Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study

Joshua A Bell; Tom G Richardson; Qin Wang; Eleanor C M Sanderson; Tom M Palmer; Venexia M Walker; Linda Marie O'Keefe; Nicholas John  Timpson; Anna  Cichonska; Heli  Julkunen; Peter Wurtz; Michael V Holmes; George Davey Smith

doi:10.1016/j.lanepe.2022.100457

Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study

Joshua A Bell^*, Tom G Richardson, Qin Wang, Eleanor C M Sanderson, Tom M Palmer, Venexia M Walker, Linda Marie O'Keefe, Nicholas John Timpson, Anna Cichonska, Heli Julkunen, Peter Wurtz, Michael V Holmes, George Davey Smith

^*Corresponding author for this work

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

9 Citations (Scopus)

89 Downloads (Pure)

Abstract

Background: The direct effects of general adiposity (body mass index (BMI)) and central adiposity (waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites are unknown.
Methods: We used new metabolic data from UK Biobank (N=109,532, a five-fold higher N over previous studies). EDTA-plasma was used to quantify 249 traits with nuclear-magnetic-resonance spectroscopy including subclass-specific lipoprotein concentrations and lipid content, plus preglycemic and inflammatory metabolites. We used univariable and multivariable two-stage leastsquares regression models with genetic risk scores for BMI and WHR as instruments to estimate total (unadjusted) and direct (mutually-adjusted) effects of BMI and WHR on metabolic traits; plus effects on statin use and interaction by sex, statin use, and age (proxy for medication use).
Findings: Higher BMI decreased apolipoprotein B and low-density lipoprotein cholesterol (LDL-C) before and after WHR-adjustment, whilst BMI increased triglycerides only before WHR-adjustment. These effects of WHR were larger and BMI-independent. Direct effects differed markedly by sex, e.g., triglycerides increased only with BMI among men, and only with WHR among women.
Adiposity measures increased statin use and showed metabolic effects which differed by statin use and age. Among the youngest (38-53y, statins-5%), BMI and WHR (per-SD) increased LDL-C (total effects: 0.04-SD, 95%CI=-0.01,0.08 and 0.10-SD, 95%CI=0.02,0.17 respectively), but only WHR directly. Among the oldest (63-73y, statins-29%), BMI and WHR directly lowered LDL-C (-0.19-
SD, 95%CI=-0.27,-0.11 and -0.05-SD, 95%CI=-0.16,0.06 respectively).
Interpretation: Excess adiposity likely raises atherogenic lipid and metabolite levels exclusively via adiposity stored centrally, particularly among women. Apparent effects of adiposity on lowering LDL-C are likely explained by an effect of adiposity on statin use.

Original language	English
Article number	100457
Journal	The Lancet Regional Health - Europe
Volume	21
DOIs	https://doi.org/10.1016/j.lanepe.2022.100457
Publication status	Published - 6 Jul 2022

Bibliographical note

Funding Information:
JAB, TGR, ES, VMW, TP, and GDS work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/3; MC_UU_00011/4) and the University of Bristol. QW is funded by a Novo Nordisk postdoctoral fellowship (NNF17OC0027034) and during this work began employment with GSK. VMW is supported by the COVID-19 Longitudinal Health and Wellbeing National Core Study, which is funded by the Medical Research Council (MC_PC_20030; MC_PC_20059). LMOK is supported by a Health Research Board (HRB) of Ireland Emerging Investigator Award (Grant ref: EIA-FA-2019-007 SCaRLeT. MVH works in a unit that receives funding from the UK MRC and is supported by a BHF Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre; and towards completion of this work began employment with 23andMe. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). This publication is the work of the authors and JAB is the guarantor for its contents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2022 The Author(s)

Keywords

Bristol Population Health Science Institute
Adiposity
BMI
WHR
Metabolism
NMR
Mendelian randomization
Epidemiology
UK Biobank

Access to Document

10.1016/j.lanepe.2022.100457Licence: CC BY

Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Elsevier at https://doi.org/10.1016/j.lanepe.2022.100457 . Please refer to any applicable terms of use of the publisher.
Final published version, 2.27 MBLicence: CC BY

Handle.net

Persistent link

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. & Davey Smith, G.
1/04/18 → 31/03/23
Project: Research
Rework of IEU 2 Tilling Programme
Tilling, K. M.
1/04/18 → 31/03/23
Project: Research

Cite this

Bell, J. A., Richardson, T. G., Wang, Q., Sanderson, E. C. M., Palmer, T. M., Walker, V. M., O'Keefe, L. M., Timpson, N. J., Cichonska, A., Julkunen, H., Wurtz, P., Holmes, M. V., & Davey Smith, G. (2022). Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study. The Lancet Regional Health - Europe, 21, [100457]. https://doi.org/10.1016/j.lanepe.2022.100457

@article{076c7034fad44bd29ac632894197e278,

title = "Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study",

abstract = "Background: The direct effects of general adiposity (body mass index (BMI)) and central adiposity (waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites are unknown.Methods: We used new metabolic data from UK Biobank (N=109,532, a five-fold higher N over previous studies). EDTA-plasma was used to quantify 249 traits with nuclear-magnetic-resonance spectroscopy including subclass-specific lipoprotein concentrations and lipid content, plus preglycemic and inflammatory metabolites. We used univariable and multivariable two-stage leastsquares regression models with genetic risk scores for BMI and WHR as instruments to estimate total (unadjusted) and direct (mutually-adjusted) effects of BMI and WHR on metabolic traits; plus effects on statin use and interaction by sex, statin use, and age (proxy for medication use).Findings: Higher BMI decreased apolipoprotein B and low-density lipoprotein cholesterol (LDL-C) before and after WHR-adjustment, whilst BMI increased triglycerides only before WHR-adjustment. These effects of WHR were larger and BMI-independent. Direct effects differed markedly by sex, e.g., triglycerides increased only with BMI among men, and only with WHR among women.Adiposity measures increased statin use and showed metabolic effects which differed by statin use and age. Among the youngest (38-53y, statins-5%), BMI and WHR (per-SD) increased LDL-C (total effects: 0.04-SD, 95%CI=-0.01,0.08 and 0.10-SD, 95%CI=0.02,0.17 respectively), but only WHR directly. Among the oldest (63-73y, statins-29%), BMI and WHR directly lowered LDL-C (-0.19-SD, 95%CI=-0.27,-0.11 and -0.05-SD, 95%CI=-0.16,0.06 respectively).Interpretation: Excess adiposity likely raises atherogenic lipid and metabolite levels exclusively via adiposity stored centrally, particularly among women. Apparent effects of adiposity on lowering LDL-C are likely explained by an effect of adiposity on statin use.",

keywords = "Bristol Population Health Science Institute, Adiposity, BMI, WHR, Metabolism, NMR, Mendelian randomization, Epidemiology, UK Biobank",

author = "Bell, {Joshua A} and Richardson, {Tom G} and Qin Wang and Sanderson, {Eleanor C M} and Palmer, {Tom M} and Walker, {Venexia M} and O'Keefe, {Linda Marie} and Timpson, {Nicholas John} and Anna Cichonska and Heli Julkunen and Peter Wurtz and Holmes, {Michael V} and {Davey Smith}, George",

note = "Funding Information: JAB, TGR, ES, VMW, TP, and GDS work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/3; MC_UU_00011/4) and the University of Bristol. QW is funded by a Novo Nordisk postdoctoral fellowship (NNF17OC0027034) and during this work began employment with GSK. VMW is supported by the COVID-19 Longitudinal Health and Wellbeing National Core Study, which is funded by the Medical Research Council (MC_PC_20030; MC_PC_20059). LMOK is supported by a Health Research Board (HRB) of Ireland Emerging Investigator Award (Grant ref: EIA-FA-2019-007 SCaRLeT. MVH works in a unit that receives funding from the UK MRC and is supported by a BHF Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre; and towards completion of this work began employment with 23andMe. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). This publication is the work of the authors and JAB is the guarantor for its contents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = jul,

day = "6",

doi = "10.1016/j.lanepe.2022.100457",

language = "English",

volume = "21",

journal = "The Lancet Regional Health - Europe",

issn = "2666-7762",

publisher = "Elsevier Limited",

}

Bell, JA, Richardson, TG, Wang, Q, Sanderson, ECM , Palmer, TM , Walker, VM, O'Keefe, LM, Timpson, NJ, Cichonska, A, Julkunen, H, Wurtz, P, Holmes, MV & Davey Smith, G 2022, 'Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study', The Lancet Regional Health - Europe, vol. 21, 100457. https://doi.org/10.1016/j.lanepe.2022.100457

Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study. / Bell, Joshua A; Richardson, Tom G; Wang, Qin et al.
In: The Lancet Regional Health - Europe, Vol. 21, 100457, 06.07.2022.

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

TY - JOUR

T1 - Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank

T2 - A multivariable Mendelian randomization study

AU - Bell, Joshua A

AU - Richardson, Tom G

AU - Wang, Qin

AU - Sanderson, Eleanor C M

AU - Palmer, Tom M

AU - Walker, Venexia M

AU - O'Keefe, Linda Marie

AU - Timpson, Nicholas John

AU - Cichonska, Anna

AU - Julkunen, Heli

AU - Wurtz, Peter

AU - Holmes, Michael V

AU - Davey Smith, George

N1 - Funding Information: JAB, TGR, ES, VMW, TP, and GDS work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/3; MC_UU_00011/4) and the University of Bristol. QW is funded by a Novo Nordisk postdoctoral fellowship (NNF17OC0027034) and during this work began employment with GSK. VMW is supported by the COVID-19 Longitudinal Health and Wellbeing National Core Study, which is funded by the Medical Research Council (MC_PC_20030; MC_PC_20059). LMOK is supported by a Health Research Board (HRB) of Ireland Emerging Investigator Award (Grant ref: EIA-FA-2019-007 SCaRLeT. MVH works in a unit that receives funding from the UK MRC and is supported by a BHF Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre; and towards completion of this work began employment with 23andMe. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). This publication is the work of the authors and JAB is the guarantor for its contents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2022 The Author(s)

PY - 2022/7/6

Y1 - 2022/7/6

N2 - Background: The direct effects of general adiposity (body mass index (BMI)) and central adiposity (waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites are unknown.Methods: We used new metabolic data from UK Biobank (N=109,532, a five-fold higher N over previous studies). EDTA-plasma was used to quantify 249 traits with nuclear-magnetic-resonance spectroscopy including subclass-specific lipoprotein concentrations and lipid content, plus preglycemic and inflammatory metabolites. We used univariable and multivariable two-stage leastsquares regression models with genetic risk scores for BMI and WHR as instruments to estimate total (unadjusted) and direct (mutually-adjusted) effects of BMI and WHR on metabolic traits; plus effects on statin use and interaction by sex, statin use, and age (proxy for medication use).Findings: Higher BMI decreased apolipoprotein B and low-density lipoprotein cholesterol (LDL-C) before and after WHR-adjustment, whilst BMI increased triglycerides only before WHR-adjustment. These effects of WHR were larger and BMI-independent. Direct effects differed markedly by sex, e.g., triglycerides increased only with BMI among men, and only with WHR among women.Adiposity measures increased statin use and showed metabolic effects which differed by statin use and age. Among the youngest (38-53y, statins-5%), BMI and WHR (per-SD) increased LDL-C (total effects: 0.04-SD, 95%CI=-0.01,0.08 and 0.10-SD, 95%CI=0.02,0.17 respectively), but only WHR directly. Among the oldest (63-73y, statins-29%), BMI and WHR directly lowered LDL-C (-0.19-SD, 95%CI=-0.27,-0.11 and -0.05-SD, 95%CI=-0.16,0.06 respectively).Interpretation: Excess adiposity likely raises atherogenic lipid and metabolite levels exclusively via adiposity stored centrally, particularly among women. Apparent effects of adiposity on lowering LDL-C are likely explained by an effect of adiposity on statin use.

AB - Background: The direct effects of general adiposity (body mass index (BMI)) and central adiposity (waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites are unknown.Methods: We used new metabolic data from UK Biobank (N=109,532, a five-fold higher N over previous studies). EDTA-plasma was used to quantify 249 traits with nuclear-magnetic-resonance spectroscopy including subclass-specific lipoprotein concentrations and lipid content, plus preglycemic and inflammatory metabolites. We used univariable and multivariable two-stage leastsquares regression models with genetic risk scores for BMI and WHR as instruments to estimate total (unadjusted) and direct (mutually-adjusted) effects of BMI and WHR on metabolic traits; plus effects on statin use and interaction by sex, statin use, and age (proxy for medication use).Findings: Higher BMI decreased apolipoprotein B and low-density lipoprotein cholesterol (LDL-C) before and after WHR-adjustment, whilst BMI increased triglycerides only before WHR-adjustment. These effects of WHR were larger and BMI-independent. Direct effects differed markedly by sex, e.g., triglycerides increased only with BMI among men, and only with WHR among women.Adiposity measures increased statin use and showed metabolic effects which differed by statin use and age. Among the youngest (38-53y, statins-5%), BMI and WHR (per-SD) increased LDL-C (total effects: 0.04-SD, 95%CI=-0.01,0.08 and 0.10-SD, 95%CI=0.02,0.17 respectively), but only WHR directly. Among the oldest (63-73y, statins-29%), BMI and WHR directly lowered LDL-C (-0.19-SD, 95%CI=-0.27,-0.11 and -0.05-SD, 95%CI=-0.16,0.06 respectively).Interpretation: Excess adiposity likely raises atherogenic lipid and metabolite levels exclusively via adiposity stored centrally, particularly among women. Apparent effects of adiposity on lowering LDL-C are likely explained by an effect of adiposity on statin use.

KW - Bristol Population Health Science Institute

KW - Adiposity

KW - BMI

KW - WHR

KW - Metabolism

KW - NMR

KW - Mendelian randomization

KW - Epidemiology

KW - UK Biobank

U2 - 10.1016/j.lanepe.2022.100457

DO - 10.1016/j.lanepe.2022.100457

M3 - Article (Academic Journal)

C2 - 35832062

SN - 2666-7762

VL - 21

JO - The Lancet Regional Health - Europe

JF - The Lancet Regional Health - Europe

M1 - 100457

ER -

Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study

Abstract

Bibliographical note

Keywords

Access to Document

Handle.net

Fingerprint

Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Rework of IEU 2 Tilling Programme

Cite this