Document Detail

Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach.
MedLine Citation:
PMID:  19906786     Owner:  NLM     Status:  MEDLINE    
CONTEXT: 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.
Paul Welsh; Eliana Polisecki; Michele Robertson; Sabine Jahn; Brendan M Buckley; Anton J M de Craen; Ian Ford; J Wouter Jukema; Peter W Macfarlane; Chris J Packard; David J Stott; Rudi G J Westendorp; James Shepherd; Aroon D Hingorani; George Davey Smith; Ernst Schaefer; Naveed Sattar
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-11-11
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  95     ISSN:  1945-7197     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-08     Completed Date:  2010-02-01     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  93-9     Citation Subset:  AIM; IM    
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MeSH Terms
Adiposity / genetics*
Aged, 80 and over
Biological Markers / blood
C-Reactive Protein / genetics
Genetic Linkage*
Genetic Markers / physiology
Inflammation / blood,  genetics*
Mendelian Randomization Analysis / methods*
Polymorphism, Single Nucleotide
Proteins / genetics
Receptor, Melanocortin, Type 4 / genetics
Grant Support
G0600705//Medical Research Council; R01 HL74753/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Biological Markers; 0/FTO protein, human; 0/Genetic Markers; 0/MC4R protein, human; 0/Proteins; 0/Receptor, Melanocortin, Type 4; 9007-41-4/C-Reactive Protein

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