Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31
Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31
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染色体5q31克罗恩病易感性单倍型的基因型-表型分析
DOI：
10.1136/jmg.40.10.792
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发表时间：
2003
影响因子：
4
通讯作者：
D. Jewell
中科院分区：
文献类型：
--
作者：
A. Armuzzi;Tariq Ahmad;K. Ling;A. de Silva;S. Cullen;D. V. van Heel;T. Orchard;K. Welsh;S. Marshall;D. Jewell
背景和目的：最近的分子数据表明，遗传因素可能是溃疡性结肠炎(UC)和克罗恩病(CD)中观察到的疾病异质性的基础。染色体5q上的一个基因座与镉的易感性有关，最近通过连锁不平衡定位到保守的250kb单倍型(5q31)。目前还没有关于该基因座对临床表型的贡献的数据。在这项病例对照研究中，我们调查了这种单倍型对CD和UC的易感性和表型的贡献。患者和方法：我们研究了330名高加索人CD患者和457名UC患者，这些患者来自英国的一个中心。通过选择跨越该易感区域的三个单核苷酸多态重建单倍型，分析与疾病易感性和表型的相关性。寻找IBD5和NOD2/CARD15之间可能存在遗传上位性的证据。结果：证实了该区域的连锁不平衡，有两种单倍型，占染色体总数的88%。对CD的易感性与常见单倍型H2的纯合性相关(PC=0.002；相对危险度(RR)2.0)。基因型-表型分析表明，这种关联在肛周疾病患者中尤其明显(PC=0.0005；RR1.7)，特别是在该单倍型纯合子个体中(PC=0.0005；RR3.0)。重要的是，在186名没有肛周疾病的患者中，没有发现与H2有关。没有证据表明IBD5和NOD2/CARD15之间存在上位性。结论：IBD5风险单倍型仅与CD相关。基因型-表型分析显示，在肛周CD患者中观察到最强的相关性。虽然涉及的确切基因尚不清楚，但这些数据为CD临床异质性的遗传学基础提供了进一步的分子证据。
Background and aims: Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in both ulcerative colitis (UC) and Crohn’s disease (CD). A locus on chromosome 5q has been implicated in susceptibility to CD, and recently refined by linkage disequilibrium mapping to a conserved 250 kb haplotype (5q31). No data regarding the contribution of this locus to clinical phenotype exist. In this case control study, we investigated the contribution of this haplotype to both susceptibility and phenotype of CD and UC. Patients and methods: We studied 330 Caucasian CD and 457 UC patients recruited from a single UK centre. Association with disease susceptibility and phenotype was analysed with haplotypes reconstructed from three single nucleotide polymorphisms chosen to span this susceptibility region. Evidence for possible genetic epistasis between IBD5 and NOD2/CARD15 was sought. Results: Linkage disequilibrium across this region was confirmed, with two haplotypes comprising 88% of all chromosomes. Susceptibility to CD, but not to UC, was associated with homozygosity for a common haplotype, H2 (pc=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (pc=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (pc=0.0005; RR 3.0). Importantly, no association with H2 was found in 186 patients without perianal disease. No evidence of epistasis between IBD5 and NOD2/CARD15 was demonstrated. Conclusions: The IBD5 risk haplotype is associated with CD only. Genotype-phenotype analysis reveals that the strongest association is observed in patients with perianal CD. While the precise gene involved is unclear, these data provide further molecular evidence for a genetic basis of the clinical heterogeneity of CD.
影响因子：
6
作者：
Lubensky, IA;Schmidt, L;Zbar, B
通讯作者：
Zbar, B
影响因子：
2.9
作者：
Blondelle, SE;Forood, B;PerezPaya, E
通讯作者：
PerezPaya, E
影响因子：
3.5
作者：
Stenoien, DL;Cummings, CJ;Mancini, MA
通讯作者：
Mancini, MA