Abdominal adiposity and cardiometabolic risk factors in children and adolescents: A Mendelian randomization analysis

Anna Viitasalo; Theresia M. Schnurr; Niina Pitkänen; Mette Hollensted; Tenna R.H. Nielsen; Katja Pahkala; Mustafa Atalay; Mads V. Lind; Sami Heikkinen; Christine Frithioff-Bøjsøe; Cilius E. Fonvig; Niels Grarup; Mika Kähönen; Germán D. Carrasquilla; Anni Larnkjaer; Oluf Pedersen; Kim F. Michaelsen; Timo A. Lakka; Jens Christian Holm; Terho Lehtimäki; Olli Raitakari; Torben Hansen; Tuomas O. Kilpeläinen

doi:10.1093/ajcn/nqz187

Abdominal adiposity and cardiometabolic risk factors in children and adolescents: A Mendelian randomization analysis

Anna Viitasalo^*
, Theresia M. Schnurr
, Niina Pitkänen
, Mette Hollensted
, Tenna R.H. Nielsen
, Katja Pahkala
, Mustafa Atalay
, Mads V. Lind
, Sami Heikkinen
, Christine Frithioff-Bøjsøe
, Cilius E. Fonvig
, Niels Grarup
, Mika Kähönen
, Germán D. Carrasquilla
, Anni Larnkjaer
, Oluf Pedersen
, Kim F. Michaelsen
, Timo A. Lakka
, Jens Christian Holm
, Terho Lehtimäki

Olli Raitakari, Torben Hansen, Tuomas O. Kilpeläinen

^*Corresponding author for this work

Paediatrics (HOL)

Research output: Contribution to journal › Article › Research › peer-review

Abstract

Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear. Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization. Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHR_adjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y. Results: WHR_adjBMI GRS was associated with higher WHR_adjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10^-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHR_adjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHR_adjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal. Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

Original language	English
Pages (from-to)	1079-1087
Number of pages	9
Journal	American Journal of Clinical Nutrition
Volume	110
Issue number	5
DOIs	https://doi.org/10.1093/ajcn/nqz187
Publication status	Published - 1 Nov 2019

Funding

1Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; 3The Children’s Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; 4Department of Pediatrics, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; 5Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, University of Turku, Turku, Finland; 6Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; 7Department of Nutrition, Exercise, and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; 8Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 9The Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; 10Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; 11Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center, Tampere University, Tampere, Finland; 12Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland; 13Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; 14Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; 15Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; and 16Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland Supported by the European Union (EU)’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement no. 796143 (to AV), the Orion Research Foundation (to AV), the Emil Aaltonen Foundation (to AV), Danish Council for Independent Research grant DFF— 6110-00183, and Novo Nordisk Foundation grants NNF17OC0026848 (to TOK) and NNF18CC0034900. UK Medical Research Council and Wellcome Trust grant 102215/2/13/2 and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC genome-wide association study data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grant funding (http://www.bristol.ac.uk/alspac/ext ernal/documents/grant-acknowledgements.pdf) is available on the ALSPAC website. This research was specifically funded by Wellcome Trust grant 086676/Z/08/Z. The Cardiovascular risk in Young Finns Study was supported by Academy of Finland grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere, and Turku University Hospitals grant X51001; the Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of the Finnish Diabetes Association; EU Horizon 2020 grant 755320 (for TAXINOMISIS); European Research Council grant 742927 (for the MULTIEPIGEN project); and the Tampere University Hospital Supporting Foundation. The Danish Childhood Obesity Biobank study is part of the research activities in TARGET (The Impact of our Genomes on Individual Treatment Response in Obese Children) and BIOCHILD (Genetics and Systems Biology of Childhood Obesity in India and Denmark). The study is part of The Danish Childhood Obesity Biobank (NCT00928473). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.cbmr.ku.dk). The study was supported by Danish Innovation Foundation grants 0603-00484B and 0603-00457B, Novo Nordisk Foundation grant NNF15OC0016544, and the Region Zealand Health and Medical Research Foundation. The Special Turku Coronary Risk Factor Intervention Project was supported by Academy of Finland grants 206374, 294834, 251360, and 275595; the Juho Vainio Foundation; Finnish Cultural Foundation; Finnish Foundation for Cardiovascular Research; Sigrid Jusélius Foundation; Yrjö Jahnsson Foundation; Finnish Diabetes Research Foundation; Novo Nordisk Foundation; Finnish Ministry of Education and Culture; Special Governmental Grants for Health Sciences Research, Turku University Hospital; and the University of Turku Foundation. The Physical Activity and Nutrition in Children study was supported by grants from the Ministry of Social Affairs and Health of Finland, Ministry of Education and Culture of Finland, Finnish Innovation Fund Sitra, Social Insurance Institution of Finland, Finnish Cultural Foundation, Juho Vainio Foundation, Foundation for Paediatric Research, Paavo Nurmi Foundation, Paulo Foundation, Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, Yrjö Jahnsson Foundation, Research Committee of the Kuopio University Hospital Catchment Area (State Research Funding), Kuopio University Hospital (EVO funding number 5031343), and the city of Kuopio. The Småbørns Kost Og Trivsel (SKOT)-I study was supported by grants from The Danish Directorate for Food, Fisheries, and Agri Business as part of the “Complementary and young child feeding (CYCF)—impact on short-and long-term development and health” project. The SKOT-II study was supported by grants from the Aase and Ejnar Danielsens Foundation and the Augustinus Foundation and contributions from the research program “Governing Obesity” by the University of Copenhagen Excellence Program for Interdisciplinary Research (www.go.ku.dk).

Keywords

abdominal adiposity
ALSPAC
cardiometabolic risk
cardiovascular disease risk
children
Mendelian randomization
meta-analysis
waist-to-hip ratio
Body Mass Index
Coronary Artery Disease/etiology
Humans
Risk Factors
Child, Preschool
Male
Diabetes Mellitus, Type 2/etiology
Adiposity
Adolescent
Mendelian Randomization Analysis
Triglycerides/blood
Female
Child
Waist-Hip Ratio

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10.1093/ajcn/nqz187

Cite this

Viitasalo, A., Schnurr, T. M., Pitkänen, N., Hollensted, M., Nielsen, T. R. H., Pahkala, K., Atalay, M., Lind, M. V., Heikkinen, S., Frithioff-Bøjsøe, C., Fonvig, C. E., Grarup, N., Kähönen, M., Carrasquilla, G. D., Larnkjaer, A., Pedersen, O., Michaelsen, K. F., Lakka, T. A., Holm, J. C., ... Kilpeläinen, T. O. (2019). Abdominal adiposity and cardiometabolic risk factors in children and adolescents: A Mendelian randomization analysis. American Journal of Clinical Nutrition, 110(5), 1079-1087. https://doi.org/10.1093/ajcn/nqz187

@article{ff600cb2526543979e7ac69a2703ac10,

title = "Abdominal adiposity and cardiometabolic risk factors in children and adolescents: A Mendelian randomization analysis",

abstract = "Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear. Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization. Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y. Results: WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95\% CI: 0.016, 0.026 SD/allele; P = 3 {\texttimes} 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95\% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95\% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95\% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95\% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95\% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal. Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.",

keywords = "abdominal adiposity, ALSPAC, cardiometabolic risk, cardiovascular disease risk, children, Mendelian randomization, meta-analysis, waist-to-hip ratio, Body Mass Index, Coronary Artery Disease/etiology, Humans, Risk Factors, Child, Preschool, Male, Diabetes Mellitus, Type 2/etiology, Adiposity, Adolescent, Mendelian Randomization Analysis, Triglycerides/blood, Female, Child, Waist-Hip Ratio",

author = "Anna Viitasalo and Schnurr, \{Theresia M.\} and Niina Pitk{\"a}nen and Mette Hollensted and Nielsen, \{Tenna R.H.\} and Katja Pahkala and Mustafa Atalay and Lind, \{Mads V.\} and Sami Heikkinen and Christine Frithioff-B{\o}js{\o}e and Fonvig, \{Cilius E.\} and Niels Grarup and Mika K{\"a}h{\"o}nen and Carrasquilla, \{Germ{\'a}n D.\} and Anni Larnkjaer and Oluf Pedersen and Michaelsen, \{Kim F.\} and Lakka, \{Timo A.\} and Holm, \{Jens Christian\} and Terho Lehtim{\"a}ki and Olli Raitakari and Torben Hansen and Kilpel{\"a}inen, \{Tuomas O.\}",

note = "Copyright {\textcopyright} American Society for Nutrition 2019.",

year = "2019",

month = nov,

day = "1",

doi = "10.1093/ajcn/nqz187",

language = "English",

volume = "110",

pages = "1079--1087",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

publisher = "Elsevier B.V.",

number = "5",

}

Viitasalo, A, Schnurr, TM, Pitkänen, N, Hollensted, M, Nielsen, TRH, Pahkala, K, Atalay, M, Lind, MV, Heikkinen, S, Frithioff-Bøjsøe, C, Fonvig, CE, Grarup, N, Kähönen, M, Carrasquilla, GD, Larnkjaer, A, Pedersen, O, Michaelsen, KF, Lakka, TA, Holm, JC, Lehtimäki, T, Raitakari, O, Hansen, T & Kilpeläinen, TO 2019, 'Abdominal adiposity and cardiometabolic risk factors in children and adolescents: A Mendelian randomization analysis', American Journal of Clinical Nutrition, vol. 110, no. 5, pp. 1079-1087. https://doi.org/10.1093/ajcn/nqz187

TY - JOUR

T1 - Abdominal adiposity and cardiometabolic risk factors in children and adolescents

T2 - A Mendelian randomization analysis

AU - Viitasalo, Anna

AU - Schnurr, Theresia M.

AU - Pitkänen, Niina

AU - Hollensted, Mette

AU - Nielsen, Tenna R.H.

AU - Pahkala, Katja

AU - Atalay, Mustafa

AU - Lind, Mads V.

AU - Heikkinen, Sami

AU - Frithioff-Bøjsøe, Christine

AU - Fonvig, Cilius E.

AU - Grarup, Niels

AU - Kähönen, Mika

AU - Carrasquilla, Germán D.

AU - Larnkjaer, Anni

AU - Pedersen, Oluf

AU - Michaelsen, Kim F.

AU - Lakka, Timo A.

AU - Holm, Jens Christian

AU - Lehtimäki, Terho

AU - Raitakari, Olli

AU - Hansen, Torben

AU - Kilpeläinen, Tuomas O.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear. Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization. Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y. Results: WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal. Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

AB - Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear. Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization. Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y. Results: WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal. Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

KW - abdominal adiposity

KW - ALSPAC

KW - cardiometabolic risk

KW - cardiovascular disease risk

KW - children

KW - Mendelian randomization

KW - meta-analysis

KW - waist-to-hip ratio

KW - Body Mass Index

KW - Coronary Artery Disease/etiology

KW - Humans

KW - Risk Factors

KW - Child, Preschool

KW - Male

KW - Diabetes Mellitus, Type 2/etiology

KW - Adiposity

KW - Adolescent

KW - Mendelian Randomization Analysis

KW - Triglycerides/blood

KW - Female

KW - Child

KW - Waist-Hip Ratio

UR - https://www.scopus.com/pages/publications/85074304925

U2 - 10.1093/ajcn/nqz187

DO - 10.1093/ajcn/nqz187

M3 - Article

C2 - 31504107

AN - SCOPUS:85074304925

SN - 0002-9165

VL - 110

SP - 1079

EP - 1087

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 5

ER -

Abdominal adiposity and cardiometabolic risk factors in children and adolescents: A Mendelian randomization analysis

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