Plasma Proteins Mediate the Causal Effect of Diet on the Development of Osteoporosis: A Mendelian Randomization Study

The causal relationship between dietary intake, plasma proteins, and osteoporosis (OP) remains uncertain. We investigated whether 38 dietary factors and 2,940 plasma proteins have a causal effect on OP using Mendelian randomization (MR).

Single-nucleotide polymorphisms (SNPs) robustly associated with 38 dietary factors and 2,940 plasma proteins were used as instrumental variables (IVs). We performed four MR approaches, including inverse variance weighted (IVW), weighted mode, MR-Egger, and weighted median. Multivariate MR analysis and mediation effect estimation were employed to evaluate potential mediating effects.

Higher consumption of ground coffee and instant coffee was statistically associated with increased OP prevalence, whereas greater water intake showed a protective trend. Among plasma proteins, 152 demonstrated significant associations with OP, with 26 linked to ground coffee consumption, 23 to instant coffee, and 5 to water intake. Notably, RAB GTPase-activating protein 1-like (RABGAP1L) appeared to mediate the association between ground coffee consumption and OP.

MR analysis indicated that ground coffee and instant coffee intake are risk factors, while water consumption is a protective factor for OP, and suggested a potential mediating role of RABGAP1L in ground coffee-induced OP. These findings should be interpreted as potential mechanistic insights rather than definitive causal proof.

The observed associations between coffee consumption and OP likely involve complex biological pathways, and the protective effect of water intake warrants further investigation in longitudinal studies.