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


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.
Timpson
N J
NJ
MRC Centre for Causal Analysis in Translational Epidemiology, Bristol University, Bristol, UK. n.j.timpson@bris.ac.uk
Nordestgaard
B G
BG
Harbord
R M
RM
Zacho
J
J
Frayling
T M
TM
Tybjærg-Hansen
A
A
Smith
G Davey
GD
D050154:Adiposity / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D003430:Cross-Sectional Studies; D003718:Denmark; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D055815:Young Adult
D015415:Biomarkers; D002097:C-Reactive Protein