C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization
Open accessAbstract
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 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).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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Previous research has shown that genetic variants associated with BMI are associated with CRP levels and uric acid concentrations, but the reverse was not found for genetic variants which are plausible instrumental variables for CRP and uric acid.
“Previous research has shown that genetic variants associated with BMI are associated with CRP levels30,39 and associated with uric acid concentrations,40 although in both cases the reverse was not found for genetic variants which are plausible IVs for CRP and for uric acid.”
From Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. (2015) · cites this paper as [30]
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- Authors
- Timpson, N. J., Nordestgaard, B. G., Harbord, R. M., Zacho, J., Frayling, T. M., Tybjærg-Hansen, A., & Davey Smith, G.
- Affiliations
- University of Bristol (GB)
- University of Copenhagen (DK)
- University of Exeter (GB)
- Corresponding author
- Timpson, N J
- Venue
- International Journal of Obesity
- Published
- 2010-08-17
- Volume
- 35
- Issue
- 2
- Pages
- 300-308
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- PMC
- PMC4783860
- OpenAlex
- W2052518513
- Cited by
- 310
- References
- 58
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 26 · 2023: 28 · 2022: 31 · 2021: 36 · 2020: 35 · 2019: 16 · 2018: 12 · 2017: 12 · 2016: 20 · 2015: 16 · 2014: 15 · 2013: 13 · 2012: 10
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- PubMed Central (acceptedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- C-reactive protein, body mass index, adiposity, causal direction, FTO, rs9939609, genetic variants, inflammation, obesity
- MeSH terms
- Adult, Aged, Aged, 80 and over, C-Reactive Protein, Cross-Sectional Studies, Denmark, Female, Genotype, Humans, Male, Middle Aged, Obesity, Sex Factors, Genetic Variation, Biomarkers, Body Mass Index, Adiposity, Young Adult, Mendelian Randomization Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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