A functional methylome map of ulcerative colitis.
A functional methylome map of ulcerative colitis.
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DOI：
10.1101/gr.138347.112
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发表时间：
2012-11
期刊：
影响因子：
7
通讯作者：
Rosenstiel P
中科院分区：
文献类型：
--
作者：
Häsler R;Feng Z;Bäckdahl L;Spehlmann ME;Franke A;Teschendorff A;Rakyan VK;Down TA;Wilson GA;Feber A;Beck S;Schreiber S;Rosenstiel P
目前的遗传风险图谱只能部分解释炎症性肠病的病因。据推测，环境因素调节表观遗传景观，从而有助于疾病的易感性，表现和进展。为了验证这一点，我们分析了DNA甲基化（DNAm），这是基因表达的表观遗传长期调节的基本机制。我们报告了一项三层全表观基因组关联研究（EWAS），该研究使用了10对表现不一致的单卵双胞胎（n = 20个人）的肠道活检，结果显示溃疡性结肠炎（UC）。使用Affymetrix UG 133 Plus 2.0阵列（第1层）生成全基因组表达扫描。使用Illumina 27k Infinium Bead Arrays进行全基因组dna扫描，鉴定甲基化可变位置（mvp，第2层），使用Nimblegen定制385k Tiling Arrays进行medip芯片鉴定差异甲基化区域（DMRs，第3层）。在两个独立的患者群体中，通过实时定量PCR和亚硫酸盐焦磷酸测序（n = 185）验证鉴定出的mvp和DMRs。EWAS鉴定了61个与疾病相关的基因座，在差异表达的转录物中含有差异dna。所有这些都构成了以前未被GWAS识别的UC的新的候选风险位点。其中有几个在功能上与炎症过程有关，如补体因子CFI、丝氨酸蛋白酶抑制剂SPINK4和粘附分子THY1（也称为CD90）。我们的研究设计排除了非疾病炎症作为已确定的dna变化的原因。该研究首次复制了UC的EWAS与受影响组织中的转录特征相结合，并证明了EWAS在揭示无法解释的疾病风险和疾病表现的分子事件方面的能力。
The etiology of inflammatory bowel diseases is only partially explained by the current genetic risk map. It is hypothesized that environmental factors modulate the epigenetic landscape and thus contribute to disease susceptibility, manifestation, and progression. To test this, we analyzed DNA methylation (DNAm), a fundamental mechanism of epigenetic long-term modulation of gene expression. We report a three-layer epigenome-wide association study (EWAS) using intestinal biopsies from 10 monozygotic twin pairs (n = 20 individuals) discordant for manifestation of ulcerative colitis (UC). Genome-wide expression scans were generated using Affymetrix UG 133 Plus 2.0 arrays (layer 1). Genome-wide DNAm scans were carried out using Illumina 27k Infinium Bead Arrays to identify methylation variable positions (MVPs, layer 2), and MeDIP-chip on Nimblegen custom 385k Tiling Arrays to identify differentially methylated regions (DMRs, layer 3). Identified MVPs and DMRs were validated in two independent patient populations by quantitative real-time PCR and bisulfite-pyrosequencing (n = 185). The EWAS identified 61 disease-associated loci harboring differential DNAm in cis of a differentially expressed transcript. All constitute novel candidate risk loci for UC not previously identified by GWAS. Among them are several that have been functionally implicated in inflammatory processes, e.g., complement factor CFI, the serine protease inhibitor SPINK4, and the adhesion molecule THY1 (also known as CD90). Our study design excludes nondisease inflammation as a cause of the identified changes in DNAm. This study represents the first replicated EWAS of UC integrated with transcriptional signatures in the affected tissue and demonstrates the power of EWAS to uncover unexplained disease risk and molecular events of disease manifestation.
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影响因子：
4.9
作者：
Gonsky, Rivkah;Deem, Richard L.;Landers, Carol J.;Derkowski, Carrie A.;Berel, Dror;McGovern, Dermot P. B.;Targan, Stephan R.
通讯作者：
Targan, Stephan R.
影响因子：
3.2
作者：
Dhir, Mashaal;Montgomery, Elizabeth A.;Glockner, Sabine C.;Schuebel, Kornel E.;Hooker, Craig M.;Herman, James G.;Baylin, Stephen B.;Gearhart, Susan L.;Ahuja, Nita
通讯作者：
Ahuja, Nita
影响因子：
3.7
作者：
Jurisic G;Iolyeva M;Proulx ST;Halin C;Detmar M
通讯作者：
Detmar M
影响因子：
11.2
作者：
Bollati, Valentina;Baccarelli, Andrea;Yang, Allen S.
通讯作者：
Yang, Allen S.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y