We investigated whether single nucleotide polymorphisms within ultraconserved 
elements (UCEs) are associated with susceptibility to overall colorectal cancer 
(CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC 
patients and 551 healthy controls. The study comprised of a training set (520 
cases and 341 controls) and a replication set (267 cases and 210 controls). We 
observed associations in rs7849 and rs1399685 with CRC risk. For example, a 
dose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval 
(CI), 0.63-1.00; P for trend = 0.05) associated with the variant allele of 
rs7849 in the training set. The significant trend toward a decrease in CRC risk 
was confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52-0.99; P 
for trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) 
risk, significant association was observed for the variant-containing genotypes 
of rs1399685 (OR, 1.77; 95% CI, 1.02-3.06) and the risk was replicated in the 
replication population (OR, 2.04; 95% CI, 1.02-4.07). The variant genotypes of 
rs9784100 and rs7849 conferred decreased risk but the associations were not 
replicated. Three right-sided CRC (RCRC) susceptibility loci were identified in 
rs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint 
effects and potential higher order gene-gene interactions among significant 
variants further categorized patients into different risk groups. Our results 
strongly suggest that several genetic variants in the UCEs may contribute to CRC 
susceptibility, individually and jointly, and that different genetic etiology 
may be involved in RCRC and LCRC.