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Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes
Open accessAbstract
IMPORTANCE: Low-density lipoprotein cholesterol (LDL-C) is causally related to coronary artery disease (CAD), but the relevance of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) is uncertain. Lowering of LDL-C levels by statin therapy modestly increases the risk of type 2 diabetes, but it is unknown whether this effect is specific to statins. OBJECTIVE: To investigate the associations of 3 routinely measured lipid fractions with CAD and diabetes through mendelian randomization (MR) using conventional MR and making use of newer approaches, such as multivariate MR and MR-Egger, that address the pleiotropy of genetic instruments where relevant. DESIGN, SETTING, AND PARTICIPANTS: Published data from genome-wide association studies were used to construct genetic instruments and then applied to investigate associations between lipid fractions and the risk of CAD and diabetes using MR approaches that took into account pleiotropy of genetic instruments. The study was conducted from March 12 to December 31, 2015. MAIN OUTCOMES AND MEASURES: Coronary artery disease and diabetes. RESULTS: Genetic instruments composed of 130 single-nucleotide polymorphisms (SNPs) were used for LDL-C (explaining 7.9% of its variance), 140 SNPs for HDL-C (6.6% of variance), and 140 SNPs for TGs (5.9% of variance). A 1-SD genetically instrumented elevation in LDL-C levels (equivalent to 38 mg/dL) and TG levels (equivalent to 89 mg/dL) was associated with higher CAD risk; odds ratios (ORs) were 1.68 (95% CI, 1.51-1.87) for LDL-C and 1.28 (95% CI, 1.13-1.45) for TGs. The corresponding OR for HDL-C (equivalent to a 16-mg/dL increase) was 0.95 (95% CI, 0.85-1.06). All 3 lipid traits were associated with a lower risk of type 2 diabetes. The ORs were 0.79 (95% CI, 0.71-0.88) for LDL-C and 0.83 (95% CI, 0.76-0.90) for HDL-C per 1-SD elevation. For TG, the MR estimates for diabetes were inconsistent, with MR-Egger giving an OR of 0.83 (95%CI, 0.72-0.95) per 1-SD elevation. CONCLUSIONS AND RELEVANCE: Routinely measured lipid fractions exhibit contrasting associations with the risk of CAD and diabetes. Increased LDL-C, HDL-C, and possibly TG levels are associated with a lower risk of diabetes. This information will be relevant to the design of clinical trials of lipid-modifying agents, which should carefully monitor participants for dysglycemia and the incidence of diabetes.
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“as pharmacological modification of C-reactive protein is unlikely to be beneficial to CHD 51 , whereas randomized evidence demonstrates the value of targeting biomarkers further upstream, e.g. interleukin-6 receptor 21,54 or interleukin 1-beta 52”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [21]
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 [21]
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“In this latter example, genetic variants used to mimic pharmacological inhibition of IL6R (and thus the effects of inhibiting pathways downstream of IL6) lead to a paradoxical increase in IL6 concentrations in the blood 21 ,”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [21]
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“Exploring inflammation-related proteins more upstream, genetic variants around the gene encoding interleukin 6 receptor (IL6R) shows an association with risk of CHD 21,54 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [21]
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“People naturally randomized to lower LDL-C had a higher risk of type 2 diabetes compared with the reference group (Figure 1), consistent with previous studies.(43,50,52-55) However, people naturally randomized to both genetic exposures had a similar risk of type 2 diabetes compared with the reference group (Figure 1),…”
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“A higher risk of coronary artery disease has been strongly correlated with elevated levels of LDL cholesterol and TGs (44).”
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“Secondly, Mendelian randomization studies have demonstrated that an elevation in serum HDL-C is associated with a reduced risk of developing T2D [121–123].”
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Richardson, T. G., Wang, Q., Sanderson, E. C. M., Mahajan, A., McCarthy, M. I., Frayling, T. M., Ala‐Korpela, M., Sniderman, A. D., Smith, G. D., & Holmes, M. V. (2021) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00086-6 · Cited by 61
Self-citationTherapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk
Masson, W. M., Lobo, M., Siniawski, D. A., Huerin, M. S., Molinero, G., Valéro, R., & Nogueira, J. P. (2018) · Diabetes & Metabolism · doi:10.1016/j.diabet.2018.02.005 · Cited by 60
Hindy, G., Åkesson, K., Melander, O., Aragam, K. G., Haas, M. E., Nilsson, P. M., Kadam, U. T., & Orho‐Melander, M. (2019) · Arthritis & Rheumatology · doi:10.1002/art.40812 · Cited by 59
“Regardless, it is intriguing that earlier MR studies have shown clear evidence that a genetically predicted decrease in LDL cholesterol level increases the risk of type 2 diabetes (30,51), similar to what was observed in our study of OA.”
ResultRevealing the effect of CETP inhibition in cardiovascular disease
Holmes, M. V., & Smith, G. D. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.156 · Cited by 56
Self-citationCohain, A. T., Barrington, W. T., Jordan, D. M., Beckmann, N. D., Argmann, C., Houten, S. M., Charney, A. W., Ermel, R., Sukhavasi, K., Franzén, O., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20750-8 · Cited by 59
A Mendelian randomization study of the role of lipoprotein subfractions in coronary artery disease
Zhao, Q., Wang, J., Miao, Z., Zhang, N. R., Hennessy, S., Small, D. S., & Rader, D. J. (2021) · eLife · doi:10.7554/elife.58361 · Cited by 57
Mendelian randomization with Egger pleiotropy correction and weakly informative Bayesian priors
Schmidt, A. F., & Dudbridge, F. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyx254 · Cited by 57
“For example, if one is interested in estimating the causal relation between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD), it is often difficult to find genes that affect HDL-C but not lowdensity lipoprotein cholesterol (LDL-C) or triglycerides.(3,4) Such a situation may indicate violat…”
BackgroundCETP (Cholesteryl Ester Transfer Protein) Concentration
Blauw, L. L., Li‐Gao, R., Noordam, R., de Mutsert, R., Trompet, S., Berbée, J. F. P., Wang, Y., van Klinken, J. B., Christen, T., van Heemst, D., et al. (2018) · Circulation Genomic and Precision Medicine · doi:10.1161/circgen.117.002034 · Cited by 54
Furtado, J. D., Ruotolo, G., Nicholls, S. J., Dullea, R., Carvajal‐Gonzalez, S., & Sacks, F. M. (2021) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.121.317181 · Cited by 53
The Role of High-Density Lipoprotein Cholesterol in 2022
Sirtori, C. R., Corsini, A., & Ruscica, M. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01012-y · Cited by 55
Clinical significance of long noncoding RNA VIM‐AS1 and CTBP1‐AS2 expression in type 2 diabetes
Omidvar, M. E., Ghaedi, H., Kazerouni, F., Kalbasi, S., Shanaki, M., Miraalamy, G., Zare, A. G., & Rahimipour, A. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28206 · Cited by 51
“They showed that higher levels of LDL‐C are associated with lower risk of diabetes in a Mendelian randomization analysis.(30) Amazingly, Lotta, et al.”
BackgroundChen, J., Li, Y., Zhang, Y., Wang, Y., Zhou, Y., Geng, T., Liu, G., Pan, A., & Liao, Y.-F. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155817 · Cited by 52
A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes
Liu, J., van Klinken, J. B., Semiz, S., van Dijk, K. W., Verhoeven, A., Hankemeier, T., Harms, A. C., Sijbrands, E. J. G., Sheehan, N. A., van Duijn, C. M., et al. (2017) · Diabetes · doi:10.2337/db17-0199 · Cited by 50
“Statistical methods that deal with pleiotropy in MR analyses, such as the Egger regression method (9; 54; 55), exist but are still being refined.”
MethodResultInfluentialLipid and metabolic syndrome traits in coronary artery disease: a Mendelian randomization study
Thomas, D. G., Wei, Y., & Tall, A. R. (2020) · Journal of Lipid Research · doi:10.1194/jlr.p120001000 · Cited by 53
“In previous smaller studies, MR of lipid traits in CAD revealed causal associations of LDL-C and TGs with CAD and suggested that pleiotropic effects of lipid trait SNPs accounted for much of the apparent protective effect of HDL-C and part of the deleterious effect of TG (9, 18, 19).”
BackgroundResultKlisic, A. N., Kavarić, N., Jovanović, M., Zvrko, E., Skerovic, V., Scepanovic, A., Medin, D., & Ninić, A. (2017) · Journal of Research in Medical Sciences · doi:10.4103/jrms.jrms_284_17 · Cited by 51
Misconceptions on the use of MR-Egger regression and the evaluation of the InSIDE assumption
Bowden, J. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyx192 · Cited by 49
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-citationLiu, X., Li, C., Sun, X., Yu, Y., Si, S., Hou, L., Yan, R., Yu, Y., Li, M., Li, H., et al. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.020187 · Cited by 44
Blood lipid genetic scores, the HMGCR gene and cancer risk: a Mendelian randomization study
Orho‐Melander, M., Hindy, G., Borgquist, S., Schulz, C., Manjer, J., Melander, O., & Stocks, T. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyx237 · Cited by 46
Hou, L., Xu, M., Yu, Y., Sun, X., Liu, X., Liu, L., Li, Y., Yuan, T., Li, W., Li, H., et al. (2020) · Molecular Medicine · doi:10.1186/s10020-019-0133-y · Cited by 44
Walker, V. M., Zheng, J., Gaunt, T. R., & Smith, G. D. (2022) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-122120-024910 · Cited by 44
Silbernagel, G., Scharnagl, H., Kleber, M. E., Delgado, G., Stojaković, T., Laaksonen, R., Erdmann, J., Rankinen, T., Bouchard, C., Landmesser, U., et al. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.12.024 · Cited by 43
Risk of neuropsychiatric adverse effects of lipid-lowering drugs: a mendelian randomization study
Alghamdi, J., Matou-Nasri, S., Alghamdi, F., Alghamdi, S., Alfadhel, M., & Padmanabhan, S. (2018) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy060 · Cited by 44
Jiang, L., Li, L., Xu, Z., Tang, Y. R., Zhai, Y., Fu, X., Liu, D., & Wu, Q. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1360874 · Cited by 43
“Previous studies have indicated that LDL-C is mostly normal in T2DM patients with abnormal lipid metabolism (45), that elevated LDL-C does not lead to a signi fi cant increase in T2DM, and genetic researches indicate that reduced LDL-C may be a protective factor for T2DM (31, 46).”
BackgroundPhenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
Schmidt, A. F., Holmes, M. V., Preiss, D., Swerdlow, D. I., Denaxas, S., Fatemifar, G., Faraway, R., Finan, C., Lumbers, R. T., Henry, A., et al. (2019) · BMC Cardiovascular Disorders · doi:10.1186/s12872-019-1187-z · Cited by 41
“In conclusion, PCSK9 SNPs associated with lower LDL-C predict a substantial reduction in the risk of MI and concordant associations with a reduction in risk of ischemic stroke, but with a modestly increased risk of T2DM.”
BackgroundInfluentialSelf-citationSoremekun, O. S., Karhunen, V., He, Y., Rajasundaram, S., Liu, B., Gkatzionis, A., Soremekun, C., Udosen, B., Musa, H. S., Silva, S., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103953 · Cited by 42
Wang, Q., Wang, Y., Lehto, K., Pedersen, N. L., Williams, D. M., & Hägg, S. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.07.007 · Cited by 42
“, SNP) affects the outcome only through its effect on the risk factor; and [3] the genetic variant and the outcome do not have common causes.”
BackgroundSattar, N. A., Toth, P. P., Blom, D. J., Koren, M. J., Soran, H., Uhart, M., Elliott, M., Cyrille, M., Somaratne, R. M., & Preiss, D. (2017) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2017.07.047 · Cited by 40
“It remains unclear whether this effect reflects the specific mechanism of the action of a statin or whether other approaches to lowering LDL cholesterol have the same diabetogenic effect.(4,5) Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein of predominantly hepatic origin that reduces th…”
Self-citationSmoking-by-genotype interaction in type 2 diabetes risk and fasting glucose
Wu, P., Rybin, D. V., Bielak, L. F., Feitosa, M. F., Franceschini, N., Li, Y., Lu, Y., Marten, J., Musani, S. K., Noordam, R., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0230815 · Cited by 45
Chen, X., Zhuang, J., Huang, H., & Wu, Y. (2021) · Scientific Reports · doi:10.1038/s41598-021-84155-3 · Cited by 41
Smith, M. L., Bull, C. J., Holmes, M. V., Smith, G. D., Sanderson, E. C. M., Anderson, E. L., & Bell, J. A. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104503 · Cited by 40
Self-citationYuan, S., & Larsson, S. C. (2019) · Diabetologia · doi:10.1007/s00125-019-05019-0 · Cited by 42
Lind, L., Ingelsson, M., Sundström, J., & Ärnlöv, J. (2021) · Open Heart · doi:10.1136/openhrt-2021-001735 · Cited by 39
“12 13 A causal action of elevated triglycerides has been proposed.”
Hypoxia inducible factor 1α inhibitor PX-478 reduces atherosclerosis in mice
Villa-Roel, N., Ryu, K., Gu, L., Esmerats, J. F., Kang, D. W., Kumar, S., & Jo, H. (2022) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2022.01.002 · Cited by 40
Natarajan, P., Pampana, A., Graham, S. E., Ruotsalainen, S., Perry, J. A., de Vries, P. S., Broome, J., Pirruccello, J. P., Honigberg, M. C., Aragam, K. G., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22339-1 · Cited by 36
HDL, cholesterol efflux, and ABCA1: Free from good and evil dualism
Ogura, M. (2022) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2022.07.004 · Cited by 44
Domingo‐Espín, J., Nilsson, O., Bernfur, K., Giudice, R. D., & Lagerstedt, J. O. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.05.014 · Cited by 38
Xue, H., & Pan, W. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009105 · Cited by 37
Mak, J. K. L., Kananen, L., Qin, C., Kuja‐Halkola, R., Tang, B., Lin, J., Wang, Y., Jääskeläinen, T., Koskinen, S. V. P., Lu, Y., et al. (2023) · Aging Cell · doi:10.1111/acel.13868 · Cited by 36
“…biomarkers have shown to be risk factors for cardiovascular diseases and diabetes (Do et al., 2013; Holmes et al., 2018; Richardson et al., 2020; White et al., 2016; Zagkos et al., 2022), some studies have also found no or inverse relationship between LDL- cholesterol and mortality risk among…”
Background
Metadata
- Authors
- 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.
- Affiliations
- University College London (GB)
- Farr Institute (GB)
- University of Oxford (GB)
- Centre for Human Genetics (GB)
- Children's Hospital of Philadelphia (US)
- University Medical Center Utrecht (NL)
- University of Glasgow (GB)
- British Heart Foundation (GB)
- Corresponding author
- Holmes, Michael V.
- ORCID
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2016-09-01
- Volume
- 1
- Issue
- 6
- Pages
- 692
- ISSN
- 2380-6583 (ISSN-L)
- PMC
- PMC5642865
- OpenAlex
- W2481252033
- Cited by
- 293
- References
- 40
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 38 · 2023: 36 · 2022: 24 · 2021: 34 · 2020: 34 · 2019: 20 · 2018: 42 · 2017: 37 · 2016: 5
- FWCI
- 38.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- JAMA Cardiology (publishedVersion, public-domain)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0515-10091, ACF-2015-21-003)
- British Heart Foundation (PG 08/008, RG/10/12/28456)
- Medical Research Council (MR/K006584/1)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- LDL cholesterol, HDL cholesterol, triglycerides, coronary artery disease, type 2 diabetes, lipid fractions, statin therapy, pleiotropy, genetic instruments, multivariate Mendelian randomization, MR-Egger, causal inference, single nucleotide polymorphisms, polygenic risk score, cardiovascular risk prediction
- MeSH terms
- Coronary Artery Disease, Diabetes Mellitus, Type 2, Humans, Lipids, Cholesterol, HDL, Cholesterol, LDL, Risk Factors, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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