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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Pharmacological modification of C-reactive protein is unlikely to be beneficial to coronary heart disease, whereas randomized evidence demonstrates the value of targeting biomarkers further upstream, for example interleukin-6 receptor or interleukin 1-beta.
“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]
MR is being widely applied to quantitative traits with the aim of discovering modifiable risk factors for disease that are causal and amenable to therapeutic modification.
“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]
Genetic variants used to mimic pharmacological inhibition of IL6R lead to a paradoxical increase in IL6 concentrations in the blood.
“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]
Genetic variants around the gene encoding interleukin 6 receptor (IL6R) show an association with risk of CHD.
“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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- 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 › Surgery › 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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