A family with ulcerative colitis maps to 7p21.1 and comprises a region with regulatory activity for the aryl hydrocarbon receptor gene.

We have mapped a locus on chromosome 7p22.3-7p15.3 spanning a 22.4 Mb region for ulcerative colitis (UC) by whole genome linkage analyses of a large Danish family. The family represent three generations with UC segregating as an autosomal dominant trait with variable expressivity. The whole-genome scan resulted in a logarithm of odds score (LOD score) of Z = 3.31, and a whole genome sequencing (WGS) of two affected excluded disease-causing mutations in the protein coding genes. Two rare heterozygote variants, rs182281985:G>A and rs541426369:G>A, both with low allele frequencies (MAF A:0.0001, gnomAD ver3.1.2), were found in clusters of ChiP-seq transcription factors binding sites close to the AHR (aryl hydrocarbon receptor) gene and the UC associated SNP rs1077773:G>A. Testing the two SNPs in a promoter reporter assay for regulatory activity revealed that rs182281985:G>A influenced the AHR promoter. These results suggest a regulatory region that include rs182281985:G>A close to the UC GWAS SNP rs1077773:G>A and further demonstrate evidence that the AHR gene on the 7p-tel region is a candidate susceptible gene for UC.

Colorectal cancer-associated SNP rs17042479 is involved in the regulation of NAF1 promoter activity.

A novel risk locus at 4q32.2, located between the Nuclear Assembly Factor 1 (NAF1) and Follistatin Like 5 (FSTL5) genes, was associated with increased risk of developing colorectal cancer (CRC), with SNP rs17042479 being the most associated. However, the link between CRC development and the risk locus at 4q32.2 is unknown. We investigated the promoter activity of NAF1 and FSTL5 and analyzed the risk locus at 4q32.2 as gene regulatory region. Our results showed that the activity of the FSTL5 promoter was low compared to the NAF1 promoter. Analyses of the NAF1 promoter in conjunction with the region containing the risk locus at 4q32.2 showed that the region functions as gene regulatory region with repressor activity on NAF1 promoter activity. The SNP rs17042479(G) increased the repressor effect of the region. CRC patients' biopsies were genotyped for SNP rs17042479(A/G), and NAF1 expression profiles were examined. We found an association between SNP rs17042479(G), cancer stage and tumor location. Additionally, patients with SNP rs17042479(G) showed lower NAF1 expression in comparison to patients with SNP rs17042479(A) in tumor tissue and the NAF1 expression in tumor tissue was lower compared to healthy tissue. The results in the study imply that reduced NAF1 expression in the tumor contribute to a more aggressive phenotype. Furthermore, this study suggests that the SNP rs17042479(G) change the expression of NAF1 and thereby increases the risk of developing CRC.