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Opposite Associations of Carbohydrate-Deficient Transferrin and  -Glutamyltransferase With Prevalent Coronary Heart Disease
Pekka Jousilahti, MD, PhD;
Erkki Vartiainen, MD, PhD;
Hannu Alho, MD, PhD;
Kari Poikolainen, MD, PhD;
Pekka Sillanaukee, PhD
Arch Intern Med. 2002;162:817-821.
ABSTRACT
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Background Moderate alcohol consumption may reduce the risk of coronary heart disease
(CHD), but excessive alcohol consumption is probably harmful to the heart.
We analyzed the association of 2 commonly used markers of alcohol consumption—carbohydrate-deficient
transferrin (CDT) and  -glutamyltransferase (GGT)—and self-reported
alcohol consumption with prevalent CHD.
Methods The study included a random sample of 3666 Finnish men aged 25 to 74
years who participated in a risk factor survey in 1997. The cross-sectional
association of CDT, GGT, and self-reported drinking with CHD was analyzed
by means of logistic regression models.
Results The CDT level was inversely and GGT level positively associated with
CHD risk. The odds ratios (adjusted for age, smoking, total and high-density
lipoprotein cholesterol levels, systolic blood pressure, and body mass index)
of CHD among men in the fourth quartiles of CDT and GGT, as compared with
the first quartiles, were 0.69 and 1.76, respectively. In a composite risk
assessment, men with normal CDT levels ( 20 U/L) and elevated GGT levels
(>80 U/L) had nearly 8-fold adjusted risk of CHD as compared with the men
with normal GGT levels and elevated CDT levels. Self-reported alcohol consumption
had an inverse association with CHD risk, which disappeared after adjustment
for the other risk factors.
Conclusions Levels of CDT and GGT may be indicators of factors behind the curvilinear
association between alcohol consumption and CHD risk. The CDT level seems
to be related to beneficial biological changes and GGT level with the changes
that are detrimental to the cardiovascular system. The inverse association
of CDT level with CHD risk will be examined further in a forthcoming prospective
study.
INTRODUCTION
THERE IS reasonably good evidence that light to moderate alcohol consumption
may reduce the risk of coronary heart disease (CHD) as compared with total
abstinence, but that excessive alcohol consumption is probably detrimental
to the heart.1-4
Even though this J-shaped association between alcohol consumption and CHD
risk has been observed in several epidemiologic studies, there still is controversy
concerning the limit for safe drinking.5 The
definition of safe limits is complicated by the fact that self-reported alcohol
intake is usually underestimated.5-6
Because of this, biological markers might be useful in the evaluation of the
risk of CHD related to alcohol consumption.
Carbohydrate-deficient transferrin (CDT) and -glutamyltransferase
(GGT) are commonly used markers of alcohol consumption.7-8
High levels of GGT have been shown to be associated with increased CHD risk.9 The association between CDT levels and the risk of
CHD has not been studied before, to our knowledge. A previous study, however,
has shown that CDT is associated with a nonatherogenic serum lipid profile
and GGT with an atherogenic profile.10 The
aim of the present study was to analyze the association of CDT and GGT, as
well as self-reported alcohol consumption, with the prevalence of CHD.
SUBJECTS AND METHODS
To assess the levels of behavioral and biological health-related factors
among the population, a large cross-sectional risk factor survey was performed
in Finland in 1997. The survey was conducted according to the World Health
Organization MONICA (Monitoring Trends and Determinants of Cardiovascular
Disease) protocol in 5 geographical areas: the Helsinki-Vantaa region in southern
Finland, the Turku-Loimaa region in southwestern Finland, Kuopio and North
Karelia provinces in eastern Finland, and the Oulu Province in northern Finland.
In each study area, an age- and sex-stratified random sample of 2000 subjects
was drawn from the population of people between the ages of 25 and 64 years.
In addition, a sample of 250 women and 500 men aged 65 to 74 years was drawn
in North Karelia and the Helsinki-Vantaa region. The total sample size was
5500 women and 6000 men. Of them, 4193 women (76%) and 4254 men (71%) participated.
Because of the relatively small number of women with CHD, only men were included
in the present study. A total of 372 men were excluded because of missing
data on CDT, GTT, or serum cholesterol levels; self-reported alcohol consumption;
smoking; blood pressure; or body mass index (BMI). Two hundred sixteen men
were excluded from the analyses because of the discrepancy between self-reported
and registered data on the occurrence of CHD or because of self-reported stroke.
Thus, 3666 men were included in the analyses. The study was approved by the
ethical committee of the National Public Health Institute, Helsinki, Finland,
and the subjects gave informed consent.
Data on smoking, alcohol consumption, and the occurrence of symptoms
of CHD were obtained from a self-administered questionnaire. Quantitative
estimation of alcohol intake was based on a set of structured questions inquiring
about the amount and frequency of drinking during the past year. Average weekly
alcohol consumption was calculated on the assumption that a standard unit
of beer, mixed drinks, spirits, and wine contained 12 g of alcohol each, whereas
a unit of cider or coolers contained 4 g of alcohol. At the study site, specially
trained nurses measured blood pressure, weight, and height by using a standardized
protocol. Weight was measured in light clothing and height without shoes.
The BMI (weight in kilograms divided by the square of height in meters) was
used as an indicator for obesity. A venous blood sample was drawn and centrifuged
within 1 hour.
Serum samples were transported at room temperature to the central laboratory,
where GGT, serum total cholesterol, and high-density lipoprotein (HDL) cholesterol
were analyzed within a few days. Serum for CDT determination was stored at
–70°C a few months before the analyses. Serum CDT levels were analyzed
by a double antibody kit (CDTect; Pharmacia & Upjohn Diagnostics AB, Uppsala,
Sweden) according to the manufacturer's instructions. Levels of GGT were measured
by a kinetic method (Oy Medix Biochemica AB, Kauniainen, Finland) based on
the recommendation of the European Committee for Clinical Laboratory Standards.
Serum total and HDL cholesterol levels were determined by an enzymatic method
(CHOD-PAP; Boehringer Mannheim, Mannheim, Germany).
Data on the occurrence of CHD were obtained from the National Social
Insurance Institution's register of subjects entitled to special reimbursement
for CHD drugs. To receive the special reimbursement, the diagnosis of CHD
is usually made by a specialist in internal medicine or a cardiologist, and
the diagnosis needs to be based on symptoms and clear ischemic changes in
the electrocardiogram, either at rest or during an exercise test, or findings
on coronary angiography. The statements documenting these findings are then
reviewed and accepted by the expert physicians of the National Social Insurance
Institution. Subjects who did not receive the special reimbursement but who
reported having CHD or stroke on the questionnaire were excluded from the
analysis. Thus, the subjects classified as having CHD probably had the disease
and those who were classified as disease free probably did not have clinically
significant atherosclerosis.
The associations of CDT, GGT, and self-reported alcohol consumption
with the prevalence of CHD were analyzed by logistic regression models. In
the analyses, the first (ie, lowest) quartiles of CDT and GGT were used as
the reference categories, and the other quartiles were included in the model
as dummy variables. In self-reported alcohol consumption, nondrinkers were
used as a reference category. The odds ratios (ORs) and 95% confidence intervals
(CIs) of prevalent CHD are presented for each quartile with a test for linear
trend across the quartiles. The composite risk assessment was done by dichotomizing
the variables by means of the recommended reference values (20 U/L for CDT
and 80 U/L for GGT) and analyzing the combined risk in the resulting 4 categories
with the help of dummy variables. All analyses were first adjusted for age
only and then further for age, smoking, serum total and HDL cholesterol levels,
blood pressure, and BMI. The associations of CDT, GGT, and self-reported alcohol
consumption with the known cardiovascular risk factors were also examined.
RESULTS
All of the analyzed markers (CDT, GGT, and self-reported alcohol consumption)
had a positive association with smoking prevalence (Table 1). The CDT level had a positive association with HDL cholesterol
level and an inverse association with BMI, but CDT level was not associated
with total cholesterol level or systolic blood pressure. The GGT level had
a positive association with total cholesterol level, systolic blood pressure,
and BMI, and an inverse association with HDL cholesterol level. Self-reported
alcohol consumption had a positive association with serum total and HDL cholesterol
levels, systolic blood pressure, and BMI. The correlation coefficients of
CDT and GGT levels with self-reported alcohol consumption were 0.32 (P<.001) and 0.24 (P<.001),
respectively. Their correlation with each other was 0.19 (P<.001).
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Table 1. Age-Adjusted Risk Factor Levels by Quartiles of CDT and GGT,
and in Categories of Self-reported Alcohol Consumption*
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The CDT level had a progressive inverse association and GGT level had
a progressive positive association with CHD risk (Table 2). The ORs of CHD among men in the second, third, and fourth
quartiles of CDT, as compared with the first quartile, were 0.83, 0.67, and
0.50 (P value for trend, <.001). The respective
ORs in the second, third, and fourth quartiles of GGT were 1.05, 1.36, and
1.67 (P value for trend, .005). The inverse association
of CDT and CHD decreased somewhat after adjustment for smoking, total and
HDL cholesterol levels, systolic blood pressure, and BMI. The positive association
between GGT and CHD changed only slightly after adjustment for the other risk
factors. Self-reported alcohol consumption had a borderline inverse association
with CHD risk, which, however, disappeared after adjustment for the other
risk factors.
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Table 2. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of Coronary
Heart Disease by Quartiles of Carbohydrate-Deficient Transferrin (CDT) and -Glutamyltransferase
(GGT), and in Categories of Self-reported Alcohol Consumption
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The OR of CHD among men with elevated CDT level (>20 U/L) and normal
GGT level (80 U/L) was 0.22 compared with men who had normal levels for
both values (Table 3). The OR
among men with elevated GGT level and normal CDT level was 2.15. When both
CDT and GGT levels were elevated, the risk did not differ from the reference
category. When the men with elevated GGT level and normal CDT level were compared
with men with elevated CDT level and normal GGT level, the age-adjusted OR
was 10.18 (95% CI, 4.13-25.14). Adjustment for the other risk factors decreased
the OR to 7.74 (95% CI, 3.06-19.57).
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Table 3. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of Coronary
Heart Disease by Combinations of Carbohydrate-Deficient Transferrin (CDT)
and -Glutamyltransferase (GGT) Levels
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COMMENT
In the present study, serum CDT and GGT levels, which were regarded
as biological markers of alcohol consumption, had opposite associations with
the prevalence of CHD. The risk of CHD decreased with increasing CDT level
but increased with increasing GGT level. The CDT and GGT levels also had contrasting
associations with major cardiovascular risk factors. High GGT level was associated
with high levels of all risk factors. Either the association of CDT with the
known cardiovascular risk factors was neutral, or high CDT levels were related
to low risk factor levels. In the composite risk assessment, men with elevated
GGT level and normal CDT level had nearly 8-fold risk (adjusted for the other
risk factors) as compared with the men with elevated CDT level and normal
GGT level.
Self-reported alcohol consumption had an inverse association with CHD,
which, however, disappeared after adjustment for the other risk factors. The
finding is at least partly explained by the cross-sectional study design and
changes in drinking behavior due to an existing disease. According to the
self-reporting, alcohol consumption among the study population was also relatively
low. This is probably partly due to underreporting among the responders, and
partly because the heaviest drinkers do not usually participate in surveys.
Several studies have shown that moderate alcohol consumption decreases
the risk of CHD, as compared with total abstinence.1-4
The primary mechanisms proposed for the cardioprotective effect of alcohol
are that alcohol has positive effects on lipid metabolism and on the hemostatic
system. It has been shown that moderate drinkers have higher HDL cholesterol
level than nondrinkers, and the HDL cholesterol–increasing effect of
alcohol has also been observed in clinical trials.11-12
A polymorphism in the gene for alcohol dehydrogenase type 3 alters the rate
of alcohol metabolism. A recent nested case-control study demonstrated that
moderate drinkers who were homozygous for the slow-oxidizing alcohol dehydrogenase
type 3 allele had higher HDL cholesterol levels and a substantially decreased
risk of CHD.13
It has also been demonstrated that alcohol has antithrombotic effects.11, 14 On the other hand, even relatively
small amounts of alcohol have been shown to increase blood pressure.15 It has been debated whether the beneficial effect
of moderate alcohol consumption on the heart is due to ethanol or some other
substances in alcoholic beverages.2 Some researches
have suggested that red wine is particularly healthful, but the issue is still
controversial. The protective effect of alcohol may also be associated with
drinking pattern.16
A positive association between GGT and the risk of CHD has been reported
previously.9 The present study is the first
one, to our knowledge, in which the association of CDT with CHD risk has been
analyzed. We can only speculate on the mechanisms for the opposite associations
of CDT and GGT with CHD. Only part of it can be explained by the known cardiovascular
risk factors, particularly lipids. It is possible that CDT is a marker for
earlier phases of alcohol consumption, and GGT might reflect toxic effects
of ethanol on hepatic lipid metabolism. It has also been shown that CDT is
a more specific marker of alcohol consumption than GGT.17
It has been suggested that CDT level reflects drinking frequency, whereas
GGT level is more influenced by drinking intensity.18
The correlation of CDT and GGT levels with self-reported alcohol consumption
was higher than their correlation with each other, suggesting that the responses
of CDT and GGT levels to alcohol consumption occur by different mechanisms.19
According to the self-reported alcohol consumption records, most of
the subjects were drinking at relatively low levels. This is the range where
the J-shaped curve relating alcohol intake to CHD first declines and then
begins to rise again. The usual explanation for such a biphasic curve is that
there are 2 or more factors involved. Our results suggest the possibility
that CDT and GGT are indicators of these factors, with CDT being related somehow
to beneficial factors from alcohol consumption and GGT to the alcohol factors
that are detrimental to the cardiovascular system.
Other factors in addition to alcohol consumption may be involved in
the association of CDT and GGT with CHD risk. For example, obesity increases
GGT levels and is also a risk factor for CHD.20
In our study, however, the positive association between GGT and CHD remained
after adjustment for the other risk factors, including BMI. Some studies have
suggested that high hemoglobin level may be a risk factor for CHD.21 The CDT level is influenced by iron metabolism, and
it increases in iron deficiency.22-23
Thus, variation in iron intake may be a confounding factor in the association
between CDT and CHD risk.
Because of the cross-sectional study design, we cannot yet draw any
causal conclusions on the association between CDT and CHD risk. The other
limitation of our study is that it included only men. Most participants were
light to moderate drinkers. Therefore, our findings may be limited to male
social drinkers.
We conclude that CDT and GGT levels have opposite associations with
CHD risk. It is possible that CDT and GGT levels tend to separate the factors
that are responsible for the positive and negative cardiovascular effects
of alcohol consumption. This novel observation may lead to better understanding
of the complex relation of alcohol to CHD risk. However, the inverse association
of CDT level with CHD risk is a preliminary finding and will be studied further
in a forthcoming prospective study among the CHD-free subjects in the present
cohort.
AUTHOR INFORMATION
Accepted for publication July 31, 2001.
Corresponding author and reprints: Pekka Jousilahti, MD, PhD, University
of Helsinki, Department of Public Health, PO Box 41, FIN-00014 University
of Helsinki, Finland (e-mail: pekka.jousilahti{at}ktl.fi).
From the Department of Public Health (Dr Jousilahti) and Research Unit
of Substance Abuse Medicine (Dr Alho), University of Helsinki, Helsinki; Department
of Epidemiology and Health Promotion (Drs Jousilahti and Vartiainen) and Department
of Mental Health and Alcohol Research (Dr Alho), National Public Health Institute,
Helsinki; Finnish Foundation for Alcohol Studies, Helsinki (Dr Poikolainen);
Oy Finnish Immunotechnology Ltd, Tampere (Dr Sillanaukee); and Department
of Medical Biochemistry and Research Unit, Tampere University and University
Hospital, Tampere (Dr Sillanaukee), Finland.
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