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Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development, but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the biological interrogation of germ-line polymorphisms within these sequences. In this study, through a forward genetic analysis of bona fide p53 binding sites identified by a genome-wide chromatin immunoprecipitation and sequence analysis, we discovered a SNP (rs1860746) within the motif sequence of a p53 binding site where p53 can function as a regulator of transcription. We found that the minor allele (T) binds p53 poorly and has low transcriptional regulation activity as compared to the major allele (G). Significantly, the homozygosity of the minor allele was found to be associated with an increased risk of ER negative breast cancer (OR = 1.47, P = 0.038) from the analysis of five independent breast cancer samples of European origin consisting of 6,127 breast cancer patients and 5,197 controls. rs1860746 resides in the third intron of the PRKAG2 gene that encodes the γ subunit of the AMPK protein, a major sensor of metabolic stress and a modulator of p53 action. However, this gene does not appear to be regulated by p53 in lymphoblastoid cell lines nor in a cancer cell line. These results suggest that either the rs1860746 locus regulates another gene through distant interactions, or that this locus is in linkage disequilibrium with a second causal mutation. This study shows the feasibility of using genomic scale molecular data to uncover disease associated SNPs, but underscores the complexity of determining the function of regulatory variants in human populations.

Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development