Abstract 5093: Genetically Elevated Lipoprotein(a) and Risk of Myocardial Infarction - a Positive Mendelian Randomization Study

Abstract

Background: High levels of lipoprotein(a) (Lp(a)) associate with increased risk of myocardial infarction (MI). We tested whether this is a causal effect using a Mendelian randomization design. Methods: We genotyped for the Lp(a) kringle IV type 2 (KIV-2) size polymorphism, which explains 21% of variation in plasma levels of Lp(a). We used a cohort study of the Danish general population, The Copenhagen City Heart Study, including 9867 individuals followed for up to 16 years during which time 599 developed MI, and a case-control study, The Copenhagen Ischemic Heart Disease Study, including 1118 MI patients and 2234 controls. Results: First, increased plasma levels of Lp(a) associated with increased risk of MI (Lp(a) tertiles, trend: p<0.001). Second, number of KIV-2 repeats inversely associated with Lp(a) levels: mean Lp(a) levels were 56, 31, 20, and 15 mg/dL for the 1 st , 2 nd , 3 rd , and 4 th quartile of KIV-2 repeats, respectively (trend, p<0.001, Figure ). Third, multifactorially adjusted hazard ratios for MI were 1.6(95% CI:1.3–.2.0), 1.3(1.0 –1.7), and 1.1(0.9 –1.4) for individuals in the 1 st , 2 nd , and 3 rd quartile, respectively, as compared to individuals in the 4 th quartile of KIV-2 repeats (Figure ). Finally, in the case-control study, multifactorially adjusted odds ratios for MI were 1.5(1.2–1.9), 1.3(1.0 –1.6), and 1.2(1.0 –1.5) for individuals in the 1 st , 2 nd , and 3 rd quartile, respectively, as compared to individuals in the 4 th quartile of KIV-2 repeats. Conclusion: Since Lp(a) levels predict MI, and since Lp(a) KIV-2 genotype predicts both life-long increased Lp(a) levels and MI, increased Lp(a) levels appear to directly cause MI. Figure. Levels of lipoprotein (a) and risk of myocardial infarction by KIV-2