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Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated
Anette Varbo1, Marianne Benn, Anne Tybjærg-Hansen
1Department of Clinical Biochemistry ( A.V., B.G.N.) and Copenhagen General Population Study (A.V., M.B., A.T.-H., B.G.N.), Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.V., M.B., A.T.-H., B.G.N.); Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark (M.B.); Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark (A.T.-H., B.G.N.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (A.T.-H.).
Insights
Elevated nonfasting remnant cholesterol causally increases inflammation and ischemic heart disease (IHD) risk. Elevated low-density lipoprotein (LDL) cholesterol also causes IHD, but independently of inflammation.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Biochemistry
Background:
- Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are linked to ischemic heart disease (IHD).
- The role of these lipoproteins in causing low-grade inflammation remains unclear.
Purpose of the Study:
- To investigate the causal associations between nonfasting remnant cholesterol, LDL cholesterol, and low-grade inflammation.
- To determine the causal relationship between these lipoproteins and ischemic heart disease (IHD).
Main Methods:
- Utilized a multidirectional Mendelian randomization design.
- Analyzed data from 60,608 individuals across three large Danish population studies.
- Genotyped participants for variants affecting lipid levels and C-reactive protein.
Main Results:
- A 1-mmol/L increase in nonfasting remnant cholesterol causally increased C-reactive protein (inflammation marker) by 28%.
- LDL cholesterol showed no causal association with increased C-reactive protein levels.
- Both nonfasting remnant cholesterol (causal risk ratio 3.3) and LDL cholesterol (causal risk ratio 1.8) were causally associated with IHD.
Conclusions:
- Nonfasting remnant cholesterol is causally linked to both low-grade inflammation and IHD.
- LDL cholesterol is causally associated with IHD, but not through an inflammatory pathway.
Background:
Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown.
Methods And Results:
We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35-39) higher C-reactive protein level and causally with a 28% (95% confidence interval, 10-48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6-7) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1-5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity.
Conclusions:
Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation.
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