APOLIPOPROTEIN POLYMORPHISMS PAIL TO DEFINE RISK OF CORONARY-ARTERY DISEASE - RESULTS OF A PROSPECTIVE, ANGIOGRAPHICALLY CONTROLLED-STUDY

Background Because genetic factors are believed to contribute to the e tiology of coronary artery disease (CAD), it has been suggested that D NA polymorphisms at candidate loci might identify individuals at high risk for developing disease. In this regard, apolipoprotein genes repr esent extremely promising loci because levels of apolipoproteins and t heir associated lipoproteins represent a major risk factor for CAD, an d rare dysfunctional mutations in these genes result in a significant risk for CAD. To date, although some reports indicate that DNA polymor phisms 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 apolipoprotei n 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 pat ients with CAD (greater than or equal to 60% stenosis of any major bra nch, n=444) and control subjects without disease (less than or equal t o 10% stenosis, n=404). A total of 12 polymorphisms were evaluated at the following loci: apolipoprotein (apo) A-I/C-III/A-IV (five restrict ion 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 ins ertion/deletion polymorphism), ape A-II (Msp I polymorphism), apo C-II (Tag I polymorphism), and ape E (protein isoforms revealed by DNA ana lysis). All subjects were of Northern European (primarily Angloscandin avian) descent, and, within each sex, patients and control subjects we re 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 association s between apolipoprotein polymorphisms and the risk of CAD (P=.10 to.9 0). The lack of association was maintained irrespective of whether the analysis was carried out for the entire sample or the contrast was ma de more stringent by comparing patients most likely to have a genetic component to their disease (ie, young patients with early-onset CAD) w ith the control subjects least likely to have genetic susceptibility ( ie, older control subjects who had ample time to develop CAD). Conclus ions Despite the fundamental role of apolipoprotein genes in lipid met abolism, 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 populat ion. Therefore, at this time we find no support for the hypothesis tha t mass screening for genetic polymorphisms at candidate loci can reduc e the burden of CAD by identifying a substantial proportion of high-ri sk individuals. Instead, it appears more appropriate to direct attenti on toward modifying high-risk behaviors to alleviate the consequences of traditional environmental risk factors.