CRP 1846G>A polymorphism increases risk of frailty

Frailty is a syndrome characterized by diminished ability to re-establish homeostasis in response to stress. We hypothesized that deficient allostatic responses to physiological challenges may predispose to frailty, that C-reactive protein (CRP) and its genetic determinants may be a measure of the integrity of the allostatic response, and that genetic determinants of the allostatic response determine the risk of frailty.

Cross-sectional study of 3778 community-dwelling older men identified by random sampling of the Australian electoral roll. Explanatory variables included demographic, clinical, lifestyle behaviors, serum high-sensitivity CRP (hsCRP), and CRP 1444C>T and 1846G>A genotypes. These respective polymorphisms increase and decrease the basal concentration of hsCRP. The study outcome was frailty defined by a score of ≥4 on the FRAIL scale.

The mean age of participants was 77.1 years (SD: 3.6) and frailty was present in 196 (5.2%). The serum concentration of hsCRP was higher in frail than non-frail men (p<0.001), but levels varied according to genotypes. The odds of frailty increased progressively from GG to GA and AA genotypes of the CRP1846G>A gene (z=3.93, p<0.001), and were 2.43 (95%CI=1.62-3.67) times greater in men with CRP1846G>A AA compared with GG genotypes. The CRP 1444C>T was not associated with frailty.

Frail people have raised serum concentrations of CRP, presumably in response to the stress of underlying cause(s). However, frail individuals carrying the CRP1846G>A polymorphism seem less able to mount an efficient allostatic response, which may underpin their increased odds of frailty.