Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

Madeleine L Smith; Caroline J Bull; Michael V.  Holmes; George Davey Smith; Eleanor C M Sanderson; Emma L Anderson; Joshua A Bell

doi:10.1101/2022.04.13.22273833

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

Madeleine L Smith^*, Caroline J Bull, Michael V. Holmes , George Davey Smith, Eleanor C M Sanderson, Emma L Anderson, Joshua A Bell

^*Corresponding author for this work

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Abstract

Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. Here, we used large-scale metabolomics data to directly compare the metabolic features of genetic liability to T2D and to CAD. We performed two-sample reverse Mendelian randomization (MR) to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites from targeted nuclear magnetic resonance spectroscopy in the UK Biobank (N=118,466). We examined the potential for medication use to distort effect estimates by examining effects of disease liability on metformin and statin use and by conducting age-stratified metabolite analyses. Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07, -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). Estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C, and LDL triglycerides. Liability to each disease was estimated to decrease apolipoprotein-A1, whilst only CAD liability was estimated with IVW to increase apolipoprotein-B (0.10 SD; 95% CI 0.03, 0.17). In pleiotropy-robust sensitivity models, T2D liability was still estimated to increase BCAAs, but several effect estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed uniquely and substantially by age for non-HDL-C traits in particular, with, e.g., pleiotropy-robust models suggesting that higher CAD liability lowers LDL-C only at older ages when use of statins is common. Our results from pleiotropy-robust models support largely distinct metabolic features of genetic liability to T2D and to CAD, particularly higher BCAAs in T2D and lower LDL-C and apolipoprotein-B in CAD. Such apparently favourable effects of CAD liability differ substantially by age and likely reflect mediation by statin use in adulthood.

Original language	English
Article number	104503
Pages (from-to)	1-13
Journal	EBioMedicine
Volume	90
Early online date	2 Mar 2023
DOIs	https://doi.org/10.1101/2022.04.13.22273833 https://doi.org/10.1016/j.ebiom.2023.104503
Publication status	Published - 1 Apr 2023

Bibliographical note

Funding Information:
Wellcome Trust [218495/Z/19/Z], UK MRC [MC_UU_00011/1; MC_UU_00011/4], the University of Bristol, Diabetes UK [17/0005587], World Cancer Research Fund [IIG_2019_2009].We thank the participants of the UK Biobank study and the genome-wide association study consortiums who made their summary statistics publicly available for this study. This research was funded in whole, or in part, by the Wellcome Trust [218495/Z/19/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MLS is supported by the Wellcome Trust through a PhD studentship [218495/Z/19/Z]. CJB, ES, MVH, GDS, JAB and ELA work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/4) and the University of Bristol. CJB is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). CJB and MLS acknowledge funding from the Wellcome Trust (202802/Z/16/Z).

Funding Information:
We thank the participants of the UK Biobank study and the genome-wide association study consortiums who made their summary statistics publicly available for this study. This research was funded in whole, or in part, by the Wellcome Trust [ 218495/Z/19/Z ]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MLS is supported by the Wellcome Trust through a PhD studentship [218495/Z/19/Z]. CJB, ES, MVH, GDS, JAB and ELA work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/4) and the University of Bristol. CJB is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). CJB and MLS acknowledge funding from the Wellcome Trust (202802/Z/16/Z).

Publisher Copyright:
© 2023 The Authors

Research Groups and Themes

Bristol Population Health Science Institute

Keywords

Type 2 diabetes
coronary artery disease
Genetics
Mendelian randomization
Metabolism
NMR
Epidemiology
UK Biobank

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1101/2022.04.13.22273833Licence: CC BY
10.1016/j.ebiom.2023.104503Licence: CC BY

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

Smith, M. L., Bull, C. J., Holmes , M. V., Davey Smith, G., Sanderson, E. C. M., Anderson, E. L., & Bell, J. A. (2023). Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study. EBioMedicine, 90, 1-13. Article 104503. https://doi.org/10.1101/2022.04.13.22273833, https://doi.org/10.1016/j.ebiom.2023.104503

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abstract = "Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. Here, we used large-scale metabolomics data to directly compare the metabolic features of genetic liability to T2D and to CAD. We performed two-sample reverse Mendelian randomization (MR) to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites from targeted nuclear magnetic resonance spectroscopy in the UK Biobank (N=118,466). We examined the potential for medication use to distort effect estimates by examining effects of disease liability on metformin and statin use and by conducting age-stratified metabolite analyses. Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07, -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). Estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C, and LDL triglycerides. Liability to each disease was estimated to decrease apolipoprotein-A1, whilst only CAD liability was estimated with IVW to increase apolipoprotein-B (0.10 SD; 95% CI 0.03, 0.17). In pleiotropy-robust sensitivity models, T2D liability was still estimated to increase BCAAs, but several effect estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed uniquely and substantially by age for non-HDL-C traits in particular, with, e.g., pleiotropy-robust models suggesting that higher CAD liability lowers LDL-C only at older ages when use of statins is common. Our results from pleiotropy-robust models support largely distinct metabolic features of genetic liability to T2D and to CAD, particularly higher BCAAs in T2D and lower LDL-C and apolipoprotein-B in CAD. Such apparently favourable effects of CAD liability differ substantially by age and likely reflect mediation by statin use in adulthood. ",

keywords = "Type 2 diabetes, coronary artery disease, Genetics, Mendelian randomization, Metabolism, NMR, Epidemiology, UK Biobank",

author = "Smith, {Madeleine L} and Bull, {Caroline J} and Holmes, {Michael V.} and {Davey Smith}, George and Sanderson, {Eleanor C M} and Anderson, {Emma L} and Bell, {Joshua A}",

note = "Funding Information: Wellcome Trust [218495/Z/19/Z], UK MRC [MC_UU_00011/1; MC_UU_00011/4], the University of Bristol, Diabetes UK [17/0005587], World Cancer Research Fund [IIG_2019_2009].We thank the participants of the UK Biobank study and the genome-wide association study consortiums who made their summary statistics publicly available for this study. This research was funded in whole, or in part, by the Wellcome Trust [218495/Z/19/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MLS is supported by the Wellcome Trust through a PhD studentship [218495/Z/19/Z]. CJB, ES, MVH, GDS, JAB and ELA work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/4) and the University of Bristol. CJB is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). CJB and MLS acknowledge funding from the Wellcome Trust (202802/Z/16/Z). Funding Information: We thank the participants of the UK Biobank study and the genome-wide association study consortiums who made their summary statistics publicly available for this study. This research was funded in whole, or in part, by the Wellcome Trust [ 218495/Z/19/Z ]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MLS is supported by the Wellcome Trust through a PhD studentship [218495/Z/19/Z]. CJB, ES, MVH, GDS, JAB and ELA work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/4) and the University of Bristol. CJB is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). CJB and MLS acknowledge funding from the Wellcome Trust (202802/Z/16/Z). Publisher Copyright: {\textcopyright} 2023 The Authors",

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doi = "10.1101/2022.04.13.22273833",

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T1 - Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease

T2 - a reverse Mendelian randomization study

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AU - Bull, Caroline J

AU - Holmes , Michael V.

AU - Davey Smith, George

AU - Sanderson, Eleanor C M

AU - Anderson, Emma L

AU - Bell, Joshua A

N1 - Funding Information: Wellcome Trust [218495/Z/19/Z], UK MRC [MC_UU_00011/1; MC_UU_00011/4], the University of Bristol, Diabetes UK [17/0005587], World Cancer Research Fund [IIG_2019_2009].We thank the participants of the UK Biobank study and the genome-wide association study consortiums who made their summary statistics publicly available for this study. This research was funded in whole, or in part, by the Wellcome Trust [218495/Z/19/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MLS is supported by the Wellcome Trust through a PhD studentship [218495/Z/19/Z]. CJB, ES, MVH, GDS, JAB and ELA work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/4) and the University of Bristol. CJB is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). CJB and MLS acknowledge funding from the Wellcome Trust (202802/Z/16/Z). Funding Information: We thank the participants of the UK Biobank study and the genome-wide association study consortiums who made their summary statistics publicly available for this study. This research was funded in whole, or in part, by the Wellcome Trust [ 218495/Z/19/Z ]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. MLS is supported by the Wellcome Trust through a PhD studentship [218495/Z/19/Z]. CJB, ES, MVH, GDS, JAB and ELA work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/4) and the University of Bristol. CJB is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). CJB and MLS acknowledge funding from the Wellcome Trust (202802/Z/16/Z). Publisher Copyright: © 2023 The Authors

PY - 2023/4/1

Y1 - 2023/4/1

N2 - Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. Here, we used large-scale metabolomics data to directly compare the metabolic features of genetic liability to T2D and to CAD. We performed two-sample reverse Mendelian randomization (MR) to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites from targeted nuclear magnetic resonance spectroscopy in the UK Biobank (N=118,466). We examined the potential for medication use to distort effect estimates by examining effects of disease liability on metformin and statin use and by conducting age-stratified metabolite analyses. Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07, -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). Estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C, and LDL triglycerides. Liability to each disease was estimated to decrease apolipoprotein-A1, whilst only CAD liability was estimated with IVW to increase apolipoprotein-B (0.10 SD; 95% CI 0.03, 0.17). In pleiotropy-robust sensitivity models, T2D liability was still estimated to increase BCAAs, but several effect estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed uniquely and substantially by age for non-HDL-C traits in particular, with, e.g., pleiotropy-robust models suggesting that higher CAD liability lowers LDL-C only at older ages when use of statins is common. Our results from pleiotropy-robust models support largely distinct metabolic features of genetic liability to T2D and to CAD, particularly higher BCAAs in T2D and lower LDL-C and apolipoprotein-B in CAD. Such apparently favourable effects of CAD liability differ substantially by age and likely reflect mediation by statin use in adulthood.

AB - Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. Here, we used large-scale metabolomics data to directly compare the metabolic features of genetic liability to T2D and to CAD. We performed two-sample reverse Mendelian randomization (MR) to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites from targeted nuclear magnetic resonance spectroscopy in the UK Biobank (N=118,466). We examined the potential for medication use to distort effect estimates by examining effects of disease liability on metformin and statin use and by conducting age-stratified metabolite analyses. Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07, -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). Estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C, and LDL triglycerides. Liability to each disease was estimated to decrease apolipoprotein-A1, whilst only CAD liability was estimated with IVW to increase apolipoprotein-B (0.10 SD; 95% CI 0.03, 0.17). In pleiotropy-robust sensitivity models, T2D liability was still estimated to increase BCAAs, but several effect estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed uniquely and substantially by age for non-HDL-C traits in particular, with, e.g., pleiotropy-robust models suggesting that higher CAD liability lowers LDL-C only at older ages when use of statins is common. Our results from pleiotropy-robust models support largely distinct metabolic features of genetic liability to T2D and to CAD, particularly higher BCAAs in T2D and lower LDL-C and apolipoprotein-B in CAD. Such apparently favourable effects of CAD liability differ substantially by age and likely reflect mediation by statin use in adulthood.

KW - Type 2 diabetes

KW - coronary artery disease

KW - Genetics

KW - Mendelian randomization

KW - Metabolism

KW - NMR

KW - Epidemiology

KW - UK Biobank

U2 - 10.1101/2022.04.13.22273833

DO - 10.1101/2022.04.13.22273833

M3 - Article (Academic Journal)

C2 - 36870196

SN - 2352-3964

VL - 90

SP - 1

EP - 13

JO - EBioMedicine

JF - EBioMedicine

M1 - 104503

ER -

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

Abstract

Bibliographical note

Research Groups and Themes

Keywords

UN SDGs

Access to Document

Handle.net

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Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this