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.
BACKGROUND
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.


METHODS
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.
Department of Clinical Biochemistry (A.L., A.V., P.R.K., B.G.N.), and The Copenhagen General Population Study (A.L., A.V., P.R.K., B.G.N.), Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N.), Frederiksberg Hospital, Copenhagen University Hospital, 2000 Frederiksberg, Denmark; and Faculty of Health and Medical Sciences (A.L., A.V., P.R.K., B.G.N.), University of Copenhagen, 1165 Copenhagen, Denmark.
Anne
A
Langsted
Department of Clinical Biochemistry (A.L., A.V., P.R.K., B.G.N.), and The Copenhagen General Population Study (A.L., A.V., P.R.K., B.G.N.), Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N.), Frederiksberg Hospital, Copenhagen University Hospital, 2000 Frederiksberg, Denmark; and Faculty of Health and Medical Sciences (A.L., A.V., P.R.K., B.G.N.), University of Copenhagen, 1165 Copenhagen, Denmark.
Anette
A
Varbo
Department of Clinical Biochemistry (A.L., A.V., P.R.K., B.G.N.), and The Copenhagen General Population Study (A.L., A.V., P.R.K., B.G.N.), Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N.), Frederiksberg Hospital, Copenhagen University Hospital, 2000 Frederiksberg, Denmark; and Faculty of Health and Medical Sciences (A.L., A.V., P.R.K., B.G.N.), University of Copenhagen, 1165 Copenhagen, Denmark.
Pia R
PR
Kamstrup
Department of Clinical Biochemistry (A.L., A.V., P.R.K., B.G.N.), and The Copenhagen General Population Study (A.L., A.V., P.R.K., B.G.N.), Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; The Copenhagen City Heart Study (B.G.N.), Frederiksberg Hospital, Copenhagen University Hospital, 2000 Frederiksberg, Denmark; and Faculty of Health and Medical Sciences (A.L., A.V., P.R.K., B.G.N.), University of Copenhagen, 1165 Copenhagen, Denmark.
Børge G
BG
Nordestgaard
D000368:Aged; D001024:Aortic Valve Stenosis / Q000097:blood* / Q000453:epidemiology / Q000209:etiology*; D002097:C-Reactive Protein / Q000378:metabolism; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000453:epidemiology; D017270:Lipoprotein(a) / Q000097:blood* / Q000235:genetics; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000453:epidemiology / Q000209:etiology*; D012307:Risk Factors
D017270:Lipoprotein(a); D002097:C-Reactive Protein