Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition
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Abstract
Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.
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Earlier CETP inhibitors (e.g. dalcetrapib) increased HDL-C but had little or no effect on LDL-C or apoB.
“earlier CETP inhibitors (e.g. dalcetrapib 76 ) that increased HDL-C but had little or no effect on LDL-C or apoB.”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [76]
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Understanding lipidomics associations and the lipoprotein-related caveats in population epidemiology
Zhao, S., Ohukainen, P., Kettunen, J., Järvelin, M., Kähönen, M. A. P., Lehtimäki, T. J., Viikari, J., Raitakari, O. T., Mäkinen, V., & Ala‐Korpela, M. (2024) · American Journal of Epidemiology · doi:10.1093/aje/kwae445 · Cited by 2 · see citing works
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Lipoprotein profile and metabolic fine-mapping of genetic lipid risk lociPreprint
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Self-citationLevels of cholesteryl ester transfer protein in female bean cake fryers in Nnewi metropolis
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Bayesian LASSO for population stratification correction in rare haplotype association studies
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Additional file 13 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545077
Self-citationAdditional file 5 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545113
Self-citationAdditional file 10 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545068
Self-citationAdditional file 19 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545095
Self-citationAdditional file 9 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545125
Self-citationAdditional file 1 of A phenome-wide association study of genetically mimicked statins
Li, S., & Schooling, C. M. (2021) · Figshare · doi:10.6084/m9.figshare.14880632
Additional file 17 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545089
Self-citationAdditional file 1 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545098
Self-citationAdditional file 15 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545083
Self-citationAdditional file 16 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545086
Self-citationAdditional file 14 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545080
Self-citationAdditional file 2 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545104
Self-citationAdditional file 3 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545107
Self-citationAdditional file 11 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545071
Self-citationAdditional file 12 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545074
Self-citationLi, Y., Li, J., Tang, X., Xu, J., Liu, R., Jiang, L., Tian, J., Zhang, Y., Wang, D., Sun, K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26668824
Additional file 6 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545116
Self-citationAdditional file 8 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545122
Self-citationChen, J., Kuang, J., Tang, X., Mao, L., Guo, X., Luo, Q., Peng, D., & Yu, B. Q. (2020) · Figshare · doi:10.6084/m9.figshare.12462806
Additional file 7 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545119
Self-citationAdditional file 4 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545110
Self-citationLi, J., Tang, X., Xu, J., Liu, R., Jiang, L., Xu, L., Tian, J., Feng, X., Wu, Y., Zhang, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23575551
Li, J., Tang, X., Xu, J., Liu, R., Jiang, L., Xu, L., Tian, J., Feng, X., Wu, Y., Zhang, Y., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23575548
Additional file 18 of DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
Gomez-Alonso, M. D. C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matías‐García, P. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13545092
Self-citationAdditional file 2 of A phenome-wide association study of genetically mimicked statins
Li, S., & Schooling, C. M. (2021) · Figshare · doi:10.6084/m9.figshare.14880635
Li, Y., Li, J., Tang, X., Xu, J., Liu, R., Jiang, L., Tian, J., Zhang, Y., Wang, D., Sun, K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26668821
- Authors
- Kettunen, J., Holmes, M. V., Allara, E., Anufrieva, O., Ohukainen, P., Oliver-Williams, C., Wang, Q., Tillin, T., Hughes, A. D., Kähönen, M., Lehtimäki, T., Viikari, J., Raitakari, O. T., Salomaa, V., Järvelin, M.-R., Perola, M., Davey Smith, G., Chaturvedi, N., Danesh, J., Di Angelantonio, E., Butterworth, A. S., & Ala-Korpela, M.
- Affiliations
- Finnish Institute for Health and Welfare (FI)
- National Institute for Health and Care Research (GB)
- University of Cambridge (GB)
- University of Oulu (FI)
- University College London (GB)
- Tampere University Hospital (FI)
- Tampere University (FI)
- University of Turku (FI)
- Oulu University Hospital (FI)
- University of Helsinki (FI)
- ORCID
- Kettunen, Johannes
- Holmes, Michael V.
- Allara, Elias
- Ohukainen, Pauli
- Oliver-Williams, Clare
- Wang, Qin
- Tillin, Therese
- Hughes, Alun D.
- Kähönen, Mika
- Lehtimäki, Terho
- Viikari, Jorma
- Raitakari, Olli T.
- Salomaa, Veikko
- Järvelin, Marjo-Riitta
- Perola, Markus
- Davey Smith, George
- Chaturvedi, Nish
- Danesh, John
- Butterworth, Adam S.
- Ala-Korpela, Mika
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-12-20
- Volume
- 17
- Issue
- 12
- Pages
- e3000572
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC6944381
- OpenAlex
- W2996623948
- Cited by
- 47
- References
- 51
- Citations by year
- 2026: 2 · 2024: 8 · 2023: 4 · 2022: 5 · 2021: 18 · 2020: 7 · 2019: 2 · 2018: 1
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Update notices
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Medical Research Council (MC_UU_12013/1, G0800270)
- National Health and Medical Research Council (APP1158958)
- Novo Nordisk Fonden (NNF17OC0026062, NNF17OC0027034)
- Terveyden Tutkimuksen Toimikunta (286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi))
- National Institute for Health Research (NIHR BTRU-2014-10024)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- cholesteryl ester transfer protein, HMG-CoA reductase inhibition, statins, LDL cholesterol, lipoprotein subclasses, coronary heart disease risk, HDL triglycerides, remnant lipoproteins, VLDL cholesterol, apolipoprotein B, lipoprotein particle size
- MeSH terms
- Adolescent, Adult, Alleles, Apolipoproteins B, Coronary Disease, Female, Follow-Up Studies, Humans, Hydroxymethylglutaryl CoA Reductases, Lipoproteins, Cholesterol, LDL, Male, Middle Aged, Triglycerides, Genetic Variation, Cohort Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol Ester Transfer Proteins, Young Adult
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