TY - JOUR
T1 - C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization
AU - Timpson, N J
AU - Nordestgaard, B G
AU - Harbord, R M
AU - Zacho, J
AU - Frayling, T M
AU - Tybjærg-Hansen, Anne
AU - Smith, G D
AU - Smith, G Davey
PY - 2011/2/1
Y1 - 2011/2/1
N2 - 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), P0.0001). 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.
AB - 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), P0.0001). 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.
U2 - 10.1038/ijo.2010.137
DO - 10.1038/ijo.2010.137
M3 - Journal article
C2 - 20714329
SN - 0307-0565
VL - 35
SP - 300
EP - 308
JO - International Journal of Obesity
JF - International Journal of Obesity
IS - 2
ER -