Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p
Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p
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DOI：
10.1073/pnas.261567999
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发表时间：
2002-01-08
影响因子：
11.1
通讯作者：
Schreiber, S
中科院分区：
文献类型：
--
作者：
Hampe, J;Frenzel, H;Schreiber, S
炎症性肠病（IBD）的遗传易感性已被流行病学和遗传分析所证实。IBD与16号染色体的广泛区域的连锁已经通过多个群体的分析建立。NOD2基因位于16号染色体上，是一个新近发现的IBD基因。由于16号染色体上的连锁区域很大，我们已经研究了NOD2不是位于该染色体上的唯一IBD基因的可能性。使用39个微卫星标记进行高密度实验，以确定额外的关联区域，并指出进一步调查的兴趣领域。在近端16 p、近端16 q和中央16 q上观察到连锁曲线的三峰构型，峰值比值对数（lod）评分分别为2.7、3.2和3.1。通过编码携带NOD2单核苷酸多态性（SNP）8和SNP13“未知”的个体对队列进行分层。“在中心峰的显著性，对应于NOD2的基因组位置，然后从3.2下降到1.2。近端p臂（lod = 2.1）和中央q臂（lod = 2.6）的最大lod评分仅发生中度变化。探索性关联分析（TRANSMIT）在D16S3068（P = 0.00028）产生了强领先优势。通过使用匿名SNPS进一步研究该标记周围的区域。鉴定了含有三个SNP的相关单倍型（峰值显著性P = 0.00027，IBD表型）。在基于NOD2基因型的分层中，该显著性增加至P = 0.0001。这些结果证实了NOD2的重要性，并为位于染色体16 p上的第二个IBD基因提供了证据。
Heritable predisposition to inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic analysis. Linkage of IBD to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2, located on proximal 16q, was recently identified as an IBD gene. As the linkage regions on chromosome 16 are large, we have investigated the possibility that NOD2 is not the only IBD gene located on this chromosome. A high-density experiment using 39 microsatellite markers was performed to identify additional regions of association, and to indicate areas of interest for further investigation. A triple-peaked configuration of the linkage curve with peak logarithm of odds (lod) scores of 2.7, 3.2, and 3.1 was observed on proximal 16p, proximal 16q, and central 16q, respectively. The cohort was stratified by coding individuals carrying the NOD2 single nucleotide polymorphism (SNP)8 and SNP13 "unknown." Significance at the central peak, corresponding to the genomic location of NOD2, then decreased from 3.2 to 1.2. The maximal lod scores on the proximal p-arm (lod = 2.1) and central q-arm (lod = 2.6) changed only moderately. An exploratory association analysis (TRANSMIT) yielded a strong lead at D16S3068 (P = 0.00028). The region around this marker was further investigated by using anonymous SNPS. An associated haplotype containing three SNPs was identified (peak significance P = 0.00027, IBD phenotype). On stratification based on NOD2 genotype, this significance increased to P = 0.0001. These results confirm the importance of NOD2 and provide evidence for a second IBD gene located on chromosome 16p.