European Heart Journal Advance Access published online on June 10, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn252
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Lifetime body mass index and later atherosclerosis risk in young adults: examining causal links using Mendelian randomization in the Cardiovascular Risk in Young Finns study
1 Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK
2 Finnish Institute of Occupational Health, Helsinki, Finland
3 The MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK
4 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
5 MRC Social and Public Health Sciences Unit, University of Glasgow, Glasgow, UK
6 Department of Clinical Physiology, Tampere University Hospital, University of Tampere Medical School, Tampere, Finland
7 Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
8 Department of Medicine, University of Turku, Turku, Finland
9 Department of Clinical Chemistry, Tampere University Hospital, University of Tampere Medical School, Tampere, Finland
10 Department of Clinical Physiology, University of Turku, Turku, Finland
Received 12 December 2007; revised 16 May 2008; accepted 22 May 2008.
* Corresponding author. Tel: +44 20 7678 8260, Fax: +44 20 7419 6732, Email: m.kivimaki{at}ucl.ac.uk
Aims: Mendelian randomization uses genetic variants related to environmentally modifiable risk factors in an attempt to improve causal inference from observational data. We examined the effect of lifetime body mass index (BMI) on adult carotid intima-media thickness (CIMT) and various atherosclerotic risk factors by using both Mendelian randomization and conventional analyses.
Methods and results: A total of 2230 individuals (1218 women), aged 3–18 at study induction, took part in clinical examinations in 1980, 1983, 1986, and, most recently, 2001 when they were aged 24–39. In these analyses we utilized the known relation between FTO polymorphism rs9939609 and BMI. The dose–response association between the number of A alleles in FTO and higher mean BMI from childhood to adulthood was confirmed, but no associations with potential confounding factors were observed. In standard regression models, lifetime BMI was associated with adult CIMT, lifetime systolic blood pressure, adult fasting glucose, and adult HOMA-index. When variation in FTO was used as an instrument for unconfounded BMI levels, similar or larger effects of lifetime BMI on all these phenotypes were found, although with wider confidence intervals.
Conclusion: Mutually supportive results from Mendelian randomization and standard regression models strengthen the evidence of the effect of lifetime BMI on atherosclerosis risk in young adults.
Key Words: Atherosclerosis • Body mass index • Mendelian randomization • Variation (genetics)
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