Editors' ChoiceObesity and Inflammation

Which Came First?

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Science Translational Medicine  27 Jan 2010:
Vol. 2, Issue 16, pp. 16ec13
DOI: 10.1126/scitranslmed.3000855

Researchers agree that obesity correlates with greater-than-normal serum concentrations of systemic inflammation biomarkers, such as C-reactive protein (CRP). But we still don’t know whether obesity leads to inflammation or inflammation promotes obesity. This raging debate drives scientists to devise new ways to answer the following question: Does inflammation create a condition that promotes the accumulation of adipocytes (fat cells)? Or do reservoirs of fat cells alter metabolism and spur inflammation? Or both?

Now, Welsh et al. have used genetic analyses and Mendelian randomization to examine the causal link between adiposity and inflammation. Mendelian randomization enables investigators to use common genetic polymorphisms to tease out causal effects from observational data complicated by multiple intercorrelated variables, such as adiposity and inflammation. They examined two common single-nucleotide polymorphisms (SNPs) in the CRP gene, one SNP in a gene associated with fat mass and obesity (FTO), and one more in a gene that regulates feeding behavior and metabolism [melanocortin 4 receptor (MC4R)]. These four SNPs, along with high-sensitivity CRP concentrations and anthropometric parameters [including body mass index (BMI)], were examined in participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), which includes patients aged 70 to 82 years of age with either vascular disease or an increased risk for vascular disease because of smoking, hypertension, or diabetes.

The results of these analyses show that the allele scores for the two common SNPs in CRP are not associated with increased BMI, whereas the allele scores for the SNPs in FTO and MC4R are associated with elevated BMI and circulating CRP. These findings suggest that the direction of causality is from increased adiposity to elevated CRP, and thus inflammation, rather than the reverse. In general, epidemiological studies uncover associations but are unable to identify causality. With Mendelian randomization, Welsh et al. were able to extend the epidemiological findings of PROSPER to shed light on the chicken-and-egg question associated with inflammation and obesity. This bidirectional genetic approach to deciphering relations between mechanistic pathways may help answer other clinically relevant causality questions.

P. Welsh et al., Unraveling the directional link between adiposity and inflammation: A bidirectional mendelian randomization approach. J. Clin. Endocrinol. Metab. 95, 93–99 (2010). [Abstract]

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