TY - JOUR
T1 - A novel SNP in a vitamin D response element of the CYP24A1 promoter reduces protein binding, transactivation, and gene expression
AU - Roff, Alanna
AU - Wilson, Robin Taylor
N1 - Funding Information:
This work was dually supported by grants from the Penn State Population Research Institute and by a General Clinical Research Center grant from NIH (M01RR10732) and GCRC Construction Grant (C06RR016499) awarded to the Pennsylvania State University College of Medicine. The authors would like to thank Dr. Philip Lazarus for the gift of normal human liver RNA and Dr. Hector DeLuca for the gift of the r24OHase-Luc plasmid. Drs. Ryan Dellinger, L. Michael Carastro, and Bandana Chatterjee all provided helpful suggestions on experimental design. Excellent technical assistance was provided by Rick Ball at the GCRC and Robert Brucklacher at the Functional Genomics Core Facility of the Section of Research Resources, Penn State College of Medicine. Ms. Diane Pague recruited and scheduled study participants, and Drs. Ryan Dellinger, Carol Ely Hepfer, and Marian Walters kindly assisted in critical reading of the manuscript.
PY - 2008/11
Y1 - 2008/11
N2 - The active form of vitamin D (1α,25(OH)2D3) 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 1α,25(OH)2D3 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.
AB - The active form of vitamin D (1α,25(OH)2D3) 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 1α,25(OH)2D3 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.
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U2 - 10.1016/j.jsbmb.2008.08.009
DO - 10.1016/j.jsbmb.2008.08.009
M3 - Article
C2 - 18824104
AN - SCOPUS:55349087215
SN - 0960-0760
VL - 112
SP - 47
EP - 54
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 1-3
ER -