Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype.
Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4223076?pdf=render |
| _version_ | 1818792209005150208 |
|---|---|
| author | Barbara K Fortini Stephanie Tring Sarah J Plummer Christopher K Edlund Victor Moreno Robert S Bresalier Elizabeth L Barry Timothy R Church Jane C Figueiredo Graham Casey |
| author_facet | Barbara K Fortini Stephanie Tring Sarah J Plummer Christopher K Edlund Victor Moreno Robert S Bresalier Elizabeth L Barry Timothy R Church Jane C Figueiredo Graham Casey |
| author_sort | Barbara K Fortini |
| collection | DOAJ |
| description | Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways. |
| first_indexed | 2024-12-18T15:23:36Z |
| format | Article |
| id | doaj.art-ce11f040ecc74e86b4da84901f5e86f9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-18T15:23:36Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ce11f040ecc74e86b4da84901f5e86f92022-12-21T21:03:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01911e11191410.1371/journal.pone.0111914Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype.Barbara K FortiniStephanie TringSarah J PlummerChristopher K EdlundVictor MorenoRobert S BresalierElizabeth L BarryTimothy R ChurchJane C FigueiredoGraham CaseyGenome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways.http://europepmc.org/articles/PMC4223076?pdf=render |
| spellingShingle | Barbara K Fortini Stephanie Tring Sarah J Plummer Christopher K Edlund Victor Moreno Robert S Bresalier Elizabeth L Barry Timothy R Church Jane C Figueiredo Graham Casey Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. PLoS ONE |
| title | Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. |
| title_full | Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. |
| title_fullStr | Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. |
| title_full_unstemmed | Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. |
| title_short | Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. |
| title_sort | multiple functional risk variants in a smad7 enhancer implicate a colorectal cancer risk haplotype |
| url | http://europepmc.org/articles/PMC4223076?pdf=render |
| work_keys_str_mv | AT barbarakfortini multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT stephanietring multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT sarahjplummer multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT christopherkedlund multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT victormoreno multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT robertsbresalier multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT elizabethlbarry multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT timothyrchurch multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT janecfigueiredo multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype AT grahamcasey multiplefunctionalriskvariantsinasmad7enhancerimplicateacolorectalcancerriskhaplotype |