Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach

Authors: WELSH, PAUL - University Of Glasgow; POLISECKI, ELIANA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ROBERTSON, MICHELE - University Of Glasgow; JAHN, SABINE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BUCKLEY, BRENDAN - Cork Institute Of Technology; DE CREAN, J.M. - Leiden University Medical Center; FORD, IAN - University Of Glasgow; JUKEMA, J WOUTER - Leiden University Medical Center; MACFARLANE, PETER - University Of Glasgow; PACKARD, CHRISTOPHER - University Of Glasgow; STOTT, DAVID - University Of Glasgow; WESTENDROP, RUDI - Leiden University Medical Center; SHEPERD, JAMES - University Of Glasgow; HINGORANI, AROON - University College Medical School - London; SMITH, GEORGE DAVEY - University Of Bristol; SCHAEFER, ERNST - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SATTAR, NAVEED - University Of Glasgow

Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/16/2009
Publication Date: 11/11/2009
Citation: Welsh, P., Polisecki, E., Robertson, M., Jahn, S., Buckley, B.M., De Crean, J., Ford, I., Jukema, J., Macfarlane, P.W., Packard, C.J., Stott, D.J., Westendrop, R.G., Sheperd, J., Hingorani, A.D., Smith, G., Schaefer, E.J., Sattar, N. 2009. Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach. Journal of Clinical Endocrinology and Metabolism. 95(1):93-99.

Interpretive Summary: It has been shown that there is a link between obesity and markers of inflammation in the bloodstream, such as C reactive protein (CRP). Our aim of the study was to explore the relationships between obesity and inflammation in a study of 5804 elderly patients. We related genetic markers of CRP and obesity to body mass index (BMI) as well as circulating levels of CRP and leptin. With increasing CRP genetic score, there was a stepwise decrease in CRP levels with about 2 mg/L difference between extremes of the score, but there was no associated change in body mass index or leptin (a marker of obesity) levels. By contrast, obesity genetic score was associated with significant changes in body mass index leptin levels and CRP levels (p=0.002). These data indicate that obesity increases CRP levels, but CRP levels do not affect obesity on a genetic basis.

Technical Abstract: 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.