LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals
Abstract
Background: Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear. Methods: We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis. Results: Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11–2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70–2.62) (Pcomparison = 0.03). Conclusion: Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.
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Large Mendelian randomisation studies indicate that increased HDL-cholesterol cannot be translated into a reduction in CVD risk.
“Further, large Mendelian randomisation studies indicate that increased HDLcholesterol cannot be translated into a reduction in CVD risk (42,43)”
From Effects of low-carbohydrate diets<i>v</i>. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials (2016) · cites this paper as [42]
The Discussion reports that genetically decreased HDL cholesterol was not associated with increased MI risk and concludes that the data do not favor isolated HDL-cholesterol raising as an antiatherogenic strategy. That supports skepticism about raising HDL, but the claim's categorical statement that increased HDL cannot reduce CVD risk goes beyond this study's hedged conclusion and its focus on MI and ischemic cardiovascular disease. (LLM, conf=0.88)
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- Authors
- Haase, C. L., Tybjærg-Hansen, A., Ali Qayyum, A., Schou, J., Nordestgaard, B. G., & Frikke-Schmidt, R.
- Affiliations
- Rigshospitalet (DK)
- Department of Clinical Biochemistry (C.L.H., A.T.-H., A.A.Q., J.S., R.F.-S.), Rigshospitalet, DK-2100 Copenhagen, Denmark
- University of Copenhagen (DK)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-02-01
- Volume
- 97
- Issue
- 2
- Pages
- E248-E256
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1999246447
- Cited by
- 282
- References
- 5
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 21 · 2023: 19 · 2022: 19 · 2021: 23 · 2020: 15 · 2019: 14 · 2018: 16 · 2017: 17 · 2016: 21 · 2015: 34 · 2014: 23 · 2013: 24 · 2012: 18
- FWCI
- 21.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- European Commission
- Gentofte Hospital
- Rigshospitalet
- Ipsen
- Medical Research Council
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- HDL cholesterol, ischemic cardiovascular disease, myocardial infarction, lecithin:cholesterol acyltransferase, genetic variants, instrumental variables, Copenhagen City Heart Study, Copenhagen General Population Study
- MeSH terms
- Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Cross-Sectional Studies, Denmark, Female, Humans, Phosphatidylcholine-Sterol O-Acyltransferase, Cholesterol, HDL, Male, Middle Aged, Registries, Cohort Studies, Myocardial Ischemia, Polymorphism, Single Nucleotide, Young Adult, Mendelian Randomization Analysis
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