A Variant of the LPA Gene Predicts Cardiovascular Event Reduction by Aspirin Therapy in a Primary Prevention Setting

Abstract

Synopsis: The risk/benefit ratio of aspirin therapy in primary prevention of cardiovascular disease does not justify the use of aspirin. The 4399Met variant of the LPA gene—a gene that encodes apolipoprotein(a)—can help identify those who may have an acceptable risk/benefit ratio for aspirin therapy in a primary prevention setting. Purpose: To investigate the association of the LPA 4399Met variant (rs3798220) with risk of coronary events and with differential response to aspirin therapy. Methods: We used regression models to investigate the association between LPA 4399Met carrier status and coronary events and the effect of aspirin therapy on event reduction on carriers and non-carriers of 4399Met in 2 settings: 1) The Women's Health Study (WHS)—a study of more than 25,000 initially healthy women who were randomized to low-dose aspirin or placebo, and 2) self-reported nonusers (n = 5330) and regular users (n = 1422) of aspirin in the Atherosclerosis Risk in Communities (ARIC) study. We investigated the effect of aspirin therapy according to LPA 4399Met carrier status in WHS. Results: Carriers of the 4399Met allele of the LPA gene, compared with non-carriers, had increased levels of plasma lipoprotein(a) (P < .0001) and over 2-fold increased risk for major cardiovascular events in the placebo group of WHS (age-adjusted hazard ratio (HR) = 2.21; 95% CI, 1.39–3.52). This excess risk was essentially eliminated by aspirin therapy: for aspirin compared with placebo the age-adjusted HR was 0.44 (95% CI, 0.20–0.94). The risk of major cardiovascular events was not significantly reduced among non-carriers (age-adjusted HR, 0.91; 95% CI, 0.77–1.08). Consistent with these findings, among nonusers of aspirin in ARIC, carriers of the 4399Met allele compared with noncarriers had increased risk of coronary heart disease (HR, 1.57; 90% CI, 1.00–2.46; 1-sided P = .049), after adjusting for age and sex. However, carriers of the 4399Met allele did not have increased risk of CHD among nonusers of aspirin (HR, 0.86; 90% CI, 0.43–1.71; P = .36). Conclusions: Carriers of the LPA 4399Met allele are at increased risk of coronary heart disease. This excess risk is ameliorated by aspirin therapy.