Human genetic insights into lipoproteins and risk of cardiometabolic disease
Open accessAbstract
Purpose of review: Human genetic studies have been successfully used to identify genes and pathways relevant to human biology. Using genetic instruments composed of loci associated with human lipid traits, recent studies have begun to clarify the causal role of major lipid fractions in risk of cardiometabolic disease. Recent findings: The causal relationship between LDL cholesterol and coronary disease has been firmly established. Of the remaining two major fractions, recent studies have found that HDL cholesterol is not likely to be a causal particle in atherogenesis, and have instead shifted the causal focus to triglyceride-rich lipoproteins. Subsequent results are refining this view to suggest that triglycerides themselves might not be causal, but instead may be a surrogate for the causal cholesterol content within this fraction. Other studies have used a similar approach to address the association between lipid fractions and risk of type 2 diabetes. Beyond genetic variation in the target of statin medications, reduced LDL cholesterol associated with multiple genes encoding current or prospective drug targets associated with increased diabetic risk. In addition, genetically lower HDL cholesterol and genetically lower triglycerides both appear to increase risk of type 2 diabetes. Summary: Results of these and future human genetic studies are positioned to provide substantive insights into the causal relationship between lipids and human disease, and should highlight mechanisms with important implications for our understanding of human biology and future lipid-altering therapeutic development.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mendelian randomization evidence suggests that elevated triglycerides linked to genetic variants may be a causal factor for atherosclerotic cardiovascular disease and possibly for premature all-cause mortality.
“More recent evidence from mendelian randomization studies has shown that elevated triglycerides associated with genetic variants may be a causal factor for ASCVD and possibly for premature all-cause mortality.”
From Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association (2019) · cites this paper as [3]
In the section on triglycerides and coronary artery disease (page not provided), the review discusses Mendelian randomization and genetic variants linking triglyceride-rich lipoproteins to coronary disease risk; its annotated reference 25 explicitly describes evidence for a causal role. Our copy does not report an association with premature all-cause mortality, so that part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703 · see citing works
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes
Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., Darius, H., Lewis, B. S., Ophuis, T. O., Jukema, J. W., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1410489 · Cited by 4,487 · see citing works
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487 · see citing works
Sequence Variations in <i>PCSK9,</i> Low LDL, and Protection against Coronary Heart Disease
Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054013 · Cited by 3,181 · see citing works
Effects of torcetrapib in patients at high risk for coronary events
Barter, P. J., Caulfield, M., Eriksson, M., Grundy, S. M., Kastelein, J. J. P., Komajda, M., Lopez-Sendon, J., Mosca, L., Tardif, J.-C., Waters, D. D., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa0706628 · Cited by 3,139 · see citing works
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
Abifadel, M., Varret, M., Rabès, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., et al. (2003) · Nature Genetics · doi:10.1038/ng1161 · Cited by 2,985 · see citing works
Willer (2013) · doi:10.1038/ng.2797 · Cited by 2,983 · see citing works
Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy
The AIM-HIGH Investigators (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1107579 · Cited by 2,911 · see citing works
Major lipids, apolipoproteins, and risk of vascular disease
The Emerging Risk Factors Collaboration* (2009) · JAMA · doi:10.1001/jama.2009.1619 · Cited by 2,731 · see citing works
Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials
Sattar, N., Preiss, D., Murray, H. M., Welsh, P., Buckley, B. M., de Craen, A. J., Seshasai, S. R. K., McMurray, J. J., Freeman, D. J., Jukema, J. W., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(09)61965-6 · Cited by 2,436 · see citing works
Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events
Robinson, J. G., Farnier, M., Krempf, M., Bergeron, J., Luc, G., Averna, M., Stroes, E. S., Langslet, G., Raal, F. J., El Shahawy, M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1501031 · Cited by 2,296 · see citing works
Effects of dalcetrapib in patients with a recent acute coronary syndrome
Schwartz, G. G., Olsson, A. G., Abt, M., Ballantyne, C. M., Barter, P. J., Brumm, J., Chaitman, B. R., Holme, I. M., Kallend, D., Leiter, L. A., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206797 · Cited by 2,022 · see citing works
KANNEL, W. B., DAWBER, T. R., KAGAN, A., REVOTSKIE, N., & STOKES, J. (1961) · Annals of Internal Medicine · doi:10.7326/0003-4819-55-1-33 · Cited by 1,837 · see citing works
Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease
Clarke, R., Peden, J. F., Hopewell, J. C., Kyriakou, T., Goel, A., Heath, S. C., Parish, S., Barlera, S., Franzosi, M. G., Rust, S., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0902604 · Cited by 1,671 · see citing works
Effects of extended-release niacin with laropiprant in high-risk patients
The HPS2-THRIVE Collaborative Group (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1300955 · Cited by 1,668 · see citing works
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
Sabatine, M. S., Giugliano, R. P., Wiviott, S. D., Raal, F. J., Blom, D. J., Robinson, J., Ballantyne, C. M., Somaratne, R., Legg, J., Wasserman, S. M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500858 · Cited by 1,509 · see citing works
Triglycerides and cardiovascular disease
Nordestgaard, B. G., & Varbo, A. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61177-6 · Cited by 1,419 · see citing works
Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia
Kastelein, J. J. P., Akdim, F., Stroes, E. S. G., Zwinderman, A. H., Bots, M. L., Stalenhoef, A. F. H., Visseren, F. L. J., Sijbrands, E. J. G., Trip, M. D., Stein, E. A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0800742 · Cited by 1,241 · see citing works
Loss-of-Function Mutations in <i>APOC3,</i> Triglycerides, and Coronary Disease
The TG and HDL Working Group of the Exome Sequencing Project, N. H. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1307095 · Cited by 1,071 · see citing works
Clinical risk factors, DNA variants, and the development of type 2 diabetes
Lyssenko, V., Jonsson, A., Almgren, P., Pulizzi, N., Isomaa, B., Tuomi, T., Berglund, G., Altshuler, D., Nilsson, P., & Groop, L. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0801869 · Cited by 938 · see citing works
Loss-of-Function Mutations in <i>APOC3</i> and Risk of Ischemic Vascular Disease
Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G., & Tybjærg-Hansen, A. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1308027 · Cited by 919 · see citing works
Common variants associated with plasma triglycerides and risk for coronary artery disease
Do, R., Willer, C. J., Schmidt, E. M., Sengupta, S., Gao, C., Peloso, G. M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., et al. (2013) · Nature Genetics · doi:10.1038/ng.2795 · Cited by 862 · see citing works
Mendelian randomization of blood lipids for coronary heart disease
Holmes, M. V., Asselbergs, F. W., Palmer, T. M., Drenos, F., Lanktree, M. B., Nelson, C. P., Dale, C. E., Padmanabhan, S., Finan, C., Swerdlow, D. I., et al. (2015) · European Heart Journal · doi:10.1093/eurheartj/eht571 · Cited by 748 · see citing works
Validating therapeutic targets through human genetics
Plenge, R. M., Scolnick, E. M., & Altshuler, D. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4051 · Cited by 712 · see citing works
Swerdlow, D. I., Preiss, D., Kuchenbaecker, K. B., Holmes, M. V., Engmann, J. E. L., Shah, T., Sofat, R., Stender, S., Johnson, P. C. D., Scott, R. A., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61183-1 · Cited by 680 · see citing works
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction
Do, R., Stitziel, N. O., Won, H.-H., Jørgensen, A. B., Duga, S., Angelica Merlini, P., Kiezun, A., Farrall, M., Goel, A., Zuk, O., et al. (2015) · Nature · doi:10.1038/nature13917 · Cited by 650 · see citing works
Self-citationZanoni, P., Khetarpal, S. A., Larach, D. B., Hancock-Cerutti, W. F., Millar, J. S., Cuchel, M., DerOhannessian, S., Kontush, A., Surendran, P., Saleheen, D., et al. (2016) · Science · doi:10.1126/science.aad3517 · Cited by 545 · see citing works
Self-citationCoding Variation in <i>ANGPTL4,</i> <i>LPL,</i> and <i>SVEP1</i> and the Risk of Coronary Disease
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1507652 · Cited by 493 · see citing works
Inactivating Mutations in <i>NPC1L1</i> and Protection from Coronary Heart Disease
The Myocardial Infarction Genetics Consortium Investigators (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1405386 · Cited by 419 · see citing works
Lotta, L. A., Sharp, S. J., Burgess, S., Perry, J. R. B., Stewart, I. D., Willems, S. M., Luan, J., Ardanaz, E., Arriola, L., Balkau, B., et al. (2016) · JAMA · doi:10.1001/jama.2016.14568 · Cited by 394 · see citing works
Sidore, C., Busonero, F., Maschio, A., Porcu, E., Naitza, S., Żołędziewska, M., Mulas, A., Pistis, G., Steri, M., Danjou, F., et al. (2015) · Nature Genetics · doi:10.1038/ng.3368 · Cited by 376 · see citing works
The impact of low-frequency and rare variants on lipid levels
ENGAGE Consortium, Surakka, I., Horikoshi, M., Mägi, R., Sarin, A.-P., Mahajan, A., Lagou, V., Marullo, L., Ferreira, T., Miraglio, B., et al. (2015) · Nature Genetics · doi:10.1038/ng.3300 · Cited by 351 · see citing works
Association 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 · see citing works
Helgadóttir, A., Grétarsdóttir, S., Þorleifsson, G., Hjartarson, E., Sigurðsson, Á., Magnusdottir, A., Jónasdóttir, Á., Kristjansson, H., Sulem, P., Oddsson, Á., et al. (2016) · Nature Genetics · doi:10.1038/ng.3561 · Cited by 248 · see citing works
Lipid lowering with PCSK9 inhibitors
Dadu, R. T., & Ballantyne, C. M. (2014) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2014.84 · Cited by 232 · see citing works
CARDIOVASCULAR RISK FACTORS AND THE 25-YEAR INCIDENCE OF DIABETES MELLITUS IN MIDDLE-AGED MEN
Feskens, E. J. M., & Kromhout, D. (1989) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a115437 · Cited by 229 · see citing works
Variant <i>ASGR1</i> Associated with a Reduced Risk of Coronary Artery Disease
Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A. B., Norddahl, G. L., Helgadottir, A., Magnusdottir, A., Jonasdottir, A., Gretarsdottir, S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1508419 · Cited by 189 · see citing works
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
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., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60312-2 · Cited by 148 · see citing works
Khetarpal, S. A., Schjoldager, K. T.-B. G., Christoffersen, C., Raghavan, A., Edmondson, A. C., Reutter, H. M., Bouhouche, A., Ouazzani, R., Peloso, G. M., Vitali, C., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.07.012 · Cited by 131 · see citing works
Tang, C. S.-M., Zhang, H., Cheung, C. Y. Y., Xu, M., Ho, J. C.-Y., Zhou, W., Cherny, S. S., Zhang, Y., Holmen, O. L., Au, K., et al. (2015) · Nature Communications · doi:10.1038/ncomms10206 · Cited by 110 · see citing works
Iotchkova, V., Huang, J., Morris, J. A., Jain, D., Barbieri, C., Walter, K., Min, J. L., Chen, L., Astle, W. J., Cocca, M., et al. (2016) · Nature Genetics · doi:10.1038/ng.3668 · Cited by 77 · see citing works
The contribution of GWAS loci in familial dyslipidemias
Ripatti, P., Rämö, J. T., Söderlund, S., Surakka, I., Matikainen, N., Pirinen, M., Pajukanta, P., Sarin, A.-P., Service, S. K., Laurila, P.-P., et al. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1006078 · Cited by 60 · see citing works
Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population
Lim, E. T., Würtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnström, K., Esko, T., Mägi, R., Inouye, M., Lappalainen, T., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004494 · Cited by 49 · see citing works
Self-citationStatins and type 2 diabetes: genetic studies on target
Frayling, T. M. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61639-1 · Cited by 22 · see citing works
Clapham, K. R., Chu, A. Y., Wessel, J., Natarajan, P., Flannick, J. A., Rivas, M. A., Sartori, S., Mehran, R., Baber, U., Fuster, V., et al. (2016) · BMC Endocrine Disorders · doi:10.1186/s12902-016-0088-8 · Cited by 11 · see citing works
Emphasizing the Burden of Proof
Krumholz, H. M. (2010) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.110.959577 · Cited by 11 · see citing works
Prediction of Incident Diabetes Mellitus in Middle-aged Adults: The Framingham Offspring Study
Wilson, P. W. F. (2007) · Archives of Internal Medicine · doi:10.1001/archinte.167.10.1068 · Cited by 4 · see citing works
Disentangling the Causal Association of Plasma Lipid Traits and Type 2 Diabetes Using Human Genetics
Saleheen, D., Rader, D. J., & Voight, B. F. (2016) · JAMA Cardiology · doi:10.1001/jamacardio.2016.2298 · Cited by 3 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Stitziel NO Stirrups KE Masca NG Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease N Engl J Med 2016 374 1134 1144 This study demonstrated that genetic variation across multiple genes leading to loss and gain of LPL function associated with risk and protection of coronary artery disease, respectively, showing a titratable effect on disease for lipoprotein lipase and its endogenous regulators. 26934567 PMC4850838
Cited by
Sorted by citations
Skulas-Ray, A. C., Wilson, P. W. F., Harris, W. S., Brinton, E. A., Kris-Etherton, P. M., Richter, C. K., Jacobson, T. A., Engler, M. B., Miller, M., Robinson, J. G., et al. (2019) · Circulation · doi:10.1161/cir.0000000000000709 · Cited by 488 · see citing works
- Authors
- Stitziel, N. O.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Stitziel, Nathan O.
- ORCID
- Stitziel, Nathan O.
- Venue
- Current Opinion in Lipidology
- Published
- 2017-04
- Volume
- 28
- Issue
- 2
- Pages
- 113-119
- ISSN
- 0957-9672 (ISSN-L)
- 1473-6535
- PMC
- PMC5584563
- OpenAlex
- W2568209410
- Cited by
- 14
- References
- 49
- Citations by year
- 2023: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 1
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Lipidology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K08HL114642, R01HL131961)
- National Human Genome Research Institute (UM1HG008853)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- lipoproteins, cardiometabolic disease, LDL cholesterol, HDL cholesterol, triglyceride-rich lipoproteins, triglycerides, coronary disease, atherogenesis, type 2 diabetes, genetic instruments, causal inference, statins
- MeSH terms
- Cardiovascular Diseases, Humans, Lipoproteins, Risk, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
