High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study

Albert Prats-Uribe; Sergi Sayols-Baixeras; Alba Fernández-Sanlés; Isaac Subirana; Robert Carreras-Torres; Gemma Vilahur; Fernando Civeira; Jaume Marrugat; Montserrat Fitó; Álvaro Hernáez; Roberto Elosua

doi:10.1016/j.metabol.2020.154351

High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study

Albert Prats-Uribe^*, Sergi Sayols-Baixeras^*, Alba Fernández-Sanlés^*, Isaac Subirana^*, Robert Carreras-Torres^*, Gemma Vilahur^*, Fernando Civeira^*, Jaume Marrugat^*, Montserrat Fitó^*, Álvaro Hernáez^*, Roberto Elosua^*

^*Corresponding author for this work

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

24 Citations (Scopus)

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Abstract

BACKGROUND: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD).

METHODS: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis.

RESULTS: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data.

CONCLUSIONS: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not.

Original language	English
Article number	154351
Number of pages	7
Journal	Metabolism
Volume	112
Early online date	3 Sept 2020
DOIs	https://doi.org/10.1016/j.metabol.2020.154351
Publication status	E-pub ahead of print - 3 Sept 2020

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Keywords

Coronary artery disease
HDL quality
High-density lipoprotein
Mendelian randomization

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Prats-Uribe, A., Sayols-Baixeras, S., Fernández-Sanlés, A., Subirana, I., Carreras-Torres, R., Vilahur, G., Civeira, F., Marrugat, J., Fitó, M., Hernáez, Á., & Elosua, R. (2020). High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study. Metabolism, 112, Article 154351. Advance online publication. https://doi.org/10.1016/j.metabol.2020.154351

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title = "High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study",

abstract = "BACKGROUND: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD).METHODS: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis.RESULTS: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data.CONCLUSIONS: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not.",

keywords = "Coronary artery disease, HDL quality, High-density lipoprotein, Mendelian randomization",

author = "Albert Prats-Uribe and Sergi Sayols-Baixeras and Alba Fern{\'a}ndez-Sanl{\'e}s and Isaac Subirana and Robert Carreras-Torres and Gemma Vilahur and Fernando Civeira and Jaume Marrugat and Montserrat Fit{\'o} and {\'A}lvaro Hern{\'a}ez and Roberto Elosua",

year = "2020",

month = sep,

day = "3",

doi = "10.1016/j.metabol.2020.154351",

language = "English",

volume = "112",

journal = "Metabolism",

issn = "0026-0495",

publisher = "W.B. Saunders",

}

TY - JOUR

T1 - High-density lipoprotein characteristics and coronary artery disease

T2 - a Mendelian randomization study

AU - Prats-Uribe, Albert

AU - Sayols-Baixeras, Sergi

AU - Fernández-Sanlés, Alba

AU - Subirana, Isaac

AU - Carreras-Torres, Robert

AU - Vilahur, Gemma

AU - Civeira, Fernando

AU - Marrugat, Jaume

AU - Fitó, Montserrat

AU - Hernáez, Álvaro

AU - Elosua, Roberto

PY - 2020/9/3

Y1 - 2020/9/3

N2 - BACKGROUND: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD).METHODS: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis.RESULTS: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data.CONCLUSIONS: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not.

AB - BACKGROUND: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD).METHODS: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis.RESULTS: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data.CONCLUSIONS: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not.

KW - Coronary artery disease

KW - HDL quality

KW - High-density lipoprotein

KW - Mendelian randomization

U2 - 10.1016/j.metabol.2020.154351

DO - 10.1016/j.metabol.2020.154351

M3 - Article (Academic Journal)

C2 - 32891675

SN - 0026-0495

VL - 112

JO - Metabolism

JF - Metabolism

M1 - 154351

ER -

High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study

Abstract

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