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- Title
C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.
- Authors
Timpson, N. J.; Nordestgaard, B. G.; Harbord, R. M.; Zacho, J.; Frayling, T. M.; Tybjærg-Hansen, A.; Davey Smith, G.
- Abstract
Context:The 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.Objective:Using 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 methods:The 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.Results:Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in logCRP 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 logCRP 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).Conclusions:Taken 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.
- Subjects
COPENHAGEN (Denmark); DENMARK; C-reactive protein; BODY mass index; GENETIC research; OBESITY; METABOLIC disorders
- Publication
International Journal of Obesity, 2011, Vol 35, Issue 2, p300
- ISSN
0307-0565
- Publication type
Article
- DOI
10.1038/ijo.2010.137