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Apolipoprotein E polymorphism modifies the alcohol-HDL association observed in the National Heart, Lung, and Blood Institute Family Heart Study^1,2,3

¹ From the Section of Preventive Medicine & Epidemiology, Evans Department of Medicine (LD and RCE), and the Department of Neurology (RHM), Boston University School of Medicine, Boston, and the Division of Epidemiology (JSP and DKA) and the Department of Laboratory Medicine and Pathology (JHE), University of Minnesota, Minneapolis

² Supported by National Heart, Lung, and Blood Institute cooperative agreement grants U01 HL56563, HL56564, HL56565, HL56566, HL56567, HL56568, and HL56569; National Heart, Lung, and Blood Institute grant 5K01-HL70444; and National Institute on Alcohol Abuse and Alcoholism grant 1 R01 AA13304.

³ Address reprint requests and correspondence to L Djoussé, Boston University School of Medicine, Room B-612, 715 Albany Street, Boston, MA 02118. E-mail: ldjousse{at}bu.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background:The apolipoprotein E gene (APOE) allele 4 is associated with an increased risk of cardiovascular disease. The presence of the 4 allele has been associated with lower concentrations of HDL cholesterol, but it is not known whether the 4 allele modifies the association between alcohol consumption and HDL-cholesterol concentrations.

Objective:The objective of the study was to assess whether the 4 allele modifies the association between alcohol consumption and HDL-cholesterol concentrations.

Design:In a cross-sectional design, we studied 670 men and women aged 26–78 y who participated in the National Heart, Lung, and Blood Institute Family Heart Study to assess whether the 4 allele of the gene APOE modifies the association between alcohol consumption and HDL-cholesterol concentrations. Alcohol data were self-reported, and we used multivariate, generalized estimating equations to assess interactions.

Results:In a model with adjustment for age, sex, body mass index, smoking, exercise, waist-hip ratio, TV viewing, and study site, there was a significant effect of the interaction between the 4 allele and alcohol consumption on HDL cholesterol (P = 0.0001). In the absence of the 4 allele, multivariate adjusted means of HDL were 1.24, 1.36, and 1.54 mmol/L among subjects who never drank and those who currently drink 0.1–12 and >12 g alcohol/d, respectively; in the presence of the 4 allele, the corresponding values were 1.19, 1.27, and 1.25 mmol/L.

Conclusion:Our data show a significant effect of the interaction between the 4 allele and alcohol consumption on HDL. The increase in HDL associated with alcohol appears to be stronger in subjects without the 4 allele than in those with the 4 allele.

Key Words: Apolipoprotein E • alcohol consumption • interaction • HDL cholesterol • lipids

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Coronary artery disease (CAD) remains the leading cause of death in the United States and other industrialized nations. As compared with no alcohol consumption, moderate alcohol consumption has been shown to be associated with a lower risk of CAD (1–3) and total mortality (4–6) and with higher concentrations of HDL cholesterol (7–9). It is believed that the ability of alcohol to raise HDL cholesterol is a key physiologic mechanism by which its moderate consumption reduces the risk of CAD. The gene encoding the apolipoprotein E (APOE) has been mapped to chromosome 19q13.2(10). Genetic polymorphism of Apo E, a protein found in VLDL and HDL, is common (11). The major isoforms E2, E3, and E4 are coded by the alleles 2, 3, and 4, respectively. APOE allele 4 has been associated with lower concentrations of HDL cholesterol (12–16), increased risk of CAD (17, 18), and higher concentrations of LDL cholesterol (12, 15) and triacylaglycerol (12) concentrations. Data on possible interaction between alcohol consumption and HDL and LDL have been inconsistent (19, 20).

In the present study, we examined whether the 4 allele of APOE modified the association between alcohol consumption and HDL cholesterol concentration in 670 white participants in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study population
Participants in this project were members of the NHLBI Family Heart Study, which is a multicenter, population-based study designed to identify and evaluate genetic and nongenetic determinants of CAD, preclinical atherosclerosis, and cardiovascular disease risk factors. Subjects were recruited from the Framingham Study in Massachusetts, the Atherosclerosis Risk in Community cohorts in North Carolina and Minnesota, and the Utah Family Health Tree in Salt Lake City. A detailed description of the NHLBI Family Heart Study has been published (21). Briefly, between 1993 and 1995, groups of persons participating in each of the parent studies were selected at random and invited to furnish an updated family health history that contained information on their parents, children, and siblings. Of 4679 persons contacted, 3150 (67%) sent their responses, and their family members were then contacted. Self-reported health data were obtained from a total of 22 908 persons (86% of those contacted). From the families responding to the health questionnaire, 588 families were chosen at random (a random group), and 566 families were selected on the basis of their higher-than-expected risk of CAD (a high-risk group). A family risk score, which related the family's age- and sex-specific incidence of CAD to that expected in the general population (22), was used to identify families for inclusion in the high-risk group. Written informed consent was obtained from each study participant, and the study protocol was reviewed and approved by each of the participating institutions.

The current analyses are based on the 670 white participants from the random sample with complete data on APOE genotype, alcohol consumption, and HDL cholesterol. The number of nonwhite subjects was inadequate for analysis.

Blood collection and assays
All participants were asked to fast for 12 h before their arrival at the study center. Evacuated tubes without additives were used to collect samples for lipids; blood samples were then spun at 3000 x g for 10 min at 4 °C. Sera were stored at –70 °C until they were shipped to a central laboratory at the Fairview-University Medical Center in Minneapolis for processing. APOE genotyping was performed by using polymerase chain reaction (PCR) to amplify a 267-bp fragment from exon 3 of APOE (23). The PCR product was digested with the HhaI restriction endonuclease (an isoschizomer of CfoI), which resulted in a specific banding pattern for the 3 isoforms of the Apo E protein when separated by polyacrylamide gel electrophoresis and silver stained. Total and HDL-cholesterol and triacylglycerol concentrations were measured by using a COBAS FARA high-speed centrifugal analyzer (Roche Diagnostic Systems, Montclair, NJ). HDL cholesterol was measured after precipitation of the other lipoprotein fractions with the use of dextran sulfate (24). For samples with triacylglycerol concentrations < 4.5 mmol/L (400 mg/dL), LDL cholesterol was calculated by using the Friedewald formula (25). For subjects with higher concentrations of triacylglycerol, LDL-cholesterol quantitation was performed on EDTA plasma by using ultracentrifugation.

Assessment of alcohol consumption
Information on alcohol consumption was obtained during the clinic interviews by asking whether the person ever consumed alcoholic beverages and whether he or she currently drinks any alcoholic beverages; if the subject answered yes to the latter question, he or she was asked specifically about the number of drinks of each type of alcoholic beverage consumed per week. Subjects who reported that they consumed alcohol in the past but currently were nondrinkers were classified as former drinkers. For purposes of the study, a "drink" was defined as a 360-mL bottle or can of beer containing 12.6 g alcohol, a 120-mL glass of wine containing 13.2 g alcohol, or a 37.5-mL shot of 80-proof spirits containing 15 g alcohol. Total alcohol was computed as sum of the 3 beverage-specific alcohol measurements. For these analyses, we considered a drink to contain 12 g alcohol. The reported total alcohol intake was highly correlated with serum gamma-glutamyltranspeptidase measured in a subsample of drinkers (r = 0.51, P < 0.0001).

Other variables
A staff-administered semiquantitative food-frequency questionnaire developed by Willett et al (26) was used to collect dietary information. The reproducibility and validity of this food-frequency questionnaire were documented elsewhere (27, 28). The intake of specific nutrients was computed by multiplying the frequency of consumption of an item by the nutrient content of specified portions. Composition values for nutrients were obtained from the Harvard University Food Composition Database derived from US Department of Agriculture sources (29) and manufacturer information.

Information on cigarette smoking and education was obtained by interview during the clinic visit. Level of physical activity during the previous year (total minutes of exercise per day) and the number of hours spent watching television each day were self-reported. Anthropometric data were collected while participants were wearing scrub suits. Diabetes mellitus was considered present if a subject was taking hypoglycemic agents, if a physician had told the subject that he or she had diabetes mellitus, or if fasting blood glucose was >7.0 mmol/L.

Statistical analyses
Apo E was measured in 754 of 2673 randomly selected study participants. We excluded 52 nonwhite subjects, because there were too few of that group for separate analysis. Of the remaining 702 participants, all of whom were white, 32 were excluded because they had the E2/E4 genotype (n = 17) or were currently undergoing treatment for hypercholesterolemia (n = 15). We used the chi-square test to ascertain whether APOE genotype distribution was in Hardy-Weinberg equilibrium. Because we did not observe an effect of a three-way interaction between sex, alcohol, and the APOE 4 allele on HDL cholesterol (P = 0.18), we present combined data for men and women. We excluded former drinkers before using generalized estimating equations (GEE). To evaluate the alcohol-Apo E interaction, we dichotomized Apo E on the basis of the presence or absence of the 4 allele and included the main effects of alcohol (continuous) and the 4 allele and the alcohol x 4 allele product term by using GEE (PROC GENMOD in SAS; SAS Institute Inc, Cary, NC). This model corrects the variance for familial clustering. The adjusted model controlled for age, sex, body mass index (BMI; in kg/m²), smoking, and exercise. In addition, we controlled for study site, waist-to-hip ratio, exogenous estrogen use by the female subjects, and hours of television watching. The full model also included education; energy intakes; intakes of dietary cholesterol, saturated and polyunsaturated fat, and fruit and vegetables; and history of diabetes mellitus. We also repeated these analyses by using Apo E to model different genotypes (E2/E2, E3/E3, E3/E4, and E4/E4). To estimate adjusted mean values of HDL-cholesterol concentration, we classified subjects as never drinkers or as current drinkers of 0.1–12 or >12 g alcohol/d. We then fitted GEE as described above. We repeated these analyses for LDL cholesterol and the ratio of total to HDL cholesterol. Sensitivity analyses were conducted in a sample excluding current drinkers consuming >30 g alcohol/d. In addition, we tested the robustness of the GEE by repeating the analyses in only one person per family. Significance level was set at 0.05. All analyses were performed by using SAS for WINDOWS software (release 8.02, WINDOWS 5.1; SAS Institute Inc, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The distribution of APOE genotype among 702 white subjects regardless of the presence of other covariates is shown in Table 1. As expected, the E3/E3 genotype was the most prevalent (60.5%). The APOE genotype distribution was in Hardy-Weinberg equilibrium (P = 0.71). Of the 670 participants included in the analyses, 48.4% were men. The mean (± SD) age was 57.2 ± 10.0 y (range: 26–78 y). Characteristics of the study participants are presented in Table 2 according to APOE allele 4 and alcohol categories. Irrespective of the 4 allele, alcohol consumption was associated with male sex, current smoking, lower prevalence of diabetes, lower BMI, higher energy intake, and higher prevalence of physical activity (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Characteristics of the 670 persons in the random sample from the National Heart, Lung, and Blood Institute Family Heart Study according to alcohol consumption and apolipoprotein E allele 41

4

4

4

We observed a significant effect of the interaction between alcohol consumption and the APOE 4 allele on HDL-cholesterol concentration (P = 0.0001) in a regression model after control for age, sex, BMI, smoking, exercise, waist-hip ratio, exogenous estrogen, television viewing, and study site. In the absence of the 4 allele, adjusted means of HDL cholesterol were 1.24, 1.36, and 1.54 mmol/L for never drinkers and current drinkers of 0.1–12 and >12 g alcohol/d, respectively (P for trend < 0.0001), in the full model (Table 3). Corresponding values for subjects with the 4 allele were 1.19, 1.27, and 1.25 mmol/L, respectively (P for trend = 0.93; Table 3). The observed results did not change when subjects consuming >3 drinks/d (>36 g alcohol/d) were excluded (P for interaction = 0.016). Further analysis restricted to subjects consuming 30 g alcohol/d did not alter our findings (P for interaction = 0.026). In the fully adjusted model, comparing never drinkers with current drinkers of >12 g alcohol/d, the net increase in HDL cholesterol was 0.30 mmol/L (11.6 mg/dL) in the absence of the 4 allele but only 0.06 mmol/L (2.3 mg/dL) in the presence of the 4 allele (Table 3). To evaluate the influence of individual APOE genotypes, we tested the interaction between alcohol and Apo E by using a mixed model in SAS and found evidence for a significant effect of the interaction between Apo E and alcohol consumption on HDL (P for interaction = 0.04; P for main effects = 0.044 and 0.24 for alcohol and Apo E, respectively).

View this table: [in this window] [in a new window]   TABLE 3. HDL and LDL cholesterol and the ratio of total to HDL cholesterol according to the absence or presence of the apolipoprotein E allele 4 and alcohol consumption among 388 randomly selected subjects who were never drinkers or are current drinkers1

4

Table 3

4

Table 3

4

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the current study, we showed a significant effect of the interaction between alcohol consumption and the 4 allele of APOE on HDL-cholesterol concentration after adjustment for major confounding factors. In the absence of the 4 allele, the magnitude of increase in HDL cholesterol between never drinkers and current drinkers of >12 g alcohol/d was 0.30 mmol/L compared with only 0.06 mmol/L in the presence of the 4 allele. Of note is that, in the highest drinking category, the average alcohol intake among subjects with the 4 allele was 31.1 g/d (2.5 drinks/d) and that among subjects without the 4 allele was 24.7 g/d (2 drinks/d). This suggests that, if the average alcohol consumption was similar between subjects with the 4 allele and those without it, then, among subjects with the 4 allele, the magnitude of difference in HDL cholesterol between never drinkers and drinkers of >12 g alcohol/d would be even less than the observed difference if we assume a linear relation between alcohol and HDL-cholesterol concentrations. However, we observed a significant effect of the interaction between alcohol and the 4 allele on HDL cholesterol even after the exclusion of subjects consuming >30 g alcohol/d (>2.5 drinks/d). This suggests that our findings were not driven by an unbalanced distribution of heavy drinkers between subjects with and without the 4 allele.

In support of our findings, several studies have shown that the 4 allele of APOE is associated with lower concentrations of HDL cholesterol (12–16). In contrast, the 4 allele had a nonsignificant association with HDL-cholesterol concentrations in another study (30). However, these latter data were unadjusted for potential confounders, and the trend was toward lower HDL-cholesterol concentrations in the presence of the 4 allele (30). Furthermore, the frequency of the 4 allele was relatively low (7.5% compared with 14% in this study) (30). In the Framingham Study, the 4 allele (present in 13.2%) was not associated with lower concentrations of HDL cholesterol after adjustment for age, BMI, and (in women) menopausal status (31).

Whereas it is established that alcohol consumption is associated with higher HDL-cholesterol concentrations (7, 9, 32), few studies have examined whether the APOE 4 allele modifies the alcohol-HDL cholesterol association. Corella et al (19) reported a significant interaction between alcohol consumption and APOE genotype on HDL cholesterol among men but not among women. In a Canadian study, whereas alcohol intake did not modify the association between BMI and HDL in subjects with the 3 allele, there was evidence for an effect of the interaction between alcohol and BMI on HDL among nonsmokers (33). The lack of interaction between alcohol and LDL in that study was consistent with findings of Corella et al (20) in men. However, the latter study found a significant effect of the interaction between alcohol and Apo E on LDL in women (20). Data from the Framingham Offspring Study showed a significant effect of the interaction between alcohol consumption and Apo E on LDL in men but not in women (19), and we have previously reported evidence for an effect of the interaction between Apo E and smoking on LDL (34). If confirmed in future studies, our findings suggest that alcohol consumption might increase HDL-cholesterol concentrations less in subjects with the 4 allele than in persons without the 4 allele.

Our study has some limitations. The interpretation of our results is limited by the cross-sectional design, which makes it difficult to ascertain the temporal relation between alcohol consumption and HDL-cholesterol concentrations. The data are limited to those from white subjects, and it is unclear whether similar results would be obtained in other ethnic groups. It is possible that subjects might have underreported their usual alcohol consumption; however, such bias is less likely to have been different between subjects with the 4 allele and subjects without it. The strong correlation between alcohol consumption and concentrations of gamma-glutamyltranspeptidase—a biomarker of alcohol consumption (35)—provides support for the validity of self-reported alcohol intake.

In conclusion, our data indicate an effect of the interaction between alcohol consumption and the APOE allele 4 on HDL-cholesterol concentrations in white men and women. This suggests that the beneficial effects of alcohol consumption on HDL cholesterol might be stronger in the absence of the 4 allele. Further studies are needed to test whether Apo E status modifies the beneficial effects of alcohol consumption on the risk of myocardial infarction.

	ACKNOWLEDGMENTS

 
This report is presented on behalf of the investigators of the NHLBI Family Heart Study, of which the participating institutions and principal staff members are Forsyth County/University of North Carolina/Wake Forest University: Gerardo Heiss, Stephen Rich, Greg Evans, HA Tyroler, Jeannette T Bensen, Catherine Paton, Delilah Posey, and Amy Haire; University of Minnesota Field Center: Donna K Arnett, Aaron R Folsom, James Pankow, James Peacock, and Greg Feitl; Boston University/Framingham Field Center: R Curtis Ellison, Richard H Myers, Yuqing Zhang, Andrew G Bostom, Luc Djoussé, Jemma B Wilk, Larry Atwood, and Greta Lee Splansky; University of Utah Field Center: Steven C Hunt, Roger R Williams (deceased), Paul N Hopkins, Hilary Coon, and Jan Skuppin; Coordinating Center, Washington University, St Louis: Michael A Province, DC Rao, Ingrid B Borecki, Yuling Hong, Mary Feitosa, Jeanne Cashman, and Avril Adelman; Central Biochemistry Laboratory, University of Minnesota: John H Eckfeldt, Catherine Leiendecker-Foster, Michael Y Tsai, and Greg Rynders; Central Molecular Laboratory, University of Utah: Mark F Leppert, Jean-Marc Lalouel, Tena Varvil, Lisa Baird; and National Heart, Lung, and Blood Institute Project Office: Phyliss Sholinsky, Millicent Higgins (retired), Jacob Keller (retired), Sarah Knox, and Lorraine Silsbee.

LD designed this project, completed the data analyses, and prepared the manuscript; JSP participated in the data analyses and critically reviewed the manuscript; DKA participated in the study design, data collection, and critically reviewed the manuscript; JHE participated in the study design, data collection, measurement of HDL cholesterol, and critically reviewed the manuscript; RHM participated in the study design, data collection, and critically reviewed the manuscript; and RCE participated in the study design, data collection, data analyses, and critically reviewed the manuscript. RCE has received limited support for research in the past from companies in the alcohol beverage industry. None of the other coauthors had a conflict of interest.

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TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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