Apolipoprotein polymorphisms fail to define risk of coronary artery disease. Results of a prospective, angiographically controlled study.
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.


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.
Marshall
H W
HW
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City.
Morrison
L C
LC
Wu
L L
LL
Anderson
J L
JL
Corneli
P S
PS
Stauffer
D M
DM
Allen
A
A
Karagounis
L A
LA
Ward
R H
RH
D000328:Adult; D000368:Aged; D000483:Alleles; D001053:Apolipoproteins / Q000235:genetics*; D001483:Base Sequence; D017023:Coronary Angiography; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000209:etiology*; D005260:Female; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012016:Reference Values; D012017:Referral and Consultation; D012307:Risk Factors
D001053:Apolipoproteins; D008055:Lipids