Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2)

Lei Fan; Xiangzhu Zhu; Yinan Zheng; Wei Zhang; Douglas L. Seidner; Reid Ness; Harvey J. Murff; Chang Yu; Xiang Huang; Martha J. Shrubsole; Lifang Hou; Qi Dai

doi:10.1016/j.nut.2021.111340

Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2)

Lei Fan, Xiangzhu Zhu, Yinan Zheng, Wei Zhang, Douglas L. Seidner, Reid Ness, Harvey J. Murff, Chang Yu, Xiang Huang, Martha J. Shrubsole, Lifang Hou, Qi Dai^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Objectives: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2. Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Results: We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5′ untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088). Conclusions: Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.

Original language	English (US)
Article number	111340
Journal	Nutrition
Volume	89
DOIs	https://doi.org/10.1016/j.nut.2021.111340
State	Published - Sep 2021

Keywords

COVID-19
Magnesium
Methylation changes
SARS-CoV-2
TMPRSS2

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Nutrition and Dietetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.nut.2021.111340

Cite this

@article{b4356c88a08f4849b0abcf6bd1c322ce,

title = "Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2)",

abstract = "Objectives: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2. Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Results: We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5′ untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088). Conclusions: Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.",

keywords = "COVID-19, Magnesium, Methylation changes, SARS-CoV-2, TMPRSS2",

author = "Lei Fan and Xiangzhu Zhu and Yinan Zheng and Wei Zhang and Seidner, {Douglas L.} and Reid Ness and Murff, {Harvey J.} and Chang Yu and Xiang Huang and Shrubsole, {Martha J.} and Lifang Hou and Qi Dai",

note = "Funding Information: This study was supported by R01 CA149633 (to Qi Dai and Chang Yu) and R01 CA202936 (to Qi Dai and Lifang Hou) from the National Cancer Institute, Department of Health and Human Services, as well as the Ingram Cancer Center Endowment Fund. Data collection, sample storage, and processing were partially conducted by the Survey and Biospecimen Shared Resource, which is supported in part by P30CA68485. Clinical visits to the Vanderbilt Clinical Research Center were supported in part by the Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. The parent study data were stored in Research Electronic Data Capture (REDCap), and data analyses (VR12960) were supported in part by the Vanderbilt Institute for Clinical and Translational Research (UL1TR000445). All authors have no conflicts of interest. The Personalized Prevention of Colorectal Cancer Trial (PPCCT) was registered at clinicaltrials.gov as NCT01105169. Funding Information: This study was supported by R01 CA149633 (to Qi Dai and Chang Yu) and R01 CA202936 (to Qi Dai and Lifang Hou) from the National Cancer Institute, Department of Health and Human Services, as well as the Ingram Cancer Center Endowment Fund. Data collection, sample storage, and processing were partially conducted by the Survey and Biospecimen Shared Resource, which is supported in part by P30CA68485. Clinical visits to the Vanderbilt Clinical Research Center were supported in part by the Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. The parent study data were stored in Research Electronic Data Capture (REDCap), and data analyses (VR12960) were supported in part by the Vanderbilt Institute for Clinical and Translational Research (UL1TR000445). All authors have no conflicts of interest. The Personalized Prevention of Colorectal Cancer Trial (PPCCT) was registered at clinicaltrials.gov as NCT01105169. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = sep,

doi = "10.1016/j.nut.2021.111340",

language = "English (US)",

volume = "89",

journal = "Nutrition",

issn = "0899-9007",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2)

AU - Fan, Lei

AU - Zhu, Xiangzhu

AU - Zheng, Yinan

AU - Zhang, Wei

AU - Seidner, Douglas L.

AU - Ness, Reid

AU - Murff, Harvey J.

AU - Yu, Chang

AU - Huang, Xiang

AU - Shrubsole, Martha J.

AU - Hou, Lifang

AU - Dai, Qi

N1 - Funding Information: This study was supported by R01 CA149633 (to Qi Dai and Chang Yu) and R01 CA202936 (to Qi Dai and Lifang Hou) from the National Cancer Institute, Department of Health and Human Services, as well as the Ingram Cancer Center Endowment Fund. Data collection, sample storage, and processing were partially conducted by the Survey and Biospecimen Shared Resource, which is supported in part by P30CA68485. Clinical visits to the Vanderbilt Clinical Research Center were supported in part by the Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. The parent study data were stored in Research Electronic Data Capture (REDCap), and data analyses (VR12960) were supported in part by the Vanderbilt Institute for Clinical and Translational Research (UL1TR000445). All authors have no conflicts of interest. The Personalized Prevention of Colorectal Cancer Trial (PPCCT) was registered at clinicaltrials.gov as NCT01105169. Funding Information: This study was supported by R01 CA149633 (to Qi Dai and Chang Yu) and R01 CA202936 (to Qi Dai and Lifang Hou) from the National Cancer Institute, Department of Health and Human Services, as well as the Ingram Cancer Center Endowment Fund. Data collection, sample storage, and processing were partially conducted by the Survey and Biospecimen Shared Resource, which is supported in part by P30CA68485. Clinical visits to the Vanderbilt Clinical Research Center were supported in part by the Vanderbilt CTSA grant UL1 RR024975 from NCRR/NIH. The parent study data were stored in Research Electronic Data Capture (REDCap), and data analyses (VR12960) were supported in part by the Vanderbilt Institute for Clinical and Translational Research (UL1TR000445). All authors have no conflicts of interest. The Personalized Prevention of Colorectal Cancer Trial (PPCCT) was registered at clinicaltrials.gov as NCT01105169. Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/9

Y1 - 2021/9

N2 - Objectives: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2. Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Results: We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5′ untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088). Conclusions: Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.

AB - Objectives: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2. Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Results: We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5′ untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088). Conclusions: Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.

KW - COVID-19

KW - Magnesium

KW - Methylation changes

KW - SARS-CoV-2

KW - TMPRSS2

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U2 - 10.1016/j.nut.2021.111340

DO - 10.1016/j.nut.2021.111340

M3 - Article

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AN - SCOPUS:85108733192

SN - 0899-9007

VL - 89

JO - Nutrition

JF - Nutrition

M1 - 111340

ER -

Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2)

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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