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 Sanderson; Tom Palmer; Venexia Walker; Linda M O'Keeffe; Nicholas J Timpson; Anna Cichonska; Heli Julkunen; Peter Würtz; 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

Lancet Reg Health Eur. 2022 Jul 6:21:100457. doi: 10.1016/j.lanepe.2022.100457. eCollection 2022 Oct.

Authors

Joshua A Bell^{1

2}, Tom G Richardson^{1

2

3}, Qin Wang^{1

4}, Eleanor Sanderson^{1

2}, Tom Palmer^{1

2}, Venexia Walker^{1

2

5}, Linda M O'Keeffe^{1

2

6}, Nicholas J Timpson^{1

2}, Anna Cichonska⁷, Heli Julkunen⁷, Peter Würtz⁷, Michael V Holmes^{1

2

4

8

9}, George Davey Smith^{1

2}

Affiliations

¹ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, UK.
⁴ Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
⁶ School of Public Health, Western Gateway Building, University College Cork, Ireland.
⁷ Nightingale Health Plc, Helsinki, Finland.
⁸ MRC Population Health Research Unit at the University of Oxford, Oxford, UK.
⁹ National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.

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 pre-glycemic and inflammatory metabolites. We used univariable and multivariable two-stage least-squares 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.

Funding: UK Medical Research Council; British Heart Foundation; Novo Nordisk; National Institute for Health Research; Wellcome Trust; Cancer Research UK.

Keywords: Adiposity; BMI; Epidemiology; Mendelian randomization; Metabolism; NMR; UK Biobank; WHR.

Abstract

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