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

TY - JOUR

T1 - Elevated Lipoprotein(a) Does Not Cause Low-Grade Inflammation Despite Causal Association With Aortic Valve Stenosis and Myocardial Infarction

T2 - A Study of 100,578 Individuals from the General Population

AU - Langsted, Anne

AU - Varbo, Anette

AU - Kamstrup, Pia R

AU - Nordestgaard, Børge G

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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 andMIwere similar after further adjustment for CRP levels. Conclusions: Elevated levels of lipoprotein(a) were not causally associated with increased lowgrade inflammation as measured through CRP despite a causal association with increased risk of aortic valve stenosis and MI.

AB - 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 andMIwere similar after further adjustment for CRP levels. Conclusions: Elevated levels of lipoprotein(a) were not causally associated with increased lowgrade inflammation as measured through CRP despite a causal association with increased risk of aortic valve stenosis and MI.

KW - Aged

KW - Aortic Valve Stenosis

KW - C-Reactive Protein

KW - Cohort Studies

KW - Denmark

KW - Female

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Inflammation

KW - Lipoprotein(a)

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Myocardial Infarction

KW - Risk Factors

U2 - 10.1210/jc.2015-1096

DO - 10.1210/jc.2015-1096

M3 - Journal article

C2 - 25938632

SN - 0021-972X

VL - 100

SP - 2690

EP - 2699

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 7

ER -