Grant: $100,001 - Department of Health and Human Services - Aug. 24, 2009
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Award Description: ARRA - Human Requirements for the Nutrient Choline. Choline is an essential nutrient that is derived from the diet, as well as from de novo synthesis of phosphatidylcholine catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). The human dietary requirement for choline has significant individual variation and is modulated by estrogen and common genetic polymorphisms. During the last 7 years of our ongoing clinical study (DK55865), we established that, when deprived of dietary choline, almost 80% of men and postmenopausal women developed fatty liver or muscle damage, while only 43% of premenopausal women developed such signs of organ dysfunction. We found that the promoter for the PEMT gene is estrogen responsive which may explain why premenopausal women are more resistant to developing organ dysfunction when fed a choline depletion diet. Moreover, postmenopausal women with a common (almost 75% of the population have one variant allele) single nucleotide polymorphism (SNP) in the promoter region of the PEMT gene (rs12325817), that abrogates estrogen induction of the gene by estrogen, had a greatly increased likelihood (odds ratio=42, p=0.03) of developing signs of choline deficiency when choline was removed from their diet. Thus this common SNP increases the dietary requirement for choline. We observed that the PEMT rs12325817 snp is abnormally distributed between premenopausal and postmenopausal subjects who we are eligible for and have been enrolled into the human choline study. Specifically, in the first cohort of subjects (n = 57) enrolled duirng the first 5 years of funding, 42 (74%) individuals carried at least one allele of this SNP, and 10 (18%) were homozygous. However, there was a discrepancy in the distribution pattern of homozygotes. Seven out of 26 men (26%) and 2 out of 16 premenopausal women (13%) carried two copies of the polymorphism, while only 1 out of 15 postmenopausal women (7%) was homozygous. As we only enrolled a small number of pre- and postmenopausal women, this pattern could have arisen by chance. Thus in the current funded study (last 2 years of funding), we have been deliberately seeking out pre- and postmenopausal women who are carriers of this SNP. To date, we are once again finding an unbalanced distribution pattern of homozygotes for this SNP with respect to menopausal status. We are observing that approximately 16% of the screened premenopausal subjects are homozygous for the PEMT rs12325817 SNP, but thus far have only been able to identify 1 postmenopausal woman (out of 47 screened; 2%) with this genotype. Both studies have used the same extensive and stringent set of eligibility criteria. We hypothesize that one or more of our exclusion criteria must be co-presenting with the homozygous genotype in postmenopausal women and would like to explore this further within the scope of our current study. We assume that there is an underlying reason to explain why the homozygous genotype occurs at a greater frequency in men and premenopausal women who are eligible for our study than in postmenopausal women. We do not believe that postmenopausal women with this SNP have higher mortality, and suggest that one or more of the rigorous set of eligibility criteria for the study is excluding them. The aim of this supplemental study is to identify the phenotype that is associated with homozygosity of the PEMT rs12325817 SNP in postmenopausal women and increase our understanding of the physiological role that the PEMT enzyme has on health, particularly after menopause.
Project Description: Since the start of this award, we have been able to allocate personnel to serve as study coordinator/project manager (Leslie Fischer) and a research technician, Hye Mee Hwang. We have also taken on a graduate student in the Nutrition Department (Caroline Um) to serve as a research assistant. We have developed all of the necessary study materials for this protocol including the consent form, recruitment flyer, telephone pre-screening script and medical history questionnaire, and have acquired IRB approval for the project. We have also begun training the research assistant in study procedures, including recruitment and data collection methods. We are currently contacting individuals who had previously expressed an interest in the adult choline study but were either deemed ineligible or declined to participate for any reason. Thus far, we have attempted to telephone 100 prospective subjects and have 11 scheduled for study visits. Our first subject is slated to participate in this study on October, 6, 2009. Once we have enrolled the first few subjects and have worked out any unforeseen issues that may arise, we will intensify our recruiting efforts and will begin advertising the study with mass informational emails and fliers placed in strategic locations around the community. We anticipate that our subject accrual rate will increase once these measures are taken.
Jobs Summary: This report shows zero jobs created because there were zero project expenditures as of 9/30/2009. The narrative below provides an estimate/description of jobs that will be created/retained once the project is begun. Jobs created/retained estimate: 0.213 Narrative: Study Coordinator ? to oversee and manage all aspects of the study including preparing regulatory documents, recruiting 250 subjects and screening them for eligibility, conducting study visits, and collecting/entering data. Research Technician ? to process and analyze all collected specimens, including DNA extraction from lymphocyte samples and conducting genotyping assays to determine which SNPs each subject carries. She will also be involved with data entry and data analysis. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 24, 2009. Help expand these official descriptions using the wiki below.