DHFR 19 bp Deletion Polymorphism and Folic Acid Utilization

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.

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Key information

Conditions

Characterize rs70991108 Polymorphism of DHFR Gene

Age range

21 year–45 year

Sex eligibility

Female

Study type

Observational

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Primary outcomes

DHFR mRNA and protein abundance

Time frame: 1 year

DHFR mRNA and protein abundance determined for the 19 bp deletion genotypes

Secondary outcomes

Reactions of folate pathway

Time frame: 1 year

Effect of DHFR 19bp deletion on reactions of folate pathway determined in cell culture conditions

Sponsors and collaborators

Lead sponsor

Tufts University

Other

Registry information

Important dates

Study start: 2013
Primary completion: 2015
Study completion: 2015
First posted: Oct 24, 2017
Registry last updated: Oct 24, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.