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DHFR 19 bp Deletion Polymorphism and Folic Acid Utilization

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03319979
Recruitment Status : Completed
First Posted : October 24, 2017
Last Update Posted : October 24, 2017
Information provided by (Responsible Party):
Tufts University

Brief Summary:
A genetic variation in the gene for the protein dihydrofolate reductase (DHFR) that is necessary to utilize folic acid (a synthetic form of the B vitamin folate found in supplements and fortified food), increases the risk for breast cancer in multivitamin users and, when present in mothers who used folic acid supplements during pregnancy, increases the risk for cancer of the eye of their children. The aim of the proposed research is to understand how a common genetic variation in the gene for DHFR affects the function of this protein and the ability of the body to use folic acid.

Condition or disease
Characterize rs70991108 Polymorphism of DHFR Gene

Detailed Description:
A 19bp deletion polymorphism of intron 1 of dihydrofolate reductase (DHFR 19bpdel) increases the risk for breast cancer, and retinoblastoma of the offspring, in folic acid supplement users. Folic acid is a synthetic form of folate present in fortified foods and supplements that must be converted to tetrahydrofolate by DHFR to enter the metabolism. Individuals homozygous for DHFR 19bpdel have higher prevalence of unmetabolized folic acid in plasma and lower incorporation of folic acid into tissues. How the DHFR19bpdel (17% homozygosity in US) affects DHFR activity and folate metabolism to increase cancer risk is not understood. Studies on this topic are urgent in the light of mandatory folic acid fortification in the US and other countries. The objective of this project is to characterize the effect of DHFR 19bpdel on DHFR activity and folate pathway reactions and to determine if the effect of DHFR 19bpdel can be alleviated with folinic acid, which is a folate source that need not be converted by DHFR. The specific aims of this project are to 1] Determine expression of DHFR mRNA and protein, splicing of intron 1 and enzyme activity in white blood cells from 3 DHFR genotypes. 2] Determine the effect of DHFR 19bpdel and folic acid or folinic acid concentration on cell growth, and folate pathway reactions in white blood cells in homozygotes for DHFR 19bpdel and those who lack the polymorphism. Results of this study will guide measures to reduce this modifiable cancer risk associated with DHFR 19bpdel.

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Study Type : Observational
Actual Enrollment : 117 participants
Observational Model: Ecologic or Community
Time Perspective: Cross-Sectional
Official Title: DHFR 19 bp Deletion Polymorphism and Folic Acid Utilization
Study Start Date : February 2013
Actual Primary Completion Date : March 2015
Actual Study Completion Date : March 2015

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. DHFR mRNA and protein abundance [ Time Frame: 1 year ]
    DHFR mRNA and protein abundance determined for the 19 bp deletion genotypes

Secondary Outcome Measures :
  1. Reactions of folate pathway [ Time Frame: 1 year ]
    Effect of DHFR 19bp deletion on reactions of folate pathway determined in cell culture conditions

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pre-menopausal women
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Healthy pre-menopausal females aged 21-45 from Metro Boston area

Inclusion Criteria:

  • Adult premenopausal women aged 21-45 in general good health, non-pregnant, minimum weight of 110 pounds.

Exclusion Criteria:

  • Smoking, a terminal illness, any known chronic illness, rheumatoid arthritis, heart, kidney, liver or gastrointestinal disease requiring treatment, antifolate medications, metformin use.
  • More than 2 drinks a day.
  • Pregnant women have different metabolism when compared to other adults hence they will not be included in the study.
  • Non-English speaking subjects will be excluded since the study involves a computer based diet history questionnaire in English. The budget for this project does not include the cost of an interpreter.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03319979

Sponsors and Collaborators
Tufts University
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Principal Investigator: Ligi Paul, Ph.D. Tufts University
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Responsible Party: Tufts University Identifier: NCT03319979    
Other Study ID Numbers: ORA# 1211023
First Posted: October 24, 2017    Key Record Dates
Last Update Posted: October 24, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Tufts University:
Folate, DHFR