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

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 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.

Figure 1

Comparison of linear relationships between circulating CRP and residual BMI observationally and when estimated employing FTO loci as an instrument for residual BMI. X and Y axes represent residual BMI and CRP respectively. Light blue points represent a scatter plot of the correlation between circulating CRP and residual BMI. Grey areas represents 95% confidence regions around instrumental variables estimates. Black area represents 95% confidence regions around simple linear regression estimates. (The 50 individuals with extreme residual BMI over 20 kg/m² are not shown on the plot but were included in the analyses that gave the fitted lines and confidence regions.)

Figure 2

Comparison of linear relationships between residual BMI and circulating CRP observationally and when estimated employing the CRP locus rs3091244 as an instrument for log transformed CRP. X and Y axes represent CRP and residual BMI respectively. Light blue points represent a scatter plot of the correlation between circulating CRP and residual BMI. Grey areas represents 95% confidence regions around instrumental variables estimates. Black area represents 95% confidence regions around simple linear regression estimates. (The 50 individuals with extreme residual BMI over 20 kg/m² are not shown on the plot but were included in the analyses that gave the fitted lines and confidence regions.)

Figure 3

Graphical representation of the reciprocal Mendelian randomization framework used in main analyses. Dotted line represents the unknown direction of relationship between circulating CRP and BMI. Relationships (i) and (ii) denote the informative associations between CRP genotypes, FTO genotypes and circulating CRP and body mass index. Single-headed arrows represent the known (and assumed causal and largely non-confounded) relationships between variation at the CRP and FTO loci and circulating CRP and body mass index respectively.