(Circulation. 1996;93:1339-1345.)
© 1996 American Heart Association, Inc.
Articles |
Common DNA Polymorphisms at the Lipoprotein Lipase Gene
Association With Severity of Coronary Artery Disease and Diabetes
From the Department of Cardiovascular Medicine, University of New South Wales, Prince Henry/Prince of Wales Hospitals, Sydney, Australia.
Correspondence to Professor David Wilcken, Department of Cardiovascular Medicine, Clinical Sciences Bldg, Prince Henry Hospital, Little Bay, NSW 2036, Australia.
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Abstract |
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Background DNA variants of the lipoprotein lipase gene are associated with changes in lipid metabolism similar to those in diabetes and may relate to the development of atherosclerotic lesions, particularly premature lesions.
Methods and Results To determine whether lipoprotein lipase gene variants are relevant to ongoing atherogenesis, we explored relationships between two common lipoprotein lipase gene polymorphic markers, Pvu II at intron 6 and HindIII at intron 8; the severity of coronary artery disease (CAD); and lipid variables in 475 white patients 65 years of age or younger. We assessed CAD severity as the number of significantly stenosed (>50% luminal obstruction) major coronary arteries at angiography and by the Green Lane coronary score. We found a significant association between the Pvu II polymorphism and the number of significantly diseased vessels (P=.0099) and coronary score (P=.028), with the Pvu II(-) alleles associated with less severe disease. The HindIII polymorphism was not associated with severity but had an additive effect with the Pvu II polymorphism. There was a close relationship between the Pvu II(+/+) genotype and the presence of diabetes (P=.0025), with an OR of 3.12 (95% CI, 1.30 to 7.49) compared with the Pvu II(-/-) genotype. The interaction between these polymorphisms and CAD severity (rather than occurrence) was independent of the levels of triglycerides and HDL cholesterol and of other lipid variables. There was also a dosage-dependent relationship between the Pvu II polymorphism and levels of triglyceride. The Pvu II(-) allele was associated with low levels and variances of triglycerides.
Conclusions We conclude that the lipoprotein lipase Pvu II polymorphism is significantly associated with CAD severity and with type II diabetes in CAD patients, independent of changes in circulating lipid levels. These findings may be relevant to mechanisms mediating atherogenesis.
Key Words: lipoproteins • coronary disease • diabetes mellitus • cholesterol
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Introduction |
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In a recent study, we examined the relationship between known atherogenic variables and the severity of premature CAD determined at angiography.1 We postulated that factors predicting the occurrence of CAD may not be quantitatively the same as those predicting CAD severity (ie, the initiating factors may not be exactly the same as the factors that cause progression). Our results identified a hierarchy of predictors of severity that was somewhat different from that thought to be associated with the occurrence of CAD. But we could account for only
50% of
the variance in CAD severity. Clearly, factors other than the standard
risk factors, which in our study also included Lp(a) and apo A-I and B,
also were contributing. In the present study, we have attempted to
identify unrecognized contributors to CAD severity by using a candidate
gene approach in a further series of consecutively referred patients.
We have explored a possible contribution from the DNA polymorphisms
of the gene for LpL because these could result in both local and
circulating atherogenic effects. LpL is a glycoprotein synthesized in the parenchymal cells of several tissues. It hydrolyzes circulating triglycerides of exogenous (chylomicron) and endogenous (VLDL) origins to provide free fatty acids for oxidation in the heart and other tissues and for storage in adipose tissue.2 It affects circulating triglyceride levels by generating lipoprotein remnants. These are then processed by hepatic lipase. After secretion, LpL is attached to the luminal surface of endothelial cells, where it not only has a major role in the metabolism of lipoproteins in the circulation but also interacts with lipoproteins locally.2 It has been demonstrated that LpL increases the retention of LDL and VLDL particles by the subendothelial matrix of the artery wall and that it potentiates their conversion to more atherogenic forms.3 These localized effects could not be assessed by measurement of either circulating LpL or triglyceride levels but could be explored by identification of genetic variants of LpL and relation of these to the presence and extent of atherosclerotic lesions.
We have now investigated first the possibility that the DNA
polymorphisms of LpL Pvu II and HindIII are
associated with CAD severity determined at angiography.
Polymorphisms of LpL Pvu II are caused by the presence
or absence of a C
T transition in intron 6 and of LpL
HindIII by the presence or absence of a TG transversion
in intron 8, and they have been reported to be associated with
circulating triglyceride levels in some
studies4 5 6 7 but not in others.7 8 These
variations are common in white populations.4 5 6 7 8 Because
diabetes has an important role in the development of CAD and
hypertriglyceridemia occurs frequently in
diabetics, we also explored the relationship between the LpL
polymorphisms and the presence of diabetes in this patient
population. We have not investigated other mutations that induce severe
LpL deficiency because they are too rare to make a significant overall
contribution in the coronary population.
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Methods |
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Patient Population
We studied men and women 65 years of age or younger who were referred consecutively to the Eastern Heart Clinic at Prince Henry Hospital (Sydney, Australia) for coronary angiographies over a 10-month period in 1994. We excluded only patients shown to have significant left main disease (>50% luminal obstruction) because it was difficult to categorize this small proportion of the total (4%) within the classification system we used (see below). Written consent was obtained from every patient after a full explanation of the study, which was approved by the Ethics Committee of the University of New South Wales.
Among the 505 patients studied, 479 (94%) were of European origin and
were classified as white. There were 15 Arabic patients (3.0%), 4
Indians (0.8%), 4 Pacific Islanders (0.8%), and 3 Asian patients
(0.6%). White patients only were used in the statistical
analysis because the numbers in other ethnic groups were too
small for meaningful analyses. Table 1
gives
demographic information about the patients. Table 2
gives the number of significantly diseased vessels in relation to sex.
Ninety-nine patients reported no angina, 173 reported stable
angina, and 207 reported unstable angina.
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A 4-mL venous blood sample was drawn into an EDTA sample tube before the angiogram after at least a 6-hour fast. The blood sample was centrifuged within 2 hours, and plasma and cellular components were stored separately at -70°C in aliquots until analysis.
DNA Analysis for the Detection of LpL Pvu II
and HindIII Polymorphisms
DNA was extracted from the frozen cellular blood component by a
salting-out method adapted from that described by Miller et
al9 for whole frozen blood. The extracted DNA was stored
at 4°C until analysis. The polymerase chain reaction was used
to detect the LpL Pvu II and HindIII RFLPs.
Primers were designed to amplify the intron 6 region of chromosome 8
for the detection of the Pvu II polymorphism as
described by Peacock et al.5 A CT transition within a
Pvu II site in the middle of intron 6 is responsible for the
Pvu II polymorphism.10 11 Digests were
subsequently run on an 8% polyacrylamide gel at 100 V for 1
hour, and two fragments of 330 and 110 bp were produced when the
restriction site was present. The HindIII
polymorphism is due to a replacement of T by G at the
HindIII site as described by Gotoda et al,12
and primers were designed to amplify the region of intron 8 for its
detection. The digests were subsequently run in a 1.5% agarose gel,
and two fragments of 600 and 115 bp were produced when the restriction
site was present.
The identified genotypes were named according to the presence or absence of the enzyme restriction sites, so Pvu II(+/+), (+/-), and (-/-) and HindIII(+/+), (+/-), and (-/-) are homozygotes for the presence of the site, heterozygotes for the presence and absence of the site, and homozygotes for the absence of the site, respectively. In 4 patients, blood samples were inappropriately stored, and no DNA samples were available for study.
Lipoprotein Analysis
Total cholesterol, HDL cholesterol, and
triglyceride levels were measured by the hospital's
Clinical Chemistry Department with standard enzymatic methods. The LDL
cholesterol levels were calculated with the Friedewald
formula. Because this formula is inaccurate when
triglyceride levels are >4.52 mmol/L, we did not estimate
LDL cholesterol in the 19 patients of the series with
triglyceride levels >4.52 mmol/L (5.93±0.23 mmol/L;
range, 4.6 to 8.4 mmol/L). We measured levels of apoA-I, apoB, and
Lp(a) using ELISA methods developed in our laboratory and reported
previously.13 14 15
Patient Histories
We obtained each patient's medical history using a
questionnaire with standardized choices of answers to be ticked during
the interview. We recorded the presence or absence (yes/no) of a
history of hypertension requiring treatment, diabetes requiring
treatment, angina pectoris, and previous myocardial infarction. A
"don't know" box was included for those patients who were not
clear about aspects of their medical history that were unavailable from
the patient's file. Current medications were recorded,
particularly the usage of lipid-lowering drugs and
ß-adrenergic blocking agents. The presence or absence of CAD
among first-degree relatives (parents and siblings) and the age of
first onset were recorded for quantitative assessment of family
history of premature CAD. We recorded the presence and severity of
angina according to whether each patient was experiencing no angina,
stable angina, or unstable angina before and during the current
hospitalization. All those classified as having unstable angina had an
increase in pain frequency and pain while at rest. The lifetime smoking
dose in pack-years and whether the patient was a current smoker or
an exsmoker were recorded as described previously,1
and BMI was measured. The patient's country of origin also was
obtained to document ethnicity.
Documentation of CAD Severity
The severity of CAD was determined as follows. The angiograms
were assessed by two cardiologists who were unaware that the patients
were to be included in the study. Each angiogram was classified either
as revealing no coronary lesion with >50% luminal
stenosis or as having one, two, or three major epicardial
coronary arteries with >50% luminal obstructions. In a second
approach, we used the Green Lane coronary scoring
system,16 which provides a numerical value for lesion
severity and takes into account the amount of myocardium
supplied by an affected vessel; the maximum score is 15.
Statistical Analysis
Levels of the quantitative variables are presented
as mean±SEM. We used a full factorial design of ANOVA to assess
relationships between the quantitative and categorical variables.
The latter included the number of significantly diseased vessels
(>50% luminal obstruction) and the LpL Pvu II and
HindIII polymorphisms. The distributions of the
quantitative variables were assessed before the ANOVA to establish
that they were normally distributed to meet the conditions required for
the analysis. Lp(a) levels were transformed to logarithmic
levels (log10) to achieve a close-to-normal distribution. We
compared the means of each subgroup and reported F values
for levels of significance using two-tailed probability values. The
equality of variances among different subgroups of diseased vessels and
genotypes was evaluated by the Bartlett-Box F test
for homogeneity of variance as appropriate.
We used log linear analysis for associations between the number
of diseased vessels and LpL Pvu II and HindIII
genotypes. The number of diseased vessels was regarded as an
ordinal variable (0, 1, 2, or 3 significantly diseased vessels). We
also explored the possible dosage effects of the Pvu II and
the HindIII polymorphisms on the number of significantly
diseased vessels by treating them as ordinal variables (+/+=1,
+/-=2, and -/-=3) using a linear-and-linear
association model in the log linear analysis. The log linear
model also was used to evaluate the relationship between
genotypes and the medical history, which included categorical
variables (eg, history of hypertension requiring treatment and
diabetes). Likelihood ratio 
2 values were used to
assess significance. Because there is a sex difference in CAD risk
profiles, we analyzed results not only among all patients but
also in male and female patients separately.
We used a logistic regression model to evaluate the interaction between the genotypes and quantitative variables in relation to the number of diseased vessels. The number of diseased vessels was regarded as the dependent ordinal variable, and all other variables were regarded as independent variables appropriately classified as quantitative or categorical. Fewer than 2% of the responses to questions were "don't know," and they were treated as missing values. The statistical analyses were executed by the SPSS statistical program.
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Results |
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Genetic Characteristics of the Patient Population
There was no difference in frequencies of the rare Pvu II(-) allele between male (0.45) and female (0.45) patients. The HindIII(-) allele tended to be less frequent among women (0.26) compared with men (0.31), although it was not statistically significant. Hardy-Weinberg equilibrium was evident for the Pvu II genotypes (P=.82) but not for the HindIII genotypes (P<.01) in this patient population. The polymorphisms of Pvu II and HindIII were in strong linkage disequilibrium (P<.0001) as shown in Table 3
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LpL Pvu II and HindIII Polymorphisms
and Number of Significantly Diseased Vessels
There was a marked association between the Pvu II
polymorphism and the number of significantly diseased vessels. As
Table 4 shows, patients with Pvu
II(-/-) genotypes were significantly less likely to
have triple-vessel disease and more likely to have no significantly
diseased vessels. The OR for Pvu II(+/+) to have
triple-vessel disease compared with Pvu
II(-/-) was 1.73 (95% CI, 1.034 to 2.895). When
Pvu II was treated as an ordinal variable, there was no
allelic dosage effect. The significant association between CAD severity
and LpL Pvu II polymorphism also was confirmed with
Green Lane coronary scores, which were highly correlated with
the number of significantly diseased vessels (r=.88,
P=.0001). There was a significant decrease in the severity
scores with the Pvu II(-) alleles (6.35±0.41,
5.61±0.30, and 4.72±0.40 for +/+, +/-, and -/-
genotypes, respectively; F=3.59, P=.028 by ANOVA).
We also conducted analyses among male and female patients
separately. The association remained statistically significant in the
350 male patients (likelihood ratio 2=14.02,
P=.02). The same trend was observed among the 125 female
patients but did not reach statistical significance (P=.21).
The small number of female patients could be the reason. Only 1 female
patient with triple-vessel disease had Pvu
II(-/-) genotype, whereas the expected number of
patients in this cell calculated by the model was 3.6. In contrast, the
LpL HindIII polymorphism did not show any association
with either the number of diseased vessels (P=.456) or the
Green Lane scores [5.63±0.29, 5.26±0.35, and 6.38±0.60 for
HindIII(+/+), (+/-), and (-/-),
respectively; P=.281].
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Because there was a strong linkage disequilibrium between
Pvu II and HindIII, we included both
polymorphisms in the log linear model. This analysis also
assessed the relationship between the diseased vessels and the
haplotypes defined by both LpL Pvu II and HindIII
polymorphisms. After the HindIII polymorphism was
controlled for, the relationship between Pvu II and the
number of diseased vessels remained highly significant
(2=16.336, P=.0026). When we
controlled for the Pvu II polymorphism,
HindIII also showed a weak relationship with CAD severity
(2=9.124, P=.0581). The
HindIII and Pvu II polymorphisms were still
in disequilibrium after we controlled for the number of significantly
diseased vessels (2=42.67, P=.000001).
The three-way interaction among these three variables also was
evident (2=15.32, P=.0531). However,
the association is weak, and combining the genotypes did not
predict the number of diseased vessels.
Using logistic regression analysis, we also included in the model the quantitative variables—levels of lipoproteins, apolipoproteins, BMI, smoking dose, and age—and the categorical variables—sex, LpL Pvu II, HindIII. The factors found to be predictive of severity in our earlier study1 —sex, diabetes, smoking dose, ratio of total cholesterol to HDL cholesterol, log Lp(a), age, positive family history, and hypertension—remained significant predictors in this study, whereas the LpL Pvu II polymorphism was still independently predictive (P<.01) of the number of significantly diseased vessels. In particular, triglyceride level was not a significant predictor of the number of significantly diseased vessels. This was the case in the analysis of all patients and when the analysis was confined to those patients not receiving lipid-lowering drugs.
LpL Pvu II and HindIII RFLPs and
Lipoprotein Variables
There was no direct association between the Pvu II or
HindIII genotype and triglyceride
levels. Mean triglyceride levels (±SEM) were 2.27±0.1 and
2.07±0.06 mmol/L for the 125 patients receiving lipid-lowering
drugs and the 354 nonusers (P=.10). Because the
usage of lipid-lowering drugs could attenuate the effect of the
polymorphisms on triglyceride levels, we assessed the
effects of both Pvu II and HindIII on
triglyceride levels only in those patients not receiving
lipid-lowering drugs. As Table 5 shows, there were
statistically significant differences among different
genotypes. There was clearly a dose-dependent relationship
between the presence of Pvu II(-) alleles and low
triglyceride levels but no consistent relationship
between triglyceride and HDL cholesterol and
the HindIII genotypes (Table 5). The relationship
between the Pvu II polymorphism and
triglyceride levels was independent of BMI in a
multivariate ANOVA even though BMI was associated with
triglyceride levels as expected (r=.158,
P=.001). BMI was not different among patients with different
Pvu II genotypes.
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We also evaluated the effects of the Pvu II and
HindIII polymorphisms on triglyceride and
HDL cholesterol levels in patients with and without
significantly diseased vessels. As Table 6 shows, the
effects were far stronger in patients with no significantly diseased
vessels. There was a linear decrease in triglyceride levels
with the presence of Pvu II(-) alleles
(P=.0044) and a linear increase in HDL
cholesterol levels with the presence of
HindIII(-) alleles (P=.023) in patients
without significantly diseased vessels. The relationship between the
Pvu II polymorphism and triglyceride levels
was more highly significant than that between the HindIII
polymorphism and HDL cholesterol levels.
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As expected, there was a significant negative correlation between levels of HDL cholesterol and triglycerides among all patients (r=-.446, P=.0001), which also was seen in patients with Pvu II(-/-) (r=-.345, P=.009), Pvu II(+/-) (r=-.505, P=.0001), and Pvu II(+/+) genotypes (r=-.430, P=.0001).
LpL Pvu II and HindIII Polymorphisms
and Diabetes and Other Medical Conditions
As Table 7 shows, the coexistence of diabetes with
the Pvu II(+/+) genotype was far more than that by
chance alone (r=.152, P=.0025 by logistic
regression analysis). The OR was 3.12 (95% CI, 1.30 to 7.49)
for the association of Pvu II(+/+) genotype with
diabetes compared with the Pvu II(-/-)
genotype (Table 7). But there was no dosage effect in relation
to the (+) allele (Table 7). The inclusion of
triglyceride levels and BMI in the predictive model did not
alter the relationship between the Pvu II polymorphism
and diabetes (r=.140, P=.007); the
triglyceride level itself, which was elevated in the
patient population as a whole, also was not significantly associated
with diabetes in our patients (P=.715), whereas BMI was
strongly associated with diabetes (r=.177,
P=.0006). The findings for diabetes were not altered after
exclusion of patients using lipid-lowering drugs or when the
analysis was among male patients only. The BMI was, as
expected, larger in the diabetic than the nondiabetic patients
(30.1±0.7 [n=55] versus 27.9±0.2 kg/m2 [n=420],
P=.003).
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Neither the Pvu II nor the HindIII
genotype was related to a positive family history of premature
CAD categorically (either negative or positive history) or
quantitatively (the number and age of first-degree relatives with
CAD). There were also no associations with hypertension (likelihood
ratio 2=4.01, P=.13), or severity of
angina pectoris (2=0.95, P=.91), or
history of myocardial infarction (2=3.25,
P=.196). Patients with unstable angina had lower apoA-I
levels (P=.012) and higher Lp(a) levels (P=.05)
than patients with no or stable angina, but other lipid variables
were not different among patients with angina of differing severity.
Lipoprotein profiles also were not different among patients with
different family histories of premature CAD.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our present study explored the association between DNA polymorphisms of the LpL gene and CAD severity. We determined severity from the number of significantly stenosed (>50%) major coronary arteries and a commonly used scoring system.16 Our findings relate to a representative group of consecutively investigated white patients judged by cardiologists to require coronary angiography. This selected patient population is, of course, different from the general population but is representative of patients currently being assessed for the diagnosis and severity of CAD. Nevertheless, the allele frequencies of Pvu II(-) and HindIII(-) in our study were similar to those found in other white populations. Ahn et al17 reported allele frequencies of 0.45 and 0.26 for Pvu II(-) and HindIII(-), respectively, in a control population (n=539). Peacock et al5 also reported frequencies of 0.435 and 0.228 for Pvu II(-) and HindIII(-), respectively, among 92 healthy control subjects. There was a strong linkage disequilibrium between the two Pvu II and HindIII polymorphisms we measured; this disequilibrium also was found in several other studies.5 6 7 8 18 19
LpL Polymorphisms, CAD Severity, and Lipids
The strong association between the Pvu II
polymorphism and the number of significantly diseased vessels
described above was independent of lipoprotein and apolipoprotein
levels, particularly triglyceride and HDL
cholesterol levels. Patients with the Pvu
II(-) allele were less likely to have severe
triple-vessel disease, whereas the +/+ genotype was
associated with more triple-vessel disease although this
association was less strong. Because the base substitution for this
polymorphism occurs in the middle of intron 6, it may not have a
direct functional role in this association. More likely, it is in
linkage disequilibrium with changes at other sites that alter the
systemic and local expression of LpL in response to environmental
change. Alternatively, it could also be in linkage disequilibrium with
some mutations that produce defective LpL with partial activity, which
is expressed with unfavorable environmental influences. For example, Ma
et al20 reported that a
ser172-cys mutation in exon 5 caused
hypertriglyceridemia during pregnancy.
Hayden et al21 recently reviewed gene and environment
interaction in relation to defective LpL expression.
We have no information on mechanisms that could be mediating the association between the Pvu II polymorphism and CAD severity, but it is known that LpL may enhance the retention of LDL and VLDL particles by the subendothelial matrix.3 The polymorphism may be relevant to that atherogenic effect. Although the Pvu II and HindIII polymorphic markers were in strong linkage disequilibrium in our study, we failed to show an independent association between the HindIII polymorphism and severity. However, there was a weak combined effect of these two polymorphisms on severity (P=.056).
Reports about the relationship between LpL polymorphisms and the severity of CAD have been controversial. Mattu et al18 and Thorn et al6 found a significant association between HindIII(+) and an increase in severity of CAD, whereas Peacock et al5 reported that HindIII(+) was associated with decreased severity. Neither group found a relationship with the Pvu II polymorphism. It is difficult to reconcile these observations except to note that the patient numbers in these studies were considerably smaller than in our own and that the other studies used only the Green Lane scoring system to quantify severity. The Green Lane score is an assessment of the extent and site of the arterial stenosis and takes into account the amount of myocardium supplied by the vessel. Although it is a good indicator of the severity of ischemic heart disease, which in our study correlated strongly with the number of significantly stenosed arteries, it represents a different end point in the evaluation of atherosclerosis, particularly in the assessment of a lipid-related atherogenic factor. Our finding that Pvu II had a stronger association with the number of diseased vessels than with the Green Lane scores could offer some support for this view. Nevertheless, the Green Lane scores in our study were also significantly related to Pvu II.
Reports about the associations between lipid variables and LpL Pvu II and HindIII polymorphism have been just as controversial. Several studies have reported significant associations between HindIII(+) and higher triglyceride and lower HDL cholesterol levels,4 5 6 7 findings not confirmed by Heinzmann et al.8 Chamberlain et al7 reported significant associations between Pvu II and triglyceride and HDL cholesterol levels, another finding not confirmed by others.4 5 6 Our findings are in agreement with those of Chamberlain et al7 in that there was a significant dosage-dependent relationship between elevated triglycerides and the Pvu II(+) allele. We also found a trend for higher triglyceride levels in patients with the HindIII(+) allele. Although no association between HindIII and HDL cholesterol levels was found in all patients, a statistically significant dosage-dependent relationship between high HDL cholesterol levels and HindIII(-) alleles was observed in patients with no significantly diseased vessels. In our study, the relationships between triglycerides and Pvu II genotypes were also stronger among subgroups of patients who were not using lipid-lowering drugs or had no significantly stenosed vessels. These findings indicate that confounding factors such as the presence of CAD or the use of lipid-lowering drugs could affect the relationship between LpL polymorphism and circulating lipid levels. Nonetheless, our study clearly identifies an important contribution by the LpL gene to the severity of coronary atherosclerosis, which may not be related to circulating levels of triglyceride and HDL cholesterol.
Pvu II Polymorphism and Diabetes
Our patients with the Pvu II(+/+) genotype were
significantly more likely to have diabetes (OR, 3.12; 95% CI, 1.30 to
7.49; P=.001). As far as we are aware, this has not been
reported previously. Hypertriglyceridemia
and decreased adipose tissue LpL activity occur commonly in diabetic
subjects22 ; therefore, it is relevant that the association
we found was independent of triglyceride levels. Our
diabetic patients as a group were considerably overweight (BMI,
30.1±0.7 kg/m2), significantly more so than the overweight
nondiabetic patients (BMI, 28.2±0.2 kg/m2), and virtually
all had non–insulin-dependent diabetes. Whether or not obese
patients homozygous for the Pvu II(+/+) genotype are
at increased risk of developing non–insulin-dependent diabetes
requires further exploration.
In summary, our study describes associations between polymorphisms of the LpL gene and CAD severity, maturity-onset diabetes, and some lipid variables. These observations may contribute to an understanding of the determinants of CAD severity.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the National Health and Medical Research Council of Australia and the Rebecca Cooper Medical Research Foundation. We wish to thank Dr Bridget Wilcken for reviewing the manuscript; L. Fenech, S. Brown, S. Brouwer, Dr Greg Cranny, and all the nurses in the Eastern Heart Clinic for their assistance in clinical data collection; A.S. Sim for laboratory assistance; and J. Kessy for data entry. We are also grateful to all the cardiologists in the department for allowing us to study their patients.
Received August 7, 1995; revision received October 25, 1995; accepted October 30, 1995.
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