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Distribution and Functional Consequences of Nucleotide Polymorphisms in the 3'-Untranslated Region of the Human Sep15 Gene¹

Departments of Human Nutrition and Dietetics [Y. J. H., A. M. D.], Surgical Oncology [R. M.], and Hematology/Oncology [W. S.], University of Illinois at Chicago, Chicago, Illinois 60612; Department of Biochemistry, University of Nebraska, The Beadle Center, Lincoln, Nebraska 68588 [K. V. K., V. N. G.]; Section on the Molecular Biology of Selenium, Basic Research Laboratory, National Cancer Institute, NIH, Bethesda, Maryland 20892 [D. L. H.]; Department of Genetic Epidemiology, National Human Genome Center, Howard University, Washington DC 20059 [C. N. R.]; Department of Preventive Medicine and Epidemiology, Loyola University, Stritch School of Medicine, Maywood, Illinois 60153 [A. L., T. E. P., R. S. C.]; and Department of Medicine [E. E. V., M. E. D.], University of Chicago, Chicago, Illinois 60637

Selenium has been shown to prevent cancer in a variety of animal model systems. Both epidemiological studies and supplementation trials have supported its efficacy in humans. However, the mechanism by which selenium suppresses tumor development remains unknown. Selenium is present in known human selenoproteins as the amino acid selenocysteine (Sec). Sec is inserted cotranslationally in response to UGA codons within selenoprotein mRNAs in a process requiring a sequence within the 3'-untranslated region (UTR), referred to as a Sec insertion sequence (SECIS) element. Recently, a human M_r 15,000 selenoprotein (Sep15) was identified that contains an in-frame UGA codon and a SECIS element in the 3'-UTR. Examination of the available cDNA sequences for this protein revealed two polymorphisms located at position 811 (C/T) and at position 1125 (G/A) located within the 3'-UTR. Here, we demonstrate significant differences in Sep15 allele frequencies by ethnicity and that the identity of the nucleotides at the polymorphic sites influences SECIS function in a selenium-dependent manner. This, together with genetic data indicating loss of heterozygosity at the Sep15 locus in certain human tumor types, suggests that Sep15 may be involved in cancer development, risk, or both.

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