"C-reactive protein levels and risk of dementia": Subgroup analyses in Mendelian randomization are likely to be misleading.

Abstract

Mendelian randomization is the use of genetic variants analogously to randomized treatment allocation in a trial to make causal inferences from observational data. In their recent paper, Hegazy and colleagues assessed associations between genetic variants in the CRP gene region, which they treated analogously to random allocation to increased levels of C-reactive protein (CRP), and risk of dementia (1). However, rather than assessing associations in the population as a whole, they assessed associations in strata of the population defined according to body mass index (BMI): those with BMI ≤25 kg/m2, and those with BMI >25 kg/m2. They observed positive associations between variants and dementia risk in the low BMI stratum, and inverse associations (although mostly not statistically significant) in the high BMI stratum. The authors interpreted the positive associations as evidence that CRP has a deleterious effect on dementia risk in low BMI individuals. However, there are reasons to be sceptical of this interpretation.