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C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization

International Journal of Obesity volume 35, pages 300–308 (2011)Cite this article

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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.

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Acknowledgements

We thank Dorthe Uldall Andersen and Anne Bank for technical assistance with genotyping, staff and participants of the Copenhagen General Population for their important contribution and Chris Boustred for assistance in preparing this paper. Funding: NJT is funded by the MRC Centre for Causal Analyses in Translational Epidemiology grant number G0600705. GDS works within the MRC Centre for Causal Analyses in Translational Epidemiology, which is capacity funded by grant G0600705. RMH is supported in part by the MRC project grant G0601625. BGN is supported by the Copenhagen County Foundation and by Herlev Hospital, Copenhagen University Hospital. TMF is funded by the Peninsula College of Medicine and Dentistry, University of Exeter. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the paper.

Author information

Authors and Affiliations

  1. MRC Centre for Causal Analysis in Translational Epidemiology, Bristol University, Bristol, UK

    N J Timpson, R M Harbord & G Davey Smith

  2. Department of Clinical Biochemistry, Faculty of Health Sciences, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark

    B G Nordestgaard & J Zacho

  3. Faculty of Health Sciences, The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark

    B G Nordestgaard, J Zacho & A Tybjærg-Hansen

  4. Department of Social Medicine, Bristol University, Bristol, UK

    R M Harbord

  5. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter,, UK

    T M Frayling

  6. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter,, UK

    T M Frayling

  7. Department of Clinical Biochemistry, Faculty of Health Sciences, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark

    A Tybjærg-Hansen

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Correspondence to N J Timpson.

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Author contributions

NJT was involved in the concept and design of this study, undertook main analyses and writing of the paper. BGN is the custodian of The Copenhagen General Population Study and was involved in the drafting of the paper. RMH was involved in statistical analysis and drafting of the paper. JZ was involved in data management and drafting of the paper. TMF was involved in initial design, concept and then drafting of the paper. ATH was involved in the running of The Copenhagen General Population Study and in drafting of the paper. GDS was involved in initial design, concept and then drafting of the paper. All authors had equal access to available data and take responsibility for data integrity.

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Timpson, N., Nordestgaard, B., Harbord, R. et al. C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int J Obes 35, 300–308 (2011). https://doi.org/10.1038/ijo.2010.137

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