TY - JOUR
T1 - Unraveling the directional link between adiposity and inflammation
T2 - A bidirectional mendelian randomization approach
AU - Welsh, Paul
AU - Polisecki, Eliana
AU - Robertson, Michele
AU - Jahn, Sabine
AU - Buckley, Brendan M.
AU - De Craen, Anton J.M.
AU - Ford, Ian
AU - Jukema, J. Wouter
AU - Macfarlane, Peter W.
AU - Packard, Chris J.
AU - Stott, David J.
AU - Westendorp, Rudi G.J.
AU - Shepherd, James
AU - Hingorani, Aroon D.
AU - Smith, George Davey
AU - Schaefer, Ernst
AU - Sattar, Naveed
N1 - Funding Information:
The leptin and CRP assays and analysis were supported by the Stroke Association . The genotyping analyses were supported by Grant R01 HL74753 from the National Institutes of Health and Contract 53-1950-5-003 from the Agricultural Research Service of the U.S. Department of Agriculture.
PY - 2010/1
Y1 - 2010/1
N2 - 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 ≥ 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m2 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.
AB - 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 ≥ 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m2 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.
UR - https://www.scopus.com/pages/publications/75149163834
U2 - 10.1210/jc.2009-1064
DO - 10.1210/jc.2009-1064
M3 - Article
AN - SCOPUS:75149163834
SN - 0021-972X
VL - 95
SP - 93
EP - 99
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 1
ER -