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

CONTEXT: The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials and the presence of causal a 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 in a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTOrs9939609) and circulating CRP (CRPrs3091244) have been used to re-examine observational associations between them. RESULTS: Observational analyses showed strong, positive association between circulating CRP and BMI (change in BMI for a doubling in logCRP of 1.03kg/m(2) (95%CI 1.00, 1.07), p<0.0001). Analysis using CRPrs3091244 to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in logCRP of −0.24kg/m(2) (95%CI −0.58, 0.11), p=0.2). In contrast, analysis using FTOrs9939609 to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per standard deviation increase in BMI 1.41(95%CI 1.10, 1.80), p=0.006). CONCLUSIONS: 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 direction of causation within inter-correlated networks of metabolic components and methods such as this provide an approach for delivering immediate and clinically applicable information.