Genetic determinants of micronutrient levels and their causal impact on osteonecrosis of the femoral head: A 2-sample Mendelian randomization study

Osteonecrosis of the femoral head (ONFH) is a debilitating condition with unclear pathophysiology. Micronutrients are implicated in bone health, but their causal relationship with ONFH remains uncertain. This study aims to investigate the potential causal relationship between circulating levels of 15 micronutrients and the risk of ONFH using a 2-sample Mendelian randomization (MR) approach. The objective was to determine whether circulating levels of specific micronutrients (copper, calcium, carotene, folate, iron, magnesium, potassium, selenium, vitamin A, vitamin B12, vitamin B6, vitamin C, vitamin D, vitamin E, and zinc) have a causal impact on the risk of ONFH. This study employed a 2-sample MR approach using summary-level data from 15 genome-wide association studies (GWAS) focused on micronutrient exposures and 1 GWAS for ONFH. The study adhered to 3 fundamental MR assumptions and used the inverse variance weighting method as the primary analysis method, supplemented by MR-Egger regression and MR-PRESSO to assess heterogeneity and pleiotropy. To minimize population stratification bias, the study included only individuals of European descent. The primary finding was a significant association between genetically predicted higher levels of potassium and a reduced risk of ONFH (OR = 0.440, 95% confidence interval (CI) 0.2012-0.959, P = .039 per 1 standard deviation). No other micronutrients showed significant associations with ONFH risk. Sensitivity analyses, including MR-Egger regression and leave-one-out analysis, confirmed the robustness of these findings. Our findings indicate a significant association between genetically predicted higher potassium levels and a reduced risk of ONFH in individuals of European descent, while no other micronutrients demonstrated significant associations. Sensitivity analyses confirmed these results, suggesting a potential protective role of potassium in ONFH.