title: Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach.
abstract: 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.
authors.affiliation: Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Welsh
authors.forename: Eliana
authors.initials: E
authors.lastname: Polisecki
authors.forename: Michele
authors.initials: M
authors.lastname: Robertson
authors.forename: Sabine
authors.initials: S
authors.lastname: Jahn
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Peter W
authors.initials: PW
authors.lastname: Macfarlane
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Packard
authors.forename: David J
authors.initials: DJ
authors.lastname: Stott
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: James
authors.initials: J
authors.lastname: Shepherd
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Ernst
authors.initials: E
authors.lastname: Schaefer
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
mesh_terms: 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
chemical_list: 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