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PLoS Med. 2014 Dec 9;11(12):e1001765. doi: 10.1371/journal.pmed.1001765. eCollection 2014 Dec.

Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change.

Author information

1
Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
2
Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
3
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
4
Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
5
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
6
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
7
Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland.
8
Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
9
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
10
Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, Tampere, Finland.
11
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
12
University Heart Center Hamburg, Hamburg, Germany.
13
Finnish Institute of Occupational Health, Helsinki, Finland.
14
Department of Obstetrics and Gynecology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
15
Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
16
Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; Primary Health Care, Central Finland Central Hospital, Jyväskylä, Finland.
17
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom.
18
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
19
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.
20
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
21
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom; Oulu University Hospital, Oulu, Finland.
22
Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Oulu University Hospital, Oulu, Finland; Computational Medicine, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.

Abstract

BACKGROUND:

Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.

METHODS AND FINDINGS:

We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92).

CONCLUSIONS:

Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.

PMID:
25490400
PMCID:
PMC4260795
DOI:
10.1371/journal.pmed.1001765
[Indexed for MEDLINE]
Free PMC Article

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