Cited by 296Lipoproteins and Cardiovascular HealthGenetic Associations and EpidemiologyDiabetes, Cardiovascular Risks, and Lipoproteins

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Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes

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White, Jon, Swerdlow, Daniel I., Preiss, David, Fairhurst-Hunter, Zammy, Keating, Brendan J., Asselbergs, Folkert W., Sattar, Naveed, Humphries, Steve E., Hingorani, Aroon D., Holmes, Michael V.·2016·JAMA Cardiology

DOI 10.1001/jamacardio.2016.1884PMC PMC5642865

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Abstract

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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Liver X Receptor cis-Repression and Cholesterol Efflux Restrain Innate Immunity and Coronary Artery Disease
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Integration of Multi-Omics in Type 2 Diabetes and Related Disorders Research
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Tracing the genetic etiology of cardiovascular disease using a hierarchy of common genetic variants derived from patient subgroups stratified by differential levels in severityPreprint
Fatakia, S. N. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/213124
“involve lipid regulation [23-26], inflammation [27-29], as well as other epigenetic agents such as an altered lifestyle [30, 31].”
Background
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Urinary Cotinine-Verified Smoking Status and Serum Lipid Profiles and Lipid Ratios in Korean Older Adults: A Nationwide Cross-Sectional StudyPreprint
Nam, M. J., Lee, C.-W., Kim, H., Yoo, J. W., Lee, K. N., Han, K., Jung, J.-H., Park, Y. G., Kim, D., & Park, J. (2021) · Research Square · doi:10.21203/rs.3.rs-1186742/v1
From the Editor
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Could uric acid to high-density lipoprotein cholesterol ratio be used to predict late-stage saphenous vein graft disease after coronary artery bypass graft surgery?
Güvenç, O., Engin, M., Demir, Ö. F., Ata, F., & Yavuz, Ş. (2022) · The European Research Journal · doi:10.18621/eurj.1205252
Evolving Therapeutic Targets
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Paradoxical mortality differential of HDL cholesterol
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A robust penalized-regression-based method for multivariable Mendelian randomization using GWAS summary statisticsPreprint
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Deciphering the Effect of High-Density Lipoprotein Cholesterol on Renal Function: a Mendelian Randomization StudyPreprint
Le, N. N., Tran, T., Gill, D., & Padmanabhan, S. (2023) · medRxiv · doi:10.1101/2023.10.18.23297196
Additional file 2 of Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study
Yang, G., & Schooling, C. M. (2023) · Figshare · doi:10.6084/m9.figshare.23621307
How safe are proprotein convertase subtilisinekexin type 9 inhibitors in diabetes?
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Valencene ameliorates ox-LDL induced foam cell formation by suppressing inflammation and modulating key proteins involved in the atherogenesis on THP-1 derived macrophages
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Innovative biomarkers in cardiovascular disease: Advances in prevention and therapeutics
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Associations between carotid artery intima-media thickness, traditional risk factors and proteins
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“However, while MR studies have con ﬁ rmed that BMI, blood pressure, LDL-cholesterol, and diabetes likely are causally related to myocardial infarction and ischemic stroke 8 – 16 , the causal role of HDL-cholesterol as a protective factor has been questioned 11,12 .”
Additional file 1 of Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study
Hu, C., Zhou, Y., Wu, X., Jia, X., Zhu, Y., Zheng, R., Wang, S., Lin, L., Qi, H., Lin, H., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26595413
Additional file 9 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059060
Additional file 2 of Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study
Hu, C., Zhou, Y., Wu, X., Jia, X., Zhu, Y., Zheng, R., Wang, S., Lin, L., Qi, H., Lin, H., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26595419
Additional file 1 of Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study
Yang, G., & Schooling, C. M. (2023) · Figshare · doi:10.6084/m9.figshare.23621304
Additional file 1 of Investigating sex-specific associations of lipid traits with type 2 diabetes, glycemic traits and sex hormones using Mendelian randomization
Yang, G., & Schooling, C. M. (2024) · Figshare · doi:10.6084/m9.figshare.26560082
Additional file 4 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059045
Additional file 8 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059057
Additional file 2 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059039
Additional file 3 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059042
Additional file 2 of Investigating sex-specific associations of lipid traits with type 2 diabetes, glycemic traits and sex hormones using Mendelian randomization
Yang, G., & Schooling, C. M. (2024) · Figshare · doi:10.6084/m9.figshare.26560085
Additional file 1 of Adiposity and lipid metabolism indicators mediate the adverse effect of glucose metabolism indicators on oogenesis and embryogenesis in PCOS women undergoing IVF/ICSI cycles
Jiang, H., Si, M., Tian, T., Shi, H., Huang, N., Chi, H., Yang, R., Long, X., & Qiao, J. (2023) · Figshare · doi:10.6084/m9.figshare.23621302
Additional file 5 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059048
Additional file 7 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059054
Additional file 6 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059051
Additional file 1 of Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies
Zhao, J., Ke, Z., Huang, R., Wen, X., Liu, W., Wang, S., Zhang, X., Zhuang, X., Pan, L., & Liao, L. (2024) · Figshare · doi:10.6084/m9.figshare.27059036
The role of testosterone in cardiovascular health: benefits and risks of replacement therapy
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Cerebrospinal fluid metabolites and their association with female reproductive disorders: insights from mendelian randomization
Zhou, Y., Wang, X., Ding, Z., Wang, Y., & Song, W. (2026) · Journal of Ovarian Research · doi:10.1186/s13048-026-02026-9
Research Progress of Atherosclerotic Lipoprotein Subfractions in Patients with Type 2 Diabetes Mellitus
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Interplay of HDL cholesterol and apoB and the risk of incident atherosclerotic cardiovascular disease in UK Biobank
Sniderman, A. D., Pencina, K. M., Thanassoulis, G., Dufresne, L., & Pencina, M. J. (2026) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwag400 · Cited by 1
VLDL Phospholipid Composition, Remnant Cholesterol, ApoB , and Coronary Artery Disease: A Network Mendelian Randomization Study
Yu, H., Zhang, X., Yang, S., Fan, Z., Zhang, D., & Dan, W. A. N. G. (2026) · Lipids · doi:10.1002/lipd.70085

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: White, Jon
Swerdlow, Daniel I.
Preiss, David
Keating, Brendan J.
Asselbergs, Folkert W.
Sattar, Naveed
Humphries, Steve E.
Hingorani, Aroon D.
Holmes, Michael V.
Venue: JAMA Cardiology
Publisher: American Medical Association (AMA)
Published: 2016-09-01
Volume: 1
Issue: 6
Pages: 692
ISSN: 2380-6583 (ISSN-L)
DOI: 10.1001/jamacardio.2016.1884
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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Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes

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