Effects of General and Central Adiposity on Circulating Lipoprotein, Lipid, and Metabolite Levels in UK Biobank: A Multivariable Mendelian Randomization Study

Overview

Journal Lancet Reg Health Eur

Specialty Health Services

Date 2022 Jul 14

PMID 35832062

Authors

Joshua A Bell

Tom G Richardson

Qin Wang

Eleanor Sanderson

Tom Palmer

Venexia Walker

Linda M OKeeffe

Nicholas J Timpson

Anna Cichonska

Heli Julkunen

Peter Wurtz

Michael V Holmes

George Davey Smith

Affiliations

Soon will be listed here.

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 (=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.

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