Single nucleotide polymorphisms (SNPs) occurring in noncoding sequences have largely been ignored in genome-wide association studies (GWAS). Yet, amounting evidence suggests that many noncoding SNPs especially those that are in the vicinity of protein coding genes play important roles in shaping chromatin structure and regulate gene expression and, as such, are implicated in a wide variety of diseases. One of such regulatory SNPs (rSNPs) is the E-cadherin (CDH1) promoter ？160C/A SNP (rs16260) which is known to affect E-cadherin promoter transcription by displacing transcription factor binding and has been extensively scrutinized for its association with several diseases especially malignancies. Findings from studying this SNP highlight important clinical relevance of rSNPs and justify their inclusion in future GWAS to identify novel disease causing SNPs. 1. Introduction Genetic variation contributes to virtually every human disease, conferring susceptibility or resistance or influencing interaction with environmental factors [1]. The most common type of human genetic variation is single nucleotide polymorphism (SNP), where two alternative bases occur at appreciable frequency (>1%) in the human population [2]. As of NCBI dbSNP Build 141 (http://www.ncbi.nlm.nih.gov/SNP/), there are about 43 million validated SNPs in human genome occurring about once in every 72 basepairs (bp). While much focus has been given to SNPs in coding sequences in genome-wide association studies (GWAS), the role of noncoding SNPs, which count more than coding SNPs, is much less studied. Many such noncoding SNPs that reside in the noncoding sequences (e.g., promoters, enhancers, and 3′ termini) surrounding protein coding genes have been shown to have profound effects on the expression of neighboring genes and can cause disease phenotypes [3, 4] and are thus called regulatory SNPs (rSNPs) [5, 6]. In 2000, when we were mapping DNA methylation in the CpG island region of the E-cadherin promoter in cancer samples using the bisulfite genomic sequencing technique [7], we accidently identified a novel C/A polymorphic site at the ？160 location of the E-cadherin promoter within the mapped region. Further molecular characterization revealed that the two alleles confer the E-cadherin promoter different transcriptional activities. Since then, this SNP (reference SNP accession rs16260) has been extensively scrutinized for its association with different types of cancer and several noncancerous diseases (Table 1) by worldwide groups including our own [8, 9]. In this review, we summarize data
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