A PROSPECTIVE CASE-CONTROL STUDY OF LIPOPROTEIN(A) LEVELS AND APO(A) SIZE AND RISK OF CORONARY HEART-DISEASE IN STANFORD 5-CITY PROJECT PARTICIPANTS

Lipoprotein(a) [Lp(a)] is formed by the assembly of LDL particles and a carbohydrate-rich protein, apolipoprotein(a) [apo(a)], which has a h igh degree of structural homology with plasminogen. While the majority of retrospective studies have found an association between Lp(a) leve l and cardiovascular disease (CVD), the few prospective studies to dat e have reported contradictory results. We conducted a nested case-cont rol study using the participants in the Stanford Five-City Project, a long-term CVD prevention trial. Participants with an incident possible or definite myocardial infarction or coronary death were matched to a single control subject for age, sex, ethnicity, residence in a treatm ent or control city, and time of survey. This process yielded 134 case -control pairs, 90 male and 44 female, for whom plasma was available f or analysis of Lp(a). Lp(a) values in nanomoles per liter were determi ned by an enzyme-Linked immunoassay that measures Lp(a) independently of apo(a) size polymorphism. Apo(a) size isoforms were determined by S DS-agarose gel electrophoresis. Median Lp(a) level in male cases was a lmost double that in control subjects (41.8 versus 21.2 nmol/L; P<.01) ; in female cases, median Lp(a) was 34% higher than in control subject s (32.5 versus 21.2 nmol/L), but this difference was not statistically significant. Among the male cases, there was an increased frequency o f small apo(a) isoforms, while no significant difference was found in apo(a) size between female cases and control subjects. The association between Lp(a) level and case-control status in men was independent of total, HDL, and non-HDL cholesterol levels, as well as apo(a) size is oform, cigarette smoking, blood pressure, and obesity. In men, the mos t efficient threshold value of Lp(a) concentration for separating case s and control subjects was 35 nmol/L; the odds ratio for being a case above this level compared with below was 2.84 (95% confidence interval : 1.53-5.27, P<.001). This study provides strong evidence that Lp(a) l evel is a prospective, independent risk factor for developing coronary artery disease in men and indicates that the size of apo(a) may also play a role. The lack of a significant, association in women deserves further evaluation in larger studies.