distribution, which could mediate its relationship with coronary heart disease.

Objectives: The objective was to determine the relationship of alcohol intake with lipoprotein particle subclasses.

Design, Setting, and Participants: The study included a cross-sectional analysis of 1850 participants of the Cardiovascular Health Study aged 65 yr and older and free of clinical cardiovascular disease.

Main Outcome Measure: Lipoprotein subclass distribution was measured with nuclear magnetic resonance spectroscopy, according to self-reported alcohol intake.

Results: Alcohol intake was associated with total low-density lipoprotein (LDL) particles in a U-shaped manner. Consumers of one or more drinks per week had the highest number of large LDL particles, whereas consumers of 7–13 drinks per week had the lowest number of small LDL particles. Alcohol intake was strongly positively associated with large- and medium-sized high-density lipoprotein (HDL) particles but had an inverse relationship with concentrations of small HDL particles and small- and medium-sized very-low-density lipoprotein particles. Average particle sizes of all three lipoproteins were positively associated with alcohol intake. Associations were generally stronger among women than men but in similar directions. Beverage type did not consistently modify these findings.

Conclusions: Alcohol intake is associated with less total LDL particles, lower levels of small LDL, HDL, and very-low-density lipoprotein particles, and higher levels of large LDL and medium- and large-sized HDL particles in older adults free of prevalent clinical cardiovascular disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MODERATE ALCOHOL consumption has been inversely associated with risk of coronary heart disease (CHD) (1). Approximately half of this association has been attributed to the higher levels of high-density lipoprotein cholesterol (HDL-C) found among moderate drinkers (2, 3). Experimental studies confirm that alcohol administration directly raises HDL-C levels, particularly among individuals with lower baseline levels (4). The nature of the other factors that mediate the association of moderate drinking with lower CHD risk is uncertain, especially in older adults in whom conventionally measured lipids are relatively weakly associated with CHD risk (5).

In analyses from the Cardiovascular Health Study (CHS) that compared participants with incident CHD with participants free of clinical or subclinical disease, lipoprotein subclass distribution was associated with risk of CHD, particularly among women, with the greatest risk seen for small dense low-density lipoprotein particles (LDL-P) (6). The association of alcohol use with lipoprotein subclass distribution has not been extensively studied, although limited epidemiological and experimental data support the hypothesis that alcohol use is associated with increases in larger, less dense LDL subfractions (7, 8).

To address these issues, we evaluated the cross-sectional associations of alcohol use with lipoprotein subclasses, as evaluated by nuclear magnetic resonance (NMR) spectroscopy among older adults free of cardiovascular disease enrolled in CHS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population and design

The CHS is a prospective study of 5888 men and women aged 65 yr or older who were randomly selected from Medicare-eligibility lists in four communities in the United States (9). Participants were not institutionalized or wheelchair dependent, did not require a proxy for consent, were not under treatment for cancer at the time of enrollment, and were expected to remain in their respective regions for at least 3 yr. In 1989 and 1990, 5201 participants were recruited and examined; in 1992 and 1993, an additional 687 participants were recruited and examined. The institutional review board at each participating center approved the study, and each participant gave informed consent.

The CHS study design and objectives have been published previously (9). The baseline examination included standardized medical history questionnaires, physical examination, resting electrocardiography, and laboratory examination. Follow-up contact occurred every 6 months, alternating between telephone calls and clinic visits.

Alcohol consumption

At the baseline visit, participants separately reported their usual frequency of consumption of beer, wine, and liquor, and the usual number of 12-ounce cans or bottles of beer, 6-ounce glasses of wine, and shots of liquor that they drank on each occasion (corresponding to ~12 g of ethanol per drink). The full text of the CHS nutritional questionnaire is publicly available (10). At baseline, participants reported whether they changed their pattern of consumption during the past 5 yr and whether they ever regularly consumed five or more drinks daily. Participants who reported abstention at baseline but responded yes to either of these questions were classified as former drinkers.

We categorized participants into categories according to weekly ethanol consumption as follows: none, former, less than 1 drink, 1–6 drinks, 7–13 drinks, and 14 or more drinks. For regression analyses, we used abstainers without former use as the reference category.

Lipoprotein measurement

Plasma collected at baseline from a total of 1622 CHS participants from the original cohort underwent NMR spectroscopy at LipoScience (Raleigh, NC) for determination of lipoprotein subclasses as part of a nested case-cohort study in CHS (6). All participants were free of clinical cardiovascular disease at baseline. These participants comprised several groups: 249 who were free of all subclinical atherosclerosis [as defined in CHS (11)]; 492 who were free of incident myocardial infarction or angina through June 30, 1995; 222 with incident angina but not myocardial infarction by this date; 213 with incident myocardial infarction; 200 with incident stroke; and 246 with subclinical cerebral infarcts by cranial magnetic resonance imaging. Participants free of incident myocardial infarction or angina and those free of all subclinical disease were sampled randomly from the CHS population, as described previously (6). Samples from an additional 228 randomly selected Black participants free of myocardial infarction or stroke from the new cohort were also analyzed, for a total of 1850 participants. In this cross-sectional analysis, we used all of the participants who had information available on alcohol use and NMR spectroscopy (n = 1841) and weighted our results to reflect the underlying CHS population free of clinical cardiovascular disease.

We measured lipoprotein particle diameters with an improved version of the automated NMR spectroscopic assay described previously (6, 12). In brief, lipoprotein subclasses emit characteristic lipid methyl group NMR signals, and the signal amplitude reflects particle concentration.

We examined the following subclass categories: large very-low-density lipoprotein particles (VLDL-P) (>60 nm; chylomicrons are included in this category), intermediate VLDL-P (35–60 nm), small VLDL-P (27–35 nm), intermediate-density lipoprotein particles (23–27 nm), large LDL-P (21.2–23.0 nm), small LDL-P (18.0–21.2 nm), large high-density lipoprotein particles (HDL-P) (8.8–13.0 nm), medium HDL-P (8.2–8.8 nm), and small HDL-P (7.3–8.2 nm). Summation of the subclasses provides levels of total LDL-P, total HDL-P, and total VLDL-P. Subclass particle concentrations are given in units of nanomoles per liter for VLDL-P and LDL-P (including intermediate-density lipoprotein particles) and micromoles per liter for HDL-P. Weighted-average VLDL-P, LDL-P, and HDL-P sizes (in nanometer diameter units) were calculated as the particle size of each subclass multiplied by its relative mass percentage as estimated from the amplitude of its NMR signal.

LDL and HDL subclass distributions determined by NMR and gradient gel electrophoresis are correlated (13, 14). LDL subclass diameters are approximately 5 nm smaller than those estimated by gradient gel electrophoresis.

We used standard enzymatic methods to determine total cholesterol, HDL-C, and triglycerides, standardized according to the Centers for Disease Control and Prevention guidelines as described previously (15). LDL-C levels were calculated using the Friedewald equation.

We undertook a minimal and consistent number of freeze-thaw cycles and prompt refreezing to ensure reliable measurement of triglyceride-rich particles (16, 17). The correlation of enzymatically measured triglycerides and VLDL triglycerides (as a measure of particle preservation) was nearly perfect (Spearman’s r = 0.94; P < 0.001).

Other covariates

We defined diabetes as a fasting blood sugar of at least 126 mg/dl or the use of antidiabetic medication. We dichotomized educational attainment (completion of high school or less vs. at least some vocational school or college) and income (less than $16,000 vs. at least $16,000 per year). We assessed leisure-time physical activity as a weighted sum of kilocalories expended in specific physical activities (18). Waist circumference, height, and weight were directly measured at the baseline visit. Dietary information was available only for participants in the original CHS cohort.

Statistical methods

To account for the particular sampling frame used to generate the sample of CHS participants whose plasma underwent spectroscopy, we used appropriate sampling weights in all analyses. We examined the relationships of alcohol consumption with lipoprotein variables adjusted by linear regression models. Adjusted models included covariates of age (in years), race, education, income, marital status, waist circumference (in centimeters), body mass index (as linear and centered quadratic terms), leisure-time energy expenditure (in kilocalories), current and former cigarette smoking, diabetes, hormone replacement therapy among women, and creatinine (in milligrams per deciliter).

A total of 31 participants took statins or did not report information on statin use at baseline, and their exclusion did not change our results. Likewise, exclusion of the 60 participants who took other lipid-lowering medications or adjustment for intake of calories, fiber, and saturated fat among participants in the original cohort did not meaningfully influence our findings.

Given the association of lipoprotein subclass distribution with other features of metabolic syndrome (19), we considered fasting insulin level as a potential mediator because it is directly affected by alcohol use (20). For analyses of large and small LDL-P, we also examined the effect of adjustment for HDL-C and two inflammatory markers (C-reactive protein and fibrinogen), both directly affected by alcohol use (4), as potential mediators for effects on LDL.

Total and large LDL-P, LDL-C concentration, HDL-related variables, and average particle sizes were symmetrically distributed. Small LDL-P number was asymmetrically distributed and was analyzed with linear regression after log transformation (with addition of 1); alternate analyses using ordinal logistic regression yielded qualitatively similar findings. We also performed log transformation of triglyceride levels and VLDL-related variables to accommodate rightward skews. As a result, percentage differences are presented for these variables.

We repeated all analyses separately in men and women. In exploratory beverage-type analyses, we examined the relationship of lipoprotein variables with intake of each beverage, simultaneously adjusting for intake of the other two beverages (21).

We excluded former drinkers in tests of linear trend. To test quadratic trend, we squared a centered linear trend variable. We used Intercooled Stata 8.0 for Windows (Stata Corporation, College Station, TX) to accommodate the sampling weights in all analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows the descriptive characteristics of the 1841 CHS participants with measurements of lipoprotein subclasses, according to usual alcohol consumption. Consistent with previous reports (22), alcohol use tended to be positively related to male sex, white race, current and former smoking, and greater physical activity.


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  		TABLE 1. Characteristics of 1841 CHS participants with lipoprotein subclass measurements, according to usual alcohol consumption

 
Alcohol consumption and LDLs

We assessed four interrelated LDL subclass measures: total LDL-C concentration (measured enzymatically) and total, large, and small LDL-P, with mean weighted concentrations of 1521, 679, and 792 nmol/liter, respectively. As seen in Table 2Go, alcohol intake was not associated with LDL-C levels but was associated with total LDL-P in a U-shaped manner (P quadratic = 0.04). However, alcohol intake had markedly different associations with the numbers of large and small LDL-P. In general, consumers of one or more drinks per week had the highest levels of large LDL-P, whereas consumers of 7–13 drinks per week had the lowest levels of small LDL-P.


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  		TABLE 2. Mean differences in LDL-C and total and large LDL-P and percentage differences in small LDL-P among CHS participants according to usual alcohol intake relative to long-term abstainers

 
We tested several possible mediators of the association between alcohol intake and small and large LDL-P in adjusted models. When HDL-C was added (Table 2Go), the positive association of alcohol intake with large LDL-P was sharply attenuated, and a positive association of heavy drinking with smaller LDL-P was evident. Adding triglyceride levels had a somewhat similar but much more modest effect (Table 2Go). Adjustment for fasting insulin or C-reactive protein and fibrinogen together had little effect on our results (data not shown), suggesting that the effect of alcohol intake on the distribution of LDL subclasses may be mediated primarily through a common metabolic pathway with its effects on HDL-C.

We found approximately similar patterns of associations between alcohol intake and levels of large and small LDL-P among men and women and participants with and without an apolipoprotein E4 (apoE4) allele (apoE data not shown) (see the supplemental data published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). In general, the directions of the associations were similar in all cases, although the associations were typically stronger among women and individuals who carried an apoE4 allele.

Alcohol consumption and HDLs

Table 3Go shows the relationship of alcohol intake with HDL-C and with total, large, medium, and small HDL-P. Mean weighted concentrations for these four classes were 34.8, 7.5, 3.7, and 23.7 µmol/liter, respectively. As expected, alcohol intake was strongly associated with total HDL-C levels. When examined separately, alcohol intake had a positive relation with large- and medium-sized HDL-P but little or even an inverse relation with levels of small HDL-P. Despite previous findings from other studies (23), there was no clear effect modification by apoE4 allele carrier status (data not shown) (see the supplemental data).


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  		TABLE 3. Mean differences in HDL-C and total, large, medium, and small HDL-P among CHS participants according to usual alcohol intake relative to long-term abstainers

 
As a composite measure, we also examined the ratio of total LDL-P to total HDL-P in relation to alcohol use. Compared with long-term abstention, the ratio was 5% lower with intake of less than one drink per week, 8% lower with one to six drinks per week, 9% lower with 7–13 drinks per week, and 11% lower with 14 or more drinks per week (P trend = 0.001).

Alcohol consumption and VLDLs

Mean weighted concentrations for total, large, medium, and small VLDL-P were 83, 4, 31, and 48 nmol/liter, respectively. Table 4Go shows the association of alcohol intake with triglycerides and levels of VLDL-P. Total triglyceride and large VLDL-P levels were lowest among consumers of 1–13 drinks per week, particularly among women. In contrast, alcohol consumption was inversely associated with total, medium, and small VLDL-P in an approximately stepwise manner.


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  		TABLE 4. Percentage differences in triglycerides and total, large, medium, and small VLDL-P among CHS participants according to usual alcohol intake relative to long-term abstainers

 
Alcohol consumption and lipoprotein size

Figure 1Go shows estimated lipoprotein size according to alcohol consumption. For all three particle types, heavier alcohol consumption tended to be associated with larger average particle size, although there was evidence of a curvilinear relationship with LDL-P size.


Figure 1
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  		FIG. 1. Adjusted differences in average HDL-P, LDL-P, and VLDL-P size relative to abstainers, according to usual weekly alcohol intake. P values for linear/quadratic trend were as follows: P < 0.001/0.25 for HDL; P < 0.001/0.02 for LDL; and P < 0.001/0.06 for VLDL. Mean differences were adjusted for age, sex, race, current smoking, former smoking, marital status, education, income, leisure-time physical activity, body mass index (linear and squared), waist circumference, diabetes, hormone replacement therapy, and serum creatinine.

 
Beverage type and lipoprotein subclasses

We also explored the associations of levels of large and small LDL-P, HDL-P, and VLDL-P with beer, wine, or liquor consumption, controlling for consumption of the other two beverages. In general, there was no clear pattern of differences among the beverages, reflected in the absence of statistically significant heterogeneity in the linear associations of specific beverages with numbers of any lipoprotein particle (P = 0.22–0.94).

All three beverages were associated with trends toward higher levels of large LDL-P and lower levels of small LDL-P, although only the wine-large particle association was statistically significant (P trend = 0.02). All three beverages were also significantly associated with higher levels of larger HDL-P, with the strongest association for liquor consumption. There were inverse trends between beverage consumption and levels of small HDL-P, but the association with beer was strongest and statistically significant (P trend = 0.03). Wine intake was inversely associated with lower levels of large VLDL-P (P trend = 0.04), whereas the other beverages were not, but all three beverage types were inversely associated with small VLDL-P.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The association of alcohol use with lipoprotein subclass distribution has not been extensively studied. Regarding HDL subclasses, data are mixed, with some studies finding increases mainly in HDL2 (the larger, less-dense HDL-P) (24) and others finding more broadly distributed increases among HDL2 and HDL3 (25). In a study of 355 Mormons, of whom only 33 drank any alcohol, Williams and Krauss (7) found that alcohol consumption was associated with higher levels of the largest LDL-P but was not associated with small, dense LDL-P or peak LDL-P diameter. In the Framingham Offspring Study, Campos et al. (26) also found no association of alcohol use with peak LDL-P diameter, but dietary data were only available for a subset of participants. Experimental studies in squirrel monkeys with high doses of alcohol show increases in larger, less dense LDL subfractions (8), although a single trial among heavily drinking Japanese men found that withdrawal from alcohol increased mean LDL-P size (27).

We found relatively complex relationships of alcohol consumption with the three classes of lipoproteins, with effects that differed by particle, dose, and sex. For LDL-P, there was a U-shaped association with total particles, with the lowest concentrations among consumers of 1–13 drinks per week among both men and women. This reflected a generally dose-dependent increase in large LDL-P that was most marked among women, with a somewhat larger 25–35% decrease in small LDL-P primarily among consumers of 1–13 drinks per week and women. Because of these parallel changes, average LDL-P size increased progressively up to 7–13 drinks per week. In summary, LDL-C (an integrated function of total LDL-P concentration and size) was not substantially different across alcohol categories but was preferentially carried on smaller numbers of larger LDL-P among consumers of 1–13 drinks per week.

The increase in HDL-C associated with alcohol intake in CHS reflected joint increases in both particle number and size. The greatest increase with alcohol intake occurred among large HDL-P, with a somewhat smaller increase among medium-sized HDL-P, and concentrations of small particles were actually lower with greater intake. These associations were quite similar among men and women and suggest that the increase in HDL-C consistently noted in feeding studies (4) may reflect both greater apoA-I and -II production (28, 29, 30, 31) and changes in catabolism.

VLDL-P levels generally decreased with heavier alcohol use in this study, with a greater decrease in small than large particles, leading to increased average size. The decrease in large VLDL-P with greater alcohol consumption appeared to plateau or even reverse among the heaviest drinkers, especially among men, accounting for the steep increase in VLDL-P size in the heaviest drinkers. Feeding studies indicate that alcohol intake increases triglyceride levels (4), but only among men, and larger, more recent trials have suggested that moderate drinking may reduce triglyceride levels in women (20, 33). Our results are roughly consistent with these latter findings, because the inverse associations we observed were stronger among women. In addition, most feeding studies have been conducted among younger individuals and often with higher doses of alcohol than are typical for the older adults in CHS.

The mechanisms by which alcohol use could alter lipoprotein distribution are apt to be multifactorial. Alcohol intake has been associated with lower cholesteryl-ester transfer protein (CETP) activity in some (34, 35, 36) but not all (37, 38, 39, 40, 41) studies. Of note, the TaqIB variant in CETP that leads to lower CETP activity influences levels of HDL-P and LDL-P in a manner similar to that seen here, including particular increases in large HDL-P and a shift from smaller to larger LDL-P (42, 43). The fact that adjustment for HDL-C (which is obviously correlated with CETP activity) reversed the association of alcohol with small and large LDL-P supports a role for CETP here. Alcohol intake also stimulates lipoprotein lipase (LPL) activity in humans (39, 44, 45) and thus could lower total VLDL-P, although LPL appears to disproportionately catabolize large rather than small VLDL (46, 47). Alcohol intake also influences lecithin cholesterol acyl transferase activity in some studies, which could further increase HDL-P size (37, 48, 49). Alcohol may also act indirectly via adiponectin, which is increased after moderate drinking (50, 51) and which itself may increase LPL and peroxisome proliferator-activated receptor-{alpha} activity (52, 53, 54).

It is uncertain which lipoprotein characteristic derived from NMR spectroscopy, if any, is most strongly associated with cardiovascular risk (19). Some (55, 56) but not all (16, 57, 58) studies have found smaller average size of LDL-P to predict risk, whereas others suggest that higher levels of total LDL-P may be the most salient characteristic (6, 13). Complicating this issue further, some, but not all (16), investigators have found higher levels of small HDL-P to be directly associated with higher risk of CHD, opposite to the effect of larger HDL-P (59, 60). Moreover, several studies have implicated large VLDL-P as a strong predictor of CHD (56, 59). These findings, when taken as a whole, would seem to suggest that alcohol consumed in moderation may produce a more atheroprotective profile than is normally recognized with standard, enzymatically measured lipids, at least in older adults.

The CHS has strengths but limitations as well. As with any observational study, the associations we observed could be related, at least in part, to differences between drinkers and nondrinkers other than their level of alcohol consumption. However, we adjusted for a wide variety of demographic, socioeconomic, and clinical factors and separated former drinkers from longer-term abstainers. To have produced the associations we found, any potential confounding factors would need to be strongly associated with both alcohol consumption and lipoprotein distribution and generally unrelated to the many demographic and clinical variables for which we controlled. We also separated longer-term abstainers from former drinkers to minimize the inclusion of "sick quitters" (61), although our definition of former drinkers may have missed some individuals who had consumed alcohol in moderation more than 5 yr before study entry.

We relied on self-reported average alcohol consumption in this study, which has been validated in other epidemiological investigations (62) but may have introduced some error into our analyses. Because detailed data on drinking patterns were not available, we could not distinguish between regular and episodic alcohol consumption, although binge-drinking rates decline with age and are likely to be low in this cohort study (32). Because CHS participants generally consumed limited amounts of individual alcoholic beverages, we also had limited power to determine how heavy alcohol consumption or beverage type relates to lipoprotein levels. The design of the case-cohort study also limited us to cross-sectional analysis to participants free of clinical cardiovascular disease, and these results might differ if evaluated longitudinally.

In conclusion, in this study of older adults, alcohol consumption was associated with larger lipoprotein particle sizes and a lower prevalence of small LDL-P and HDL-P, as measured by NMR spectroscopy. Confirmation of these findings in larger and younger cohorts is needed, but these results implicate lipoprotein particles as potentially important intermediates between alcohol intake and lower risk of CHD.


   Footnotes
 
The research reported in this article was supported by National Heart, Lung, and Blood Institute Grants N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01 HC-15103 and National Institute on Alcohol Abuse and Alcoholism Grant R21-AA-00499. A full list of participating Cardiovascular Health Study investigators and institutions can be found at http://www.chs-nhlbi.org.

Disclosure Statement: The authors have nothing to disclose.

First Published Online April 17, 2007

Abbreviations: apo, Apolipoprotein; C, cholesterol; CETP, cholesteryl-ester transfer protein; CHD, cardiovascular disease; CHS, Cardiovascular Health Study; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; NMR, nuclear magnetic resonance; P, particle; VLDL, very-low-density lipoprotein.

Received November 6, 2006.

Accepted April 9, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. H. O'Keefe, K. A. Bybee, and C. J. Lavie
Alcohol and Cardiovascular Health: The Razor-Sharp Double-Edged Sword
J. Am. Coll. Cardiol., September 11, 2007; 50(11): 1009 - 1014.
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