Magnesium Treatment on Methylation Changes of Transmembrane Serine Protease 2 (TMPRSS2)

Fan, L.; Zhu, X.; Zheng, Y.; Zhang, W.; Seidner, D. L.; Ness, R.; Murff, H. J.; Yu, C.; Huang, X.; Shrubsole, M. J.; Hou, L.; Dai, Q.

Background: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike (S) protein priming. Objectives: To test the hypothesis that Mg treatment leads to DNA methylation changes in TMPRSS2. Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2x2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. Results: We found that 12-week of personalized Mg treatment significantly increased 5-mC methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to placebo arm (decreased by 0.1%) in those aged < 65 years old. The difference remained statistically significant after adjusting for age, sex and baseline methylation as well as FDR correction (FDR-adjusted P=0.014). Additionally, Mg treatment significantly reduced 5-hmC level at cg26337277 (close proximity to TSS200 and 5'UTR, promoter) by 2.3% compared to increases by 7.1% in the placebo arm after adjusting for covariates in those aged < 65 years old (P=0.003). The effect remained significant at FDR of 0.10 (adjusted P value=0.088). Conclusion: Among individuals aged younger than 65 years with the Ca:Mg intake ratios equal to or over 2.6, reducing Ca:Mg ratios to around 2.3 increased 5-mC modifications (i.e. cg16371860) and reduced 5-hmC modifications (i.e. cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention for the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.