Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach.
BACKGROUND
Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven.


OBJECTIVE
The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach.


METHODS
In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4, counting each pair of alleles related to CRP levels or BMI.


RESULTS
With increasing CRP allele score, there was a stepwise decrease in CRP levels (P for trend < 0.0001) and a 1.98 mg/liter difference between extremes of the allele score distribution, but there was no associated change in BMI or leptin levels (P >or= 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m(2) difference between extremes; P for trend 0.002); 2) an increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend 0.0027); and 3) increased CRP levels (1.24 mg/liter difference between extremes; P for trend 0.002).


CONCLUSIONS
Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors.
Welsh
Paul
P
Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
Polisecki
Eliana
E
Robertson
Michele
M
Jahn
Sabine
S
Buckley
Brendan M
BM
de Craen
Anton J M
AJ
Ford
Ian
I
Jukema
J Wouter
JW
Macfarlane
Peter W
PW
Packard
Chris J
CJ
Stott
David J
DJ
Westendorp
Rudi G J
RG
Shepherd
James
J
Hingorani
Aroon D
AD
Smith
George Davey
GD
Schaefer
Ernst
E
Sattar
Naveed
N
D050154:Adiposity / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers / Q000502:physiology; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics
D015415:Biomarkers; D005819:Genetic Markers; C470072:MC4R protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D002097:C-Reactive Protein; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human