Circulating 16 micronutrients concentration and risk of abdominal aortic aneurysm: a two-sample mediation Mendelian randomization analysis

Abdominal aortic aneurysm (AAA) is a severe cardiovascular disease involving various genetic and metabolic factors. Micronutrients play critical roles in cardiovascular health, yet their specific impacts on AAA remain unclear. This study aims to explore the effects of micronutrients calcium and zinc on AAA risk mediated by plasma proteins using the two-sample Mendelian Randomization (MR) approach. Utilizing large-scale GWAS data from the UK Biobank; FinnGen databases and Decode database, we assessed the causal relationships between 16 micronutrients concentration and AAA risk and analyzed potential mechanisms mediated by plasma proteins. Strict statistical methods were used to select genetic instrumental variables, and multivariable MR analyses were conducted to dissect direct and indirect effects. Genetically predicted calcium and zinc levels showed nominally significant associations with AAA risk (IVW Ca: OR 2.32, 95% CI 1.04–5.18, p = 0.04; IVW Zn: OR 1.24, 95% CI 1.05–1.47, p = 0.01). Proteome-wide MR analyses identified several AAA-associated plasma proteins. Among the zinc-related analyses, inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2) was identified as a partial and preliminary mediating factor for the zinc-AAA association. The mediation analysis suggested a modest mediated proportion through ITIH2 (4.65%, 95% CI 0.701%-8.59%). These findings should be interpreted cautiously because the zinc analysis was based on two instrumental variables and the primary micronutrient screen was exploratory. This study provides suggestive genetic evidence that calcium and zinc may be associated with AAA risk. In addition, ITIH2 may act as a partial and preliminary mediator of the zinc-AAA association, although the mediated proportion was modest and the evidence requires validation in larger datasets. These results highlight the need for further investigation of micronutrients, plasma proteins, and AAA biology before clinical translation.