Elevated Lipoprotein(a) Does Not Cause Low-Grade Inflammation Despite Causal Association With Aortic Valve Stenosis and Myocardial Infarction: A Study of 100 578 Individuals from the General Population

Context: It is unknown whether elevated lipoprotein(a) is causally associated with low-grade inflammation. Objective: We tested the hypothesis that elevated lipoprotein(a) is observationally and causally associated with low-grade inflammation together with aortic valve stenosis and myocardial infarction. Design and Setting: Using a multidirectional Mendelian randomization approach, we studied 100 578 individuals from the Danish general population with plasma levels of and/or genotypes known to affect levels of lipoprotein(a) and C-reactive protein (CRP), and using information regarding diagnosis of aortic valve stenosis and of myocardial infarction (MI) from registries. Results: Observationally, CRP increased by 29% (95% confidence interval [CI], 23-34) per 50-mg/dL increase in lipoprotein(a). However, two LPA single nucleotide polymorphisms (SNPs) and the kringle IV type 2 (KIV-2) genotype that were associated with 98, 95, and 68 mg/dL higher lipoprotein( a) levels were not causally associated with increased CRP levels. For aortic valve stenosis, a 1-SD increase in lipoprotein(a) levels was associated observationally with a multifactorially adjusted hazard ratio of 1.23 (95% CI, 1.06-1.41), with corresponding causal risk ratios of 1.38 (1.23-1.55) based on LPA SNPs and of 1.21 (1.06-1.40) based on LPA KIV-2 genotype. For myocardial infarction, corresponding values were 1.20 (1.10; 1.31) observationally, and 1.18 (1.11; 1.26) and 1.31 (1.22; 1.42) causally, respectively. Observational hazard ratios for aortic valve stenosis and MI were similar after further adjustment for CRP levels. Conclusions: Elevated levels of lipoprotein(a) were not causally associated with increased low-grade inflammation as measured through CRP despite a causal association with increased risk of aortic valve stenosis and MI.