• N J Timpson, B G Nordestgaard, R M Harbord, J Zacho, T M Frayling, A Tybjærg-Hansen, and Smith G Davey GD.
• MRC Centre for Causal Analysis in Translational Epidemiology, Bristol University, Bristol, UK. n.j.timpson@bris.ac.uk
• Int J Obes (Lond). 2011 Feb 1; 35 (2): 300-8.

ContextThe assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed.ObjectiveUsing reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique.Participants And MethodsThe study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them.ResultsObservational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in log CRP of 1.03 kg m(-2) (95% confidence interval (95% CI): 1.00, 1.07), P<0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in log CRP of -0.24 kg m(-2) (95% CI: -0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006).ConclusionsTaken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components.

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