Circulation, Vol 89, 567-577, Copyright © 1994 by American Heart Association
HW Marshall, LC Morrison, LL Wu, JL Anderson, PS Corneli, DM Stauffer, A Allen, LA Karagounis and RH Ward
BACKGROUND: Because genetic factors are believed to contribute to the
etiology of coronary artery disease (CAD), it has been suggested that DNA
polymorphisms at candidate loci might identify individuals at high risk for
developing disease. In this regard, apolipoprotein genes represent
extremely promising loci because levels of apolipoproteins and their
associated lipoproteins represent a major risk factor for CAD, and rare
dysfunctional mutations in these genes result in a significant risk for
CAD. To date, although some reports indicate that DNA polymorphisms at
these loci are associated with increased risk of CAD, other reports have
failed to find such associations. METHODS AND RESULTS: To resolve the
question of whether genetic polymorphisms at apolipoprotein loci can be
used to identify individuals at increased risk for CAD, we evaluated the
distribution of apolipoprotein genetic polymorphisms in a large series of
subjects (n = 848) undergoing coronary angiography. Blinded assessment of
angiograms was used to discriminate between patients with CAD (> or =
60% stenosis of any major branch, n = 444) and control subjects without
disease (< or = 10% stenosis, n = 404). A total of 12 polymorphisms were
evaluated at the following loci: apolipoprotein (apo) A-I/C-III/A-IV (five
restriction site polymorphisms--Msp I, Pst I, Sst I, Pvu IIa, Pvu IIb), apo
B (three restriction site polymorphisms--Xba I, EcoRI, Msp I, plus an
insertion/deletion polymorphism), apo A-II (Msp I polymorphism), apo C- II
(Taq I polymorphism), and apo E (protein isoforms revealed by DNA
analysis). All subjects were of Northern European (primarily
Angloscandinavian) descent, and, within each sex, patients and control
subjects were of comparable age. All 12 loci were in Hardy-Weinberg
equilibrium, with no indication of population heterogeneity. As expected,
patients were distinguished from control subjects by their lipid profiles
and a higher frequency of known risk factors for CAD. However, analysis by
log-linear models indicated that there were no significant associations
between apolipoprotein polymorphisms and the risk of CAD (P = .10 to .90).
The lack of association was maintained irrespective of whether the analysis
was carried out for the entire sample or the contrast was made more
stringent by comparing patients most likely to have a genetic component to
their disease (ie, young patients with early-onset CAD) with the control
subjects least likely to have genetic susceptibility (ie, older control
subjects who had ample time to develop CAD). CONCLUSIONS: Despite the
fundamental role of apolipoprotein genes in lipid metabolism, we find no
evidence that common genetic polymorphisms of the major apolipoprotein loci
have a significant influence on the risk of developing angiographically
defined CAD in this representative population. Therefore, at this time we
find no support for the hypothesis that mass screening for genetic
polymorphisms at candidate loci can reduce the burden of CAD by identifying
a substantial proportion of high-risk individuals. Instead, it appears more
appropriate to direct attention toward modifying high- risk behaviors to
alleviate the consequences of traditional environmental risk factors.
ARTICLES
Apolipoprotein polymorphisms fail to define risk of coronary artery disease. Results of a prospective, angiographically controlled study
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City.
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