A novel SNP in a vitamin D response element of the CYP24A1 promoter reduces protein binding, transactivation, and gene expression.
The active form of vitamin D (1alpha,25(OH)(2)D(3)) is known to have antiproliferative effects and has been implicated in cancers of the colon, breast, and prostate. These cancers occur more frequently among African Americans than Caucasians, and individuals with African ancestry are known to have approximately twofold lower levels of serum vitamin D (25(OH)D) compared with individuals of European ancestry. However, epidemiological studies of the vitamin D receptor (VDR) have shown inconsistent associations with cancer risk, suggesting that differences in other genes in the pathway may be important. We sought to identify functionally significant polymorphic variants in CYP24A1, a gene that is highly inducible by 1alpha,25(OH)(2)D(3) and that encodes the primary catabolic enzyme in the pathway. Here we report the identification of six novel SNPs in the human CYP24A1 promoter, including one at nucleotide -279 occurring within the distal vitamin D response element (VDRE2). Our experiments demonstrate that the VDRE2 variant results in decreased protein binding and transactivation in vitro, and reduced expression of CYP24A1 in cultured primary human lymphocytes provides evidence for an effect in vivo. This variant was only observed in our African American population, and represents a first step toward understanding differences in disease risk among racial/ethnic groups.
Roff
Alanna
A
Department of Public Health Sciences and Penn State Cancer Institute, Cancer Prevention and Control Program, Penn State College of Medicine, Hershey, PA 17033, USA.
Wilson
Robin Taylor
RT
D001741:Black or African American; D002117:Calcitriol / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation; D030181:Vitamin D Response Element; D065668:Vitamin D3 24-Hydroxylase; D044465:White People
D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol