Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Participants who have the GG genotype will be assigned to magnesium glycinate.

Participants who have the GG genotype will be assigned to placebo group

Participants who have the GA/AA genotype will be assigned to magnesium glycinate

Participants who have the GA/AA genotype will be assigned to placebo group

Oral administration of magnesium glycinate daily for 12 weeks

Magnesium glycinate

Oral administration of identical-appearing placebo daily for 12 weeks

Placebo

Qi Dai, MD, PhD

Chang Yu, PhD

Martha J Shrubsole, Ph.D.

Colorectal cancer is the fourth most common incident cancer and the second most common cause of cancer death in the United States, with approximately 150,000 new cases and 57,000 deaths per year. High calcium intake and magnesium may protect against colorectal cancer and adenoma, however, results have been inconsistent. We found that genetic makeup, associated with magnesium absorption and re-absorption, significantly interacted with the calcium and magnesium ratio in relation to the both adenomatous and hyperplastic polyps. Participants who carried at least one 1482Ile allele (G-\>A)of TRPM7 and who consumed diets with a high calcium/magnesium ratio were at a higher risk of adenoma and hyperplastic polyps than were participants who did not carry the polymorphism. We hypothesize that the reduction in the dietary Ca/Mg ratio may change the markers directly related to tumorigenesis. The primary aims of this study are to conduct a randomized placebo-controlled intervention trial to test whether reducing the Ca/mg intake ratio through magnesium supplementation has effects on the related biomarkers. We will also examine whether the effect of modulating Ca/Mg intake ratio may be more pronounced among those who carry the 1482Ile allele compared those who don't carry the 1482Ile allele. Results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies to prevent occurrence of colorectal adenoma, and thus, colorectal cancer through dietary change or nutritional fortification.

Precision-Based Magnesium Trial

Personalized Prevention of Colorectal Cancer Trial (PPCCT)

TRPM7 and MLKL have been detected using immunohistochemical (IHC) techniques.

Ki67:BAX and Ki67:TUNEL have been analyzed using immunohistochemical (IHC) techniques.

Cox2 has been analyzed using immunohistochemical (IHC)

Serum magnesium concentration was determined using 7D70 Magnesium Reagent Kit from Abbot Laboratories (Abbott Park, IL) the assay was conducted at the Vanderbilt Pathology Laboratory Services.

Body magnesium status obtained using magnesium tolerance test (MTT)

Assays of CRP for 180 participants were performed using immuno turbidimetric immunoassay based commercial assay kits (Pointe Scientific, Inc, Canton, MI) at Vanderbilt Lipid Laboratory

Urinary PGE-M level was measured using a liquid chromatography/tandem mass spectrometric method at the Integrated Health Sciences Facility Core of the Vanderbilt Center in Molecular Toxicology.

Vanderbilt University Medical Center

Professor

Micronutrients

All Drugs and Chemicals

Bone Density Conservation Agents

Vitamins

Vitamin D

Cholecalciferol

Vitamin D3

Calciferol

Participants who have the GG genotype will be assigned to magnesium glycinate

One striking observation is that a large portion of the inter-person variation in serum 25-hydroxyvitamin D (25(OH)D) levels is unexplained. In vitro and in vivo studies indicate vitamin D synthesizing and metabolizing enzymes are Mg-dependent. Magnesium (Mg) supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. The investigators reported in 2013 from observational studies conducted in the general US population that Mg intake significantly interacted with vitamin D intake in affecting vitamin D status as well as interacted with serum 25(OH)D in risk of cardiovascular disease mortality and, maybe, colorectal cancer mortality. The potential interaction between Mg and vitamin D was supported by two subsequent studies, including a Finnish cohort study and a mouse study.

In the parent study (Personalized Prevention of Colorectal Cancer Trial, NCT01105169), the investigators proposed to measure blood concentration of total 25(OH)D as a secondary aim using Elisa approach. However, following the novel finding of Mg-vitamin D interaction published by the investigators in 2013, they submitted a separate grant application to NCI which was funded in 2014. In the new study, the investigators proposed to use a LC-MS approach, which is more accurate and specific than an Elisa method, to measure 5 vitamin D metabolites. This new ancillary study allows the investigators to evaluate whether Mg supplementation differentially affects vitamin D synthesis and metabolism dependent on baseline serum 25(OH)D levels using existing biospecimens collected in our double-blind placebo-controlled randomized chemoprevention trial.

Magnesium Treatment on Vitamin D Metabolism in Participants Completed Personalized Prevention of Colorectal Cancer Trial

Effect of Magnesium Treatment on Vitamin D Resistance

25-Hydroxyvitamin D3 was extracted from plasma by liquid extraction and measured by using a novel liquid chromatography-mass spectrometry (LC-MS) method.

25-Hydroxyvitamin D3 was extracted from plasma by liquid extraction, and measured by using a novel liquid chromatography-mass spectrometry (LC-MS) method

24,25-dihydroxyvitamin D3 was extracted from plasma by liquid extraction, and detected by using a novel liquid chromatography-mass spectrometry (LC-MS) method.

1,25-dihydroxyvitamin D3 was extracted from plasma using ALPCO immunoextraction kit following manufacturer's protocols. It was detected by a liquid chromatography-mass spectrometry (LC-MS) method.

1,25-dihydroxyvitamin D2 were extracted from plasma using ALPCO immunoextraction kit following manufacturer's protocols. It was detected by a liquid chromatography-mass spectrometry (LC-MS) method.

Research Associate Professor

Symptoms and General Pathology

Inflammation

Calcium

Calcium, Dietary

Martha Shrubsole, PhD

In addition to microbiota-host interaction on inflammatory response, many enzymes, including three enzymes critical in gluconeogenesis and transport of amino acids and carbohydrates in energy metabolism, are dependent on the Ca/Mg ratio, indicating critical roles of the Ca/Mg ratio in carbohydrate fermentation and energy metabolism in bacteria. In pilot metagenomic study conducted by the investigators, they found all the significantly changed biologic functions within the microbial community caused by a reduction in the Ca/Mg ratio are biologically dependent on the Ca/Mg ratio or Mg. It is striking that the functions with significant changes in stool samples were centered on the fermentation of carbohydrates and energy metabolism while the functions in rectal swabs were related to immune response. Tissue also had a distinct profile from stool and swab.

These findings have very broad clinical and public health significance for many inflammation-related diseases or metabolic disorders. Due to the small sample size in the pilot study, the investigators plan to confirm these findings using the biospecimens collected in the parent study (Personalized Prevention of Colorectal Cancer Trial, NCT01105169).

Calcium: Magnesium Balance, Microbiota, and Necroptosis and Inflammation

Conduct high-throughput quantitative PCR for Bifidobacterium and Lactobacillus in stool, rectal swab, and rectal mucosa samples

Conduct immunohistochemistry for necroptosis-related biomarkers in rectal mucosa samples

Research Professor

Nutritional and Metabolic Diseases

Colonic Neoplasms

Magnesium Deficiency

Deficiency Diseases

Malnutrition

Nutrition Disorders

Herbal and Botanical

Cola

Based on the magnesium (Mg) tolerance test, the "gold standard" test of Mg status, more than 50% US participants had Mg deficiency. Observations suggest that the associations between high Mg intake and disease risks may completely differ by the underlying Mg status. Due to major limitations, the Mg tolerance test is not used in conventional clinical practice and rarely used in research. Instead, serum Mg is used for clinical diagnosis. However, serum Mg performs very poorly at identifying those with Mg deficiency. There is a great need to develop implementable, sensitive, and specific biomarkers which can be easily used for identifying people with Mg deficiency.

It is known that DNA methylation changes are inducible by environmental exposures, including nutrients, and reversible when the exposure disappears. We propose to identify 5-hmC/5-mC biomarkers for Mg deficiency by a 4- phase EWAS study in the "Personalized Prevention of Colorectal Cancer Trial \[PPCCT, R01CA149633; PI, Dai \& Yu\]" with a total of 240 participants. Mg tolerance test will be used as the gold standard. Finally, using newly identified biomarkers, we will evaluate if 12-week Mg treatment reduces TRPM7 expression, essential in Mg homeostasis and colorectal carcinogenesis, in rectal tissues only among those with Mg deficiency.

Methylomic Biomarkers for Magnesium Deficiency in the Personalized Prevention of Colorectal Cancer Trial

Methylomic Biomarkers for Magnesium Deficiency and Colon Neoplasia Prevention

DNA was extract from WBC samples and measured by using TAB-Seq \& TAB-Array protocol

Plasma SAM, SAH, homocysteine and methionine measured by stable-isotope dilution liquid chromatography-electrospray tandem mass spectrometry (LC-ESI-MS/MS)

Professor of Medicine

Participants will be assigned to magnesium glycinate

Participants will be assigned to placebo group

Between 2000 and 2015, mortality due to Alzheimer's disease (AD) increased by 123%. No drugs have yet been approved to stop or slow the progression of AD. A delay of five years in the expression of AD would reduce the incidence rate by half. Thus, it is critical to develop novel prevention strategies to delay the onset of this common disease.

As an ancillary study conducted within a precision-based randomized trial (R01CA149633; PI, Dai \& Yu\]"), the investigators reduced Ca:Mg ratios to 2.3 through 3-month personalized Mg supplementation among those who consumed high Ca:Mg ratio diet, but otherwise in good general health. The investigators test the hypothesis that actively reducing the Ca:Mg ratio among those aged \>65 years who consume high Ca:Mg ratio diets improves cognitive function compared to the placebo arm. The investigators further conduct molecular epidemiologic studies to understand the molecular mechanisms.

Ca:Mg Ratio and Cognitive Function

Ca:Mg Ratio and Cognitive Function in the Personalized Prevention of Colorectal Cancer Trial

Montreal Cognitive Assessment (MoCA) Scoring: The test consists of 30 items, and each item is worth one point, resulting in a maximum score of 30. A higher score indicates better cognitive functioning.

The changes of MoCA score=Score at 12 weeks minus Score at baseline.

5-mC methylation (CpG sites) in Apolipoprotein E (APOE) were measure by TET-assisted bisulfite (TAB)-Array.

5-mC methylation changes=value at 12 weeks minus value at baseline.

National Cancer Institute (NCI)

The definition of adverse event and/or serious adverse event is from the clinicaltrials.gov Definitions.

We conducted safety and compliance calls to collect adverse event data.

Magnesium glycinate: Oral administration of magnesium glycinate daily for 12 weeks

Participants Were Assigned to Magnesium Glycinate

Placebo: Oral administration of identical-appearing placebo daily for 12 weeks

Participants Were Assigned to Placebo

Participants Will be Assigned to Magnesium Glycinate

Participants Will be Assigned to Placebo

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Measure Description: Cognitive function was measured by the Montreal Cognitive Assessment (MoCA) which is used to evaluate people with memory loss or other symptoms of cognitive decline. Scores on the MoCA range 0-30. Higher values represent a better outcome. A score of 26 or above is considered normal.

Overall MoCA Score at Baseline

Dr. Qi Dai

IRB approval was obtained to add the MoCA component on Dec.11 2012. From Dec. 12, 2012 to Jan 30, 2016, 129 participants enrolled the study. Among them, 123 (95.3%) completed pre-and post- treatment MoCA were included in the analysis.

Overall Score Changes From Baseline by Magnesium Treatment vs. Placebo

123 participants who completed both pre- and post-treatment MoCA tests are included in the analysis.

Overall Score Changes From Baseline by Magnesium Treatment vs. Placebo (Aged ≤65 Years Old)

123 participants who completed pre-and post- treatment MoCA were included in the analysis.

Overall Score Changes From Baseline by Magnesium Treatment vs. Placebo (Aged >65 Years Old)

cg18768621

cg13496662

123 participants who completed both pre- and post-treatment MoCA tests were included in the analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Precision-Based Magnesium Trial	NCT01105169	Colorectal Canc...	Magnesium glyci... Placebo	40 Years - 85 Years	Vanderbilt University Medical Center
Magnesium Treatment on Vitamin D Metabolism in Participants Completed Personalized Prevention of Colorectal Cancer Trial	NCT03265483	Colorectal Canc...	Magnesium glyci... Placebo	40 Years - 85 Years	Vanderbilt University Medical Center
Magnesium Treatment on Vitamin D Metabolism in Participants Completed Personalized Prevention of Colorectal Cancer Trial	NCT03265483	Colorectal Canc...	Magnesium glyci... Placebo	40 Years - 85 Years	Vanderbilt University Medical Center
Calcium: Magnesium Balance, Microbiota, and Necroptosis and Inflammation	NCT04229992	Colorectal Canc...	Magnesium glyci... Placebo	40 Years - 85 Years	Vanderbilt University Medical Center
Methylomic Biomarkers for Magnesium Deficiency in the Personalized Prevention of Colorectal Cancer Trial	NCT04196803	Colorectal Canc...	Magnesium glyci... Placebo	40 Years - 85 Years	Vanderbilt University Medical Center
Ca:Mg Ratio and Cognitive Function	NCT04196023	Cognitive Funct...	Magnesium glyci... Placebo	40 Years - 85 Years	Vanderbilt University Medical Center
Methylomic Biomarkers for Magnesium Deficiency in the Personalized Prevention of Colorectal Cancer Trial	NCT04196803	Colorectal Canc...	Magnesium glyci... Placebo	40 Years - 85 Years	Vanderbilt University Medical Center

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