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Case-control study of vitamin D, dickkopf homolog 1 (DKK1) gene methylation, VDR gene polymorphism and the risk of colon adenoma in African Americans.

ABSTRACT: There are sparse data on genetic, epigenetic and vitamin D exposure in African Americans (AA) with colon polyp. Consequently, we evaluated serum 25(OH) D levels, vitamin D receptor (VDR) polymorphisms and the methylation status of the tumor suppressor gene dickkopf homolog 1 (DKK1) as risk factors for colon polyp in this population.The case-control study consisted of 93 patients with colon polyp (cases) and 187 healthy individuals (controls) at Howard University Hospital. Serum levels of 25(OH)D (including D3, D2, and total) were measured by liquid chromatography-mass spectrometry. DNA analysis focused on 49 single nucleotide polymorphisms (SNPs) in the VDR gene. Promoter methylation analysis of DKK1 was also performed. The resulting data were processed in unadjusted and multivariable logistic regression analyses.Cases and controls differed in vitamin D status (D(3)<50 nmol/L: Median of 35.5 in cases vs. 36.8 in controls nmol/L; P?=?0.05). Low levels of 25(OH)D(3) (<50 nmol/L) were observed in 86% of cases and 68% of controls and it was associated with higher risks of colon polyp (odds ratio of 2.7, 95% confidence interval 1.3-3.4). The SNP analysis showed no association between 46 VDR polymorphisms and colon polyp. The promoter of the DKK1 gene was unmethylated in 96% of the samples.We found an inverse association between serum 25(OH)D(3) and colon polyp in AAs. VDR SNPs and DKK1 methylation were not associated with colon polyp. Vitamin D levels may in part explain the higher incidence of polyp in AAs.

SUBMITTER: Ashktorab H

PROVIDER: S-EPMC3192764 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Case-control study of vitamin D, dickkopf homolog 1 (DKK1) gene methylation, VDR gene polymorphism and the risk of colon adenoma in African Americans.

Ashktorab Hassan H Nguza Bijou B Fatemi Mehrnaz M Nouraie Mehdi M Smoot Duane T DT Schäffer Alejandro A AA Kupfer Sonia S SS Camargo Carlos A CA Brim Hassan H

PloS one 20111013 10

<h4>Background</h4>There are sparse data on genetic, epigenetic and vitamin D exposure in African Americans (AA) with colon polyp. Consequently, we evaluated serum 25(OH) D levels, vitamin D receptor (VDR) polymorphisms and the methylation status of the tumor suppressor gene dickkopf homolog 1 (DKK1) as risk factors for colon polyp in this population.<h4>Methods</h4>The case-control study consisted of 93 patients with colon polyp (cases) and 187 healthy individuals (controls) at Howard Universit ...[more]

PMID: 22022386

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Project description:BACKGROUND & AIMS:African Americans have the greatest colorectal cancer (CRC) burden in the United States; interethnic differences in protective effects of vitamin D might contribute to disparities. 1?,25(OH)2D3 vitamin D (the active form of vitamin D) induces transcription of the uridine phosphorylase gene (UPP1) in colon tissues of European Americans but to a lesser extent in colon tissues of African Americans. UPP1-knockout mice have increased intestinal concentrations of uridine and Deoxyuridine triphosphate (dUTP), have increased uridine-induced DNA damage, and develop colon tumors. We studied 1?,25(OH)2D3 regulation of UPP1 and uridine-induced DNA damage in the colon and differences in these processes between African and European Americans. METHODS:We quantified expression and activity of UPP1 in response to 1?,25(OH)2D3 in young adult mouse colonic cells, human CRC cells (LS174T), and organoids (derived from rectosigmoid biopsy samples of healthy individuals undergoing colonoscopies) using quantitative polymerase chain reaction, immunoblot, and immunocytochemistry assays. Binding of the vitamin D receptor to UPP1 was tested by chromatin immunoprecipitation. Uridine-induced DNA damage was measured by fragment-length analysis in repair enzyme assays. Allele-specific 1?,25(OH)2D3 responses were tested using luciferase assays. RESULTS:Vitamin D increased levels of UPP1 mRNA, protein, and enzymatic activity and increased vitamin D receptor binding to the UPP1 promoter in young adult mouse colonic cells, LS174T cells, and organoids. 1?,25(OH)2D3 significantly reduced levels of uridine and uridine-induced DNA damage in these cells, which required UPP1 expression. Organoids derived from colon tissues of African Americans expressed lower levels of UPP1 after exposure to 1?,25(OH)2D3 and had increased uridine-induced DNA damage compared with organoids derived from tissues of European Americans. Luciferase assays with the T allele of single nucleotide polymorphism rs28605337 near UPP1, which is found more frequently in African Americans than European Americans, expressed lower levels of UPP1 after exposure to 1?,25(OH)2D3 than assays without this variant. CONCLUSIONS:We found vitamin D to increase expression of UPP1, leading to reduce uridine-induced DNA damage, in colon cells and organoids. A polymorphism in UPP1 found more frequently in African Americans than European Americans reduced UPP1 expression upon cell exposure to 1?,25(OH)2D3. Differences in expression of UPP1 in response to vitamin D could contribute to the increased risk of CRC in African Americans.

Dataset Information

Case-control study of vitamin D, dickkopf homolog 1 (DKK1) gene methylation, VDR gene polymorphism and the risk of colon adenoma in African Americans.

Publications

Case-control study of vitamin D, dickkopf homolog 1 (DKK1) gene methylation, VDR gene polymorphism and the risk of colon adenoma in African Americans.

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