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The following is a summary of “Causal inference study of plasma proteins and blood metabolites mediating the effect of obesity-related indicators on osteoporosis,” published in the February 2025 issue of Frontiers in Endocrinology by Huang et al. 

Osteoporosis and obesity were recognized as major public health concerns, with observational studies suggesting a possible link, while Mendelian randomization (MR) analysis addressed limitations in determining causality.  

Researchers conducted a retrospective study to examine the causal relationship between obesity-related indicators and osteoporosis using a 2-sample MR analysis and to identify potential mediators.   

They obtained 53 obesity-related indicators, 3,282 plasma protein lists, and 452 blood metabolite lists from a public dataset as instrumental variables. Osteoporosis genome-wide association study (GWAS) data from the MRC IEU Open GWAS database served as outcome indicators. The 2-sample univariate MR, multivariate MR, and intermediate MR analyses were conducted to determine the causal relationship and mediating factors between obesity-related indicators and osteoporosis.  

The results showed that 31 obesity-related indicators had a significant causal relationship with osteoporosis (P < 0.05), except for waist circumference (id: Ieu-a-71, OR = 1.00566). The remaining 30 indicators reduced osteoporosis risk (Odds Ratio (OR) : 0.983–0.996). Among 25 plasma protein indicators with significant associations (P < 0.05), 10, including ANKED46, KLRF1, LPO, and CA9, had a protective effect (OR: 0.996–0.999), while 15, such as ATP1B1 and zinc finger (ZNF) protein 175, increased risk (OR: 1.001–1.004). For blood metabolites, alanine (id: Met a-469, OR: 1.071) increased osteoporosis risk, while 6 others, including uridine and 1-linoleoylglycerophosphoethanolamine, were protective (P < 0.05, OR: 0.961–0.992). The MR analysis confirmed correct causal directions, with no significant heterogeneity or horizontal pleiotropy. Multivariate and mediated MR analysis indicated that the protective effect of obesity-related indicators on osteoporosis may be mediated by histone-lysine N-methyltransferase (EHMT2) in plasma proteins and alanine in blood metabolites.  

Investigators concluded that obesity might offer protection against osteoporosis, possibly through EHMT2 in plasma proteins and alanine in blood metabolites. 

Source: frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1435295/full