Systematic association mapping identifies NELL1 as a novel IBD disease gene.
Systematic association mapping identifies NELL1 as a novel IBD disease gene.
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DOI：
10.1371/journal.pone.0000691
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发表时间：
2007-08-08
期刊：
影响因子：
3.7
通讯作者：
Schreiber S
中科院分区：
文献类型：
--
作者：
Franke A;Hampe J;Rosenstiel P;Becker C;Wagner F;Häsler R;Little RD;Huse K;Ruether A;Balschun T;Wittig M;Elsharawy A;Mayr G;Albrecht M;Prescott NJ;Onnie CM;Fournier H;Keith T;Radelof U;Platzer M;Mathew CG;Stoll M;Krawczak M;Nürnberg P;Schreiber S
克罗恩病（CD）是炎症性肠病（IBD）的一个亚型，是一种复杂的多基因疾病。尽管近期研究已成功鉴定出与CD相关的基因变异，但这些易感位点仅能解释该疾病遗传度的一小部分。在此，我们报道了对393例德国CD患者和399例对照进行的多阶段全基因组扫描结果。在检测的116,161个单核苷酸多态性中，证实了与已知的CD易感基因NOD2、5q31单倍型以及近期报道的位于5p13.1的CD位点存在关联。此外，编码nel样1前体（NELL1，11p15.1号染色体）的基因中的SNP rs1793004在独立的基于德国人群和家系的样本（942例患者，1082例对照，375个三联体）中显示出一致的疾病相关性。随后在454个法国/加拿大CD三联体的独立样本中进行的精细定位和重复验证支持了NELL1相关性的真实性。在一个大型德国溃疡性结肠炎（UC）样本中的进一步证实表明NELL1是一个普遍存在的IBD易感位点（合并p<10⁻⁶；比值比 = 1.66，95%置信区间：1.30 - 2.11）。新的5p13.1位点也在法国/加拿大样本以及一个独立的英国CD患者队列（453例患者，521例对照，对于SNP rs1992660合并p<10⁻⁶）中得到重复验证。有几个关联在至少一个独立样本中得到重复验证，表明ITGB6（上游）、GRM8（下游）、OR5V1（下游）、PPP3R2（下游）、NM_152575（上游）和HNF4G（内含子）参与其中。
Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10−6; OR = 1.66, 95% CI: 1.30–2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10−6 for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron).
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影响因子：
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通讯作者：
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