Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype.
Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype.
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DOI：
10.1371/journal.pone.0111914
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Casey G
中科院分区：
文献类型：
--
作者：
Fortini BK;Tring S;Plummer SJ;Edlund CK;Moreno V;Bresalier RS;Barry EL;Church TR;Figueiredo JC;Casey G
结直肠癌（CRC）的全基因组关联研究（GWAS）已经鉴定出许多与适度风险相关的常见变异。几种风险变体映射在TGFβ/BMP信号通路基因附近，包括SMAD 7 18q21.1内含子内的rs 4939827。先前的一项研究表明，一种新的SNP（novel 1或rs 58920878）是SMAD 7内含子4中增强子元件内的功能变体。在这项研究中，我们表明，四个SNP，包括新的1（rs6507874，rs6507875，rs 8085824和rs 58920878）在连锁不平衡（LD）与索引SNP rs 4939827表现出等位基因特异性增强子的SMAD 7的一个大的，多组分增强子的影响。所有四种SNP均显示与CRC细胞系的核提取物结合的等位基因特异性蛋白质。此外，一些风险相关等位基因与SMAD 7在正常结肠组织中的表达增加相关。最后，我们表明增强子对BMP 4刺激有反应。综上所述，我们认为18q21.1相关的CRC风险是由于调节SMAD 7表达的四种功能变体，并可能干扰TGFβ/BMP信号通路中的BMP负反馈回路。
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.
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DOI：
10.1007/978-1-61779-316-5_20
发表时间：
2011
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
O'Geen, Henriette;Echipare, Lorigail;Farnham, Peggy J
通讯作者：
Farnham, Peggy J
影响因子：
5.3
作者：
Peters U;Hutter CM;Hsu L;Schumacher FR;Conti DV;Carlson CS;Edlund CK;Haile RW;Gallinger S;Zanke BW;Lemire M;Rangrej J;Vijayaraghavan R;Chan AT;Hazra A;Hunter DJ;Ma J;Fuchs CS;Giovannucci EL;Kraft P;Liu Y;Chen L;Jiao S;Makar KW;Taverna D;Gruber SB;Rennert G;Moreno V;Ulrich CM;Woods MO;Green RC;Parfrey PS;Prentice RL;Kooperberg C;Jackson RD;Lacroix AZ;Caan BJ;Hayes RB;Berndt SI;Chanock SJ;Schoen RE;Chang-Claude J;Hoffmeister M;Brenner H;Frank B;Bézieau S;Küry S;Slattery ML;Hopper JL;Jenkins MA;Le Marchand L;Lindor NM;Newcomb PA;Seminara D;Hudson TJ;Duggan DJ;Potter JD;Casey G
通讯作者：
Casey G
影响因子：
3.5
作者：
Biancolella, Michela;Fortini, Barbara K.;Casey, Graham
通讯作者：
Casey, Graham
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
5.3
作者：
Benchabane, H;Wrana, JL
通讯作者：
Wrana, JL