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Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Open accessAbstract
Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
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“In contrast, Mendelian randomization studies do not provide compelling evidence that HDL-C is causally associated with the risk of ASCVD [49,61,62].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [61]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Mendelian randomization studies further support the notion that HDL-C may not be causally related to CHD risk”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [111]
Experimental — accuracy not yet measuredIn the citing paper
“The causative role of HDL-C for protection against CVD has been questioned in several studies utilizing Mendelian randomization. 87,89,91,92”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [92]
In the citing paper
“As described below, findings from GWAS have increasing translational impact through identification of novel therapeutic targets67, prioritization (and deprioritization) of existing ones68 and development of polygenic scores that quantify individual genetic risk69.”
From A brief history of human disease genetics (2020) · cites this paper as [68]
In the citing paper
“The causative role of HDL-C for protection against CVD has been questioned in several studies utilizing Mendelian randomization.87,89,91,92”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [92]
In the citing paper
“Dietary interventions which raise HDL-C may not necessarily translate into CVD risk reduction, as serum HDL-c has recently been called into question regarding its role in the causal pathway of CVD (110).”
From Food Consumption and its Impact on Cardiovascular Disease: Importance of Solutions Focused on the Globalized Food System (2015) · cites this paper as [110]
In the citing paper
“With increasing availability of large-scale phenotyping (and genotyping), MR is being widely applied to quantitative traits (e.g. markers or adiposity, such as body mass index 13-16 ; blood lipids such as HDL-cholesterol 17-19 ; inflammation-related proteins such as interleukin-6 receptor 20,21 12 ) with the aim of discovering modifiable risk factors for disease that are causal and amenable to the”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [20]
In the citing paper
“For example, whilst inflammation in general has long been postulated to influence vascular disease 49,50 , MR has been able to test whether particular elements in the inflammatory response cause 20 or are caused by 51 disease.”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [20]
In the citing paper
“The interleukin 6 receptor (IL6R) is a drug target that alters CRP (see Figure 3 ), and for which genetic evidence supports a causal role of IL6R in CHD 20 54”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [20]
In the citing paper
“In contrast, recent studies have failed to demonstrate that high HDL-C acquired naturally or pharmacologically, is associated with reduced CVD risk.5-11,18”
From Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?: New Insights From the Framingham Offspring Study (2016) · cites this paper as [11]
In the citing paper
“Similarly, a Mendelian randomization study failed to identify polymorphisms associated with high HDL-C that correlate with reduced CVD risk.11”
From Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?: New Insights From the Framingham Offspring Study (2016) · cites this paper as [11]
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BackgroundAssociation of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes
White, J., Swerdlow, D. I., Preiss, D., Fairhurst-Hunter, Z., Keating, B. J., Asselbergs, F. W., Sattar, N., Humphries, S. E., Hingorani, A. D., & Holmes, M. V. (2016) · JAMA Cardiology · doi:10.1001/jamacardio.2016.1884 · Cited by 293
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BackgroundHDL cholesterol: reappraisal of its clinical relevance
März, W., Kleber, M. E., Scharnagl, H., Speer, T., Zewinger, S., Ritsch, A., Parhofer, K. G., von Eckardstein, A., Landmesser, U., & Laufs, U. (2017) · Clinical Research in Cardiology · doi:10.1007/s00392-017-1106-1 · Cited by 275
“This stands in contrast to genetic factors which increase LDL cholesterol, because monogenetic (familial hypercholesterolemia) and polygenetic factors increasing LDL cholesterol consistently lead to concordant changes in the CV risk (positive Mendelian randomisation) [43, 44].”
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“The genetic risk score was defined as before (56).”
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“Nevertheless, previous studies showed high agreement in results from MR methods using GWAS summary data and individual-level data [60,107]; Furthermore, our analyses of individual-level data for schizophrenia led to the same conclusion as our analyses using summary statistics data, confirming the…”
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Progress and promise in understanding the genetic basis of common diseases
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“Recent Mendelian randomization studies, however, cast doubt on the causal role of HDL-C in CVD [361].”
Surprises from genetic analyses of lipid risk factors for atherosclerosis
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“Concordant with the genetic data, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) ultimately provided RCT data demonstrating that ezetimibe in fact does reduce CHD risk.27 The totality of the existing genetic data and RCT data strongly argue that LDL-C is causal for CHD and, as a…”
InfluentialSelf-citationThe many weak instruments problem and Mendelian randomization
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“Mendelian randomization uses genetic variants as instrumental variables to investigate the effects of modifiable risk factors for disease such as weight, blood pressure, cholesterol, alcohol, and tobacco consumption on different outcomes of interest [1–9].”
BackgroundFruchart, J.-C., Santos, R. D., Aguilar-Salinas, C., Aikawa, M., Al Rasadi, K., Amarenco, P., Barter, P. J., Ceska, R., Corsini, A., Després, J.-P., et al. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0864-7 · Cited by 140
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“Studies that have reported increased CVD risk in COCP users have mostly studied women at reproductive age, during which the absolute risk for CVD events is generally low e.g. approximately two incidences of arterial thrombosis and seven incidences of venous thrombosis per 10 000 person-years in current users of third-…”
ResultInfluentialSelf-citationHDL from an Alzheimer's disease perspective
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Novel and future lipid-modulating therapies for the prevention of cardiovascular disease
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High-resolution genetic mapping of putative causal interactions between regions of open chromatin
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Genetics of coronary artery disease in the post‐GWAS era
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“Age 41 (11) 46 (10) 49 (10) 53 (10) 53 (10) 46 (10) 51 (10) 52 (11) 54 (9)”
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“Although inverse associations between HDL cholesterol concentration and occlusive CVD have been widely reported in large prospective studies,(1,2) including the CKB,(35) the causal relevance of such associations has not been established.(12,36,37) In a prospective study, HDL efflux capacity was inversely associated wi…”
BackgroundResultSelf-citationMethylation at CPT1A locus is associated with lipoprotein subfraction profiles
Wood, A. C., Aslibekyan, S. W., Absher, D., Hopkins, P. N., Sha, J., Tsai, M. Y., Tiwari, H. K., Waite, L. L., Zhi, D., & Arnett, D. K. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m048504 · Cited by 80
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“Genetic studies suggest that differences in HDL-C levels do not affect CVD risk (19).”
BackgroundLipid disorders in children living with overweight and obesity- large cohort study from Poland
Brzeziński, M., Metelska, P., Myśliwiec, M., & Szlagatys‐Sidorkiewicz, A. (2020) · Lipids in Health and Disease · doi:10.1186/s12944-020-01218-6 · Cited by 73
“Studies assessing the genetic differences determining lipid profile (both LDLC and HDL-C levels) show that genetic background can be an important factor for the future outcome of low or elevated levels of blood lipids [34, 35].”
Riaz, H., Khan, S. U., Rahman, H., Shah, N. P., Kaluski, E., Lincoff, A. M., & Nissen, S. E. (2019) · European Journal of Preventive Cardiology · doi:10.1177/2047487318816495 · Cited by 61
“85) despite significantly increasing HDL levels.(50) The major limitations of this analysis are that this is a pooled analysis of individual trials as we did not have access to the individual patient data.”
Gender-specific associations between lipids and cognitive decline in the elderly
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“…in the women who had never used HT and with higher HDL-C levels remains to be clarified but could involve genetic vulnerability related to HDL-C (Voight et al., 2012) as well as estrogen receptors or metabolizing enzymes which could modulate the response of HDL-C to hormonal treatment…”
Backgroundvan der Graaf, A., Claringbould, A., Rimbert, A., Heijmans, B. T., Hoen, P. A. C. ’., van Meurs, J. B. J., Jansen, R., Franke, L., Westra, H.-J., Li, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18716-x · Cited by 58
Self-citationSystems genetics applications in metabolism research
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Duparc, T., Ruidavets, J., Genoux, A., Ingueneau, C., Najib, S., Ferrières, J., Perret, B., & Martinez, L. O. (2020) · Scientific Reports · doi:10.1038/s41598-020-65100-2 · Cited by 54
Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition
Kettunen, J., Holmes, M. V., Allara, E., Anufrieva, O., Ohukainen, P., Oliver-Williams, C., Wang, Q., Tillin, T., Hughes, A. D., Kähönen, M., et al. (2019) · PLOS Biology · doi:10.1371/journal.pbio.3000572 · Cited by 47
Self-citationPhenotypes and Genotypes of High Density Lipoprotein Cholesterol in Exceptional Longevity
Milman, S., Atzmon, G., Crandall, J. P., & Barzilai, N. (2013) · Current Vascular Pharmacology · doi:10.2174/1570161111666131219101551 · Cited by 46
“variation (rs3764261) was related to a 4% decreased risk of myocardial infarction; albeit this risk reduction may not have been solely the result of a raised HDL[58].”
BackgroundInfluentialMonitoring of lipids, enzymes, and creatine kinase in patients on lipid-lowering drug therapy
Wiklund, O., Pirazzi, C., & Romeo, S. (2013) · Current Cardiology Reports · doi:10.1007/s11886-013-0397-8 · Cited by 45
“Furthermore, genetic studies using mendelian randomization do not support HDL as a direct causative agent for disease [37].”
BackgroundDietary cholesterol increases paraoxonase 1 enzyme activity
Kim, D. S., Burt, A., Ranchalis, J., Richter, R. J., Marshall, J. K., Nakayama, K. S., Jarvik, E. R., Eintracht, J. F., Rosenthal, E. A., Furlong, C. E., et al. (2012) · Journal of Lipid Research · doi:10.1194/jlr.p030601 · Cited by 45
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias
Catapano, A. L., Graham, I. M., Backer, G. D., Wiklund, O., Chapman, M. J., Drexel, H., Hoes, A. W., Jennings, C. S., Landmesser, U., Pedersen, T. R., et al. (2016) · Kardiologia Polska · doi:10.5603/kp.2016.0157 · Cited by 48
Self-citationTangier disease: update for 2020
Hooper, A. J., Hegele, R. A., & Burnett, J. R. (2020) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000669 · Cited by 42
Wu, Z., Lou, Y., Qiu, X., Liu, Y., Lu, L., Chen, Q., & Jin, W. (2014) · BMC Medical Genetics · doi:10.1186/s12881-014-0118-1 · Cited by 40
“[77] utilized the Asn396Ser polymorphism in the endothelial lipase gene (LIPG) and a genetic score containing 14 common single nucleotide polymorphisms (solely concerning HDL-C) as two instruments for Mendelian randomization.”
Metadata
- Authors
- Voight, B. F., Peloso, G. M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M. K., Hindy, G., Hólm, H., Ding, E. L., Johnson, T., Schunkert, H., Samani, N. J., Clarke, R., Hopewell, J. C., Thompson, J. F., Li, M., Thorleifsson, G., Newton-Cheh, C., Musunuru, K., Pirruccello, J. P., Saleheen, D., Chen, L., Stewart, A. F., Schillert, A., Thorsteinsdottir, U., Thorgeirsson, G., Anand, S., Engert, J. C., Morgan, T., Spertus, J., Stoll, M., Berger, K., Martinelli, N., Girelli, D., McKeown, P. P., Patterson, C. C., Epstein, S. E., Devaney, J., Burnett, M.-S., Mooser, V., Ripatti, S., Surakka, I., Nieminen, M. S., Sinisalo, J., Lokki, M.-L., Perola, M., Havulinna, A., de Faire, U., Gigante, B., Ingelsson, E., Zeller, T., Wild, P., de Bakker, P. I. W., Klungel, O. H., Maitland-van der Zee, A.-H., Peters, B. J. M., de Boer, A., Grobbee, D. E., Kamphuisen, P. W., Deneer, V. H. M., Elbers, C. C., Onland-Moret, N. C., Hofker, M. H., Wijmenga, C., Verschuren, W. M., Boer, J. M., van der Schouw, Y. T., Rasheed, A., Frossard, P., Demissie, S., Willer, C., Do, R., Ordovas, J. M., Abecasis, G. R., Boehnke, M., Mohlke, K. L., Daly, M. J., Guiducci, C., Burtt, N. P., Surti, A., Gonzalez, E., Purcell, S., Gabriel, S., Marrugat, J., Peden, J., Erdmann, J., Diemert, P., Willenborg, C., König, I. R., Fischer, M., Hengstenberg, C., Ziegler, A., Buysschaert, I., Lambrechts, D., Van de Werf, F., Fox, K. A., El Mokhtari, N. E., Rubin, D., Schrezenmeir, J., Schreiber, S., Schäfer, A., Danesh, J., Blankenberg, S., Roberts, R., McPherson, R., Watkins, H., Hall, A. S., Overvad, K., Rimm, E., Boerwinkle, E., Tybjaerg-Hansen, A., Cupples, L. A., Reilly, M. P., Melander, O., Mannucci, P. M., Ardissino, D., Siscovick, D., Elosua, R., Stefansson, K., O'Donnell, C. J., Salomaa, V., Rader, D. J., Peltonen, L., Schwartz, S. M., Altshuler, D., & Kathiresan, S.
- Affiliations
- University of Pennsylvania (US)
- Boston University (US)
- Harvard University (US)
- Lund University (SE)
- deCODE Genetics (Iceland) (IS)
- Brigham and Women's Hospital (US)
- Queen Mary University of London (GB)
- University of Lübeck (DE)
- University of Leicester (GB)
- University of Oxford (GB)
- Broad Institute (US)
- University of Cambridge (GB)
- Ottawa Heart Institute (CA)
- Population Health Research Institute (CA)
- McGill University (CA)
- Vanderbilt University (US)
- University of Missouri–Kansas City (US)
- University of Münster (DE)
- University of Verona (IT)
- Queen's University Belfast (GB)
- MedStar Washington Hospital Center (US)
- GlaxoSmithKline (United States) (US)
- University of Helsinki (FI)
- Helsinki University Hospital (FI)
- Finnish Institute for Health and Welfare (FI)
- Karolinska Institutet (SE)
- Johannes Gutenberg University Mainz (DE)
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- University Medical Center Groningen (NL)
- St. Antonius Ziekenhuis (NL)
- National Institute for Public Health and the Environment (NL)
- Center for Non-Communicable Diseases (PK)
- University of Michigan (US)
- Massachusetts General Hospital (US)
- University of North Carolina at Chapel Hill (US)
- Hospital del Mar Research Institute (ES)
- University Hospital Regensburg (DE)
- Universitair Ziekenhuis Leuven (BE)
- University of Edinburgh (GB)
- University Hospital Schleswig-Holstein (DE)
- Max Rubner Institut (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University of Leeds (GB)
- Aarhus University (DK)
- The University of Texas Health Science Center at Houston (US)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Ospedale di Parma (IT)
- University of Washington (US)
- Corresponding author
- Kathiresan, Sekar
- ORCID
- Voight, Benjamin F
- Peloso, Gina M
- Jensen, Majken K
- Hindy, George
- Hólm, Hilma
- Ding, Eric L
- Johnson, Toby
- Schunkert, Heribert
- Samani, Nilesh J
- Clarke, Robert
- Hopewell, Jemma C
- Thompson, John F
- Li, Mingyao
- Musunuru, Kiran
- Pirruccello, James P
- Saleheen, Danish
- Chen, Li
- Stewart, Alexandre FR
- Schillert, Arne
- Anand, Sonia
- Engert, James C
- Morgan, Thomas
- Spertus, John
- Stoll, Monika
- Martinelli, Nicola
- Girelli, Domenico
- McKeown, Pascal P
- Patterson, Christopher C
- Mooser, Vincent
- Ripatti, Samuli
- Surakka, Ida
- Nieminen, Markku S
- Sinisalo, Juha
- Lokki, Marja-Liisa
- Perola, Markus
- Havulinna, Aki
- Gigante, Bruna
- Ingelsson, Erik
- Zeller, Tanja
- Wild, Philipp
- Klungel, Olaf H
- Peters, Bas J M
- Grobbee, Diederick E
- Kamphuisen, Pieter W
- Deneer, Vera H M
- Elbers, Clara C
- Wijmenga, Cisca
- Verschuren, WM Monique
- Boer, Jolanda MA
- Demissie, Serkalem
- Willer, Cristen
- Do, Ron
- Abecasis, Gonçalo R
- Boehnke, Michael
- Mohlke, Karen L
- Daly, Mark J
- Burtt, Noël P
- Purcell, Shaun
- Gabriel, Stacey
- Marrugat, Jaume
- Erdmann, Jeanette
- König, Inke R
- Fischer, Marcus
- Hengstenberg, Christian
- Ziegler, Andreas
- Buysschaert, Ian
- Lambrechts, Diether
- Fox, Keith A
- Schreiber, Stefan
- Danesh, John
- Blankenberg, Stefan
- McPherson, Ruth
- Watkins, Hugh
- Hall, Alistair S
- Overvad, Kim
- Rimm, Eric
- Boerwinkle, Eric
- Cupples, L Adrienne
- Reilly, Muredach P
- Melander, Olle
- Mannucci, Pier M
- Ardissino, Diego
- Siscovick, David
- Salomaa, Veikko
- Rader, Daniel J
- Peltonen, Leena
- Altshuler, David
- Kathiresan, Sekar
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 380
- Issue
- 9841
- Pages
- 572-580
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC3419820
- OpenAlex
- W1240353884
- Cited by
- 148
- References
- 36
- Citations by year
- 2026: 11 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 9 · 2021: 19 · 2020: 16 · 2019: 9 · 2018: 10 · 2017: 8 · 2016: 12 · 2015: 8 · 2014: 9 · 2013: 6 · 2012: 13
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- OpenAgrar (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- WOS
- Funders
- Wellcome Trust (090532)
- British Heart Foundation (RG/08/014/24067)
- National Institutes of Health (n01hc25195-41-0-1)
- National Heart, Lung, and Blood Institute (N01-HC-025195)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- HDL cholesterol, myocardial infarction, causal inference, endothelial lipase, genetic score, LDL cholesterol, cardiovascular risk, genetic instruments, single nucleotide polymorphisms, lipid biomarkers, confounding by indication, reverse causality
- MeSH terms
- Gene Frequency, Humans, Lipase, Cholesterol, HDL, Cholesterol, LDL, Myocardial Infarction, Prospective Studies, Risk Factors, Biomarkers, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis
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