SNPs associated with colorectal cancer at 15q13.3 affect risk enhancers that modulate GREM1 gene expression.
SNPs associated with colorectal cancer at 15q13.3 affect risk enhancers that modulate GREM1 gene expression.
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DOI：
10.1002/humu.24166
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发表时间：
2021-03
期刊：
影响因子：
3.9
通讯作者：
Casey G
中科院分区：
文献类型：
--
作者：
Fortini BK;Tring S;Devall MA;Ali MW;Plummer SJ;Casey G
几项结直肠癌（CRC）的全基因组关联研究已确定染色体15q13.3上的单核苷酸多态性（SNP）与CRC风险相关。为了鉴定这种关联背后的功能变体，我们研究了与风险相关SNP rs 4779584连锁不平衡的SNP，该SNP与结肠相关组织和细胞中表征的调控区/增强子元件重叠。我们鉴定了几个在体外表现出增强子活性的含SNP的调控区，包括一个与等位基因特异性对增强子活性的影响相关的SNP（rs 1406389）。该增强子或先前在该区域中报道的另一种增强子的缺失与CRISPR/Cas9基因组编辑后GREM 1表达的降低相关。GREM 1是这些增强子的一个靶点，这一点得到了基因型-组织表达数据集中横结肠而不是乙状结肠中rs 1406389和GREM 1表达之间的表达定量性状基因座相关性的进一步支持。综上所述，我们得出结论，15q13.3区域包含至少两个功能变体，它们映射到不同的增强子，并通过调节GREM 1表达来影响CRC风险。
Several genome wide association studies of colorectal cancer (CRC) have identified single nucleotide polymorphisms (SNPs) on chromosome 15q13.3 associated with CRC risk. To identify functional variant(s) underlying this association, we investigated SNPs in linkage disequilibrium with the risk‐associated SNP rs4779584 that overlapped regulatory regions/enhancer elements characterized in colon‐related tissues and cells. We identified several SNP‐containing regulatory regions that exhibited enhancer activity in vitro, including one SNP (rs1406389) that correlated with allele‐specific effects on enhancer activity. Deletion of either this enhancer or another enhancer that had previously been reported in this region correlated with decreased expression of GREM1 following CRISPR/Cas9 genome editing. That GREM1 is one target of these enhancers was further supported by an expression quantitative trait loci correlation between rs1406389 and GREM1 expression in the transverse but not sigmoid colon in the Genotype‐Tissue Expression dataset. Taken together, we conclude that the 15q13.3 region contains at least two functional variants that map to distinct enhancers and impact CRC risk through modulation of GREM1 expression.
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影响因子：
4.7
作者：
Lubbe, Steven J.;Whiffin, Nicola;Houlston, Richard S.
通讯作者：
Houlston, Richard S.
影响因子：
3.5
作者：
Biancolella, Michela;Fortini, Barbara K.;Casey, Graham
通讯作者：
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Jaeger E;Leedham S;Lewis A;Segditsas S;Becker M;Cuadrado PR;Davis H;Kaur K;Heinimann K;Howarth K;HMPS Collaboration;East J;Taylor J;Thomas H;Tomlinson I
通讯作者：
Tomlinson I
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen