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 journalArticle (Academic Journal)peer-review

9 Citations (Scopus)
89 Downloads (Pure)


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 languageEnglish
Article number100457
JournalThe Lancet Regional Health - Europe
Publication statusPublished - 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)


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


Dive into the research topics of 'Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study'. Together they form a unique fingerprint.

Cite this