Rs10419226

rs10419226 is a variant on 19p13 associated with esophageal adenocarcinoma and Barrett&#8217;s esophagus, a precancerous condition characterized by aberrant localization of specialized intestinal cells in the epithelial lining of the esophagus. The SNP is an A/C (minor/major plus-strand allele) intronic variant of CRTC1, a CREB-regulated transcription coactivator. In one of the first genome wide association studies of esophageal adenocarcinoma, rs10419226 was the most significant hit with a p-value of 3.55x10-10, odds ratio of 1.18, and a 95% confidence interval of 1.12-1.24.

The aforementioned study by Levine et al. was conducted in two phases. In the first phase, 1516 esophageal adenocarcinoma cases and 2416 Barrett&#8217;s esophagus cases were collected by the Barrett&#8217;s and Esophageal Adenocarcinoma Consortium (BEACON). These cases were compared to a set of 3209 control samples, 1022 of which were drawn from a previous melanoma study. All samples were of European descent (genomic inflation factor (&#955;) was 1.039, suggesting little to no population stratification amongst the samples), and were histologically verified before genotyping via the Illumina HumanOmni1-Quad platform. The array allowed for the direct assessment of 922,031 autosomal and X-chromosome SNPs. Variants not found on the array were imputed, though the discovery of rs10419226 was based on array data alone. To enhance statistical power, the related diseases, Barrett&#8217;s esophagus and esophageal adenocarcinoma, were ultimately treated as a single phenotype, as separate analyses for each case called the same associated SNPs with similar odd ratios.

In the second phase of the study, a replication study was conducted where 94 of the most significantly associated SNPs (p < 1x10-4) from the first phase were selected for further assessment via a genotyping assay. In this phase, 874 esophageal adenocarcinoma cases and 759 Barrett&#8217;s esophagus cases were evaluated, along with 6911 controls. In both the discovery and replication studies, the rs10419226 variant was the most significant hit.

Though it is currently unknown whether rs10419226 is a causal variant for esophageal adenocarcinoma and Barrett&#8217;s esophagus, there is some evidence suggesting that this locus may play a functional role in the onset of these diseases. The associated gene, CRTC1, is oncogenic, as deregulation of CRTC1 signaling advances tumorigenic esophageal cell migration and invasion. The intronic variant may also be a regulator of expression, as this particular SNP was previously identified as an expression quantitative trait locus (eQTL) for PIKR32 in lymphoblastoid cell lines. PIK3R2 is highly expressed in gastrointestinal tumors and interacts with epidermal growth factor (EGF), a hormone that has been shown to heal gastroesophageal ulcers and inhibit gastric acid secretion. In Barrett&#8217;s esophagus and esophageal adenocarcinoma, the EGF receptor is also highly expressed.