Proteins associated with incident metabolic syndrome in population-based cohorts

The metabolic syndrome (MetS) identifies persons with clustering of multiple cardiometabolic risk factors. The underlying pathology inducing this clustering is not fully known. We used a targeted proteomics assay to identify associations of circulating proteins with MetS and its components, cross-sectionally and longitudinally.

We explored and validated associations of 86 cardiovascular proteins, assessed using a proximity extension assay, with the MetS in two independent cohorts; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 996) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 785). The analyses were adjusted for smoking, exercise habits, education, and energy and alcohol intake.

Nine proteins were associated with all five components of the MetS in PIVUS using FDR < 0.05 in a cross-sectional analysis. Of those nine proteins, only Interleukin-1 receptor antagonist protein (IL-1RA) was associated with all five components of the MetS in ULSAM using p < 0.05. IL-1RA levels were associated with incident MetS (n = 109) in PIVUS during a 5-year follow-up (HR 1.76 for a 1 SD change (95% CI 1.38, 2.24), p = 4.3*10^-6). IL-1RA was however not causally related to MetS in a two-sample Mendelian randomization analysis using published data.

Circulating IL-1RA was related to all five components of the MetS in a cross-sectional analysis in two independent samples, as well as to incident MetS in a longitudinal analysis. However, Mendelian randomization analyses did not provide support for a causal role for IL-1RA in the development of MetS.