Plasma metal concentrations and their interactions with genetic susceptibility on homocysteine levels

Limited studies have evaluated the associations of multiple metal exposures with homocysteine (Hcy) levels, which were independent risk factor for cardiovascular disease (CVD). Furthermore, the interactions between genetic variants and plasma metals in relation to Hcy levels were largely unknown. We aimed to explore the associations of multiple plasma metals (including metalloids arsenic [As] and selenium [Se]) with Hcy levels and whether their associations were modified by genetic susceptibility. We included 2989 participants from the baseline of the Dongfeng-Tongji cohort (DFTJ cohort) and conducted a cross-sectional study to explore the associations of 17 plasma metals with serum Hcy levels. Both multi-variable linear regression model (single-metal model) and LASSO penalized regression model (multiple-metal model) were used to identify the Hcy-associated metals. The weighted genetic risk score (GRS) was calculated based on 18 established Hcy-associated genetic variants. For metals that were associated with Hcy, we further assessed the gene-metal interactions on Hcy levels. Among 17 metals, plasma molybdenum (Mo), strontium (Sr), and Zinc (Zn) were positively associated with Hcy levels, whereas Se was inversely associated with Hcy levels in both single- and multiple-metal models. We also observed that the genetic predisposition to Hcy significantly modified the association between plasma Se and serum Hcy levels (P for interaction = 0.003), while no significant gene-metal interactions were found for Mo, Sr, and Zn (all P for interactions > 0.05). These findings provide novel insight into the associations of the plasma concentrations of Mo, Se, Sr and Zn with Hcy levels and address the importance of Se as a potential upstream modifiable factor for the personalized prevention of elevated Hcy levels and CVD.