Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany.
PLoS One. 2007 Aug 8;2(8):e691. doi: 10.1371/journal.pone.0000691.
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).
克罗恩病（CD）是炎症性肠病（IBD）的一个亚实体，是一种复杂的多基因疾病。尽管最近的研究已经成功地确定了与 CD 相关的遗传变异，但这些易感基因座仅解释了疾病遗传率的一部分。在这里，我们报告了对 393 例德国 CD 病例和 399 例对照的多阶段全基因组扫描。在测试的 116,161 个单核苷酸多态性中，与已知的 CD 易感基因 NOD2、5q31 单倍型和最近报道的 5p13.1 处的 CD 基因座的关联得到了确认。此外，在基因编码 nel-like 1 前体（NELL1，染色体 11p15.1）中的 SNP rs1793004 也在独立的德国人群和家族样本中表现出一致的疾病相关性（942 例病例，1082 例对照，375 例三胞胎）。在 454 例法国/加拿大 CD 三胞胎的独立样本中进行的后续精细定位和复制支持了 NELL1 关联的真实性。在一个大型德国溃疡性结肠炎（UC）样本中的进一步确认表明，NELL1 是一个普遍存在的 IBD 易感基因座（合并 p<10(-6)；OR = 1.66，95%CI：1.30-2.11）。新的 5p13.1 基因座也在法国/加拿大样本和独立的英国 CD 患者组中得到了复制（453 例病例，521 例对照，SNP rs1992660 的合并 p<10(-6)）。至少有一个独立样本中复制了几个关联，表明 ITGB6（上游）、GRM8（下游）、OR5V1（下游）、PPP3R2（下游）、NM_152575（上游）和 HNF4G（内含子）的参与。
