Extreme MetaboHealth scores in three cohort studies associate with plasma protein markers for inflammation and cholesterol transport.

The MetaboHealth score is a highly informative health indicator in ageing studies and yet contains only a small number of metabolites. Here we estimate the heritability of the score in 726 monozygotic (MZ) and 450 dizygotic (DZ) twin pairs, and test for association with plasma proteins by comparing extreme scoring individuals selected from two large population cohorts -the Leiden Longevity Study (LLS) and the Rotterdam Study (RS) and discordant monozygotic twin pairs from the Netherlands Twin Register (NTR). The heritability for the MetaboHealth score was estimated at 40%. In 50 high and 50 low scoring MetaboHealth groups from LLS and RS, we uncovered significant differences in plasma proteins, notably in 3 (out of 15) cytokines (GDF15, IL6, and MIG), and 106 proteins (out of 289) as determined by Mass Spectrometry based proteomics analysis. A high MetaboHealth score associated with an increased level for 42 serum proteins, predominantly linked to inflammation and immune response, including CRP and HPT. A low score associated with decreased levels of 71 proteins enriched in high-density lipoprotein (HDL) remodeling and cholesterol transport pathways, featuring proteins such as APOA1, APOA2, APOA4, and TETN. In MZ twins selected for maximal discordance within a pair we found 68 serum proteins associated with the MetaboHealth score indicating that a minor part of the associations observed in LLS and RS is likely explained by genetic influences. Taken together, our study sheds light on the intricate interplay between MetaboHealth, plasma proteins, cytokines, and genetic influences, paving the way for future investigations aimed at optimizing this mortality risk indicator.