Armuzzi A, Ahmad T, Ling K-L, de Silva A, Cullen S, van Heel D, Orchard T R, Welsh K I, Marshall S E, Jewell D P
Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Oxford, UK.
Gut. 2003 Aug;52(8):1133-9. doi: 10.1136/gut.52.8.1133.
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.
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.
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 (p(c)=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (p(c)=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (p(c)=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.
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.
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）中所观察到的疾病异质性的基础。5号染色体长臂上的一个基因座与CD易感性有关，最近通过连锁不平衡定位将其精细定位到一个保守的250kb单倍型（5q31）。尚无关于该基因座对临床表型影响的数据。在这项病例对照研究中，我们调查了该单倍型对CD和UC易感性及表型的影响。
我们研究了从英国一个中心招募的330例白种人CD患者和457例UC患者。采用从跨越该易感区域的三个单核苷酸多态性重建的单倍型分析其与疾病易感性和表型的相关性。探寻IBD5与NOD2/CARD15之间可能存在基因上位性的证据。
证实了该区域存在连锁不平衡，两种单倍型占所有染色体的88%。一种常见单倍型H2的纯合性与CD易感性相关，而与UC易感性无关（p(c)=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为明显（p(c)=0.0005；RR 1.7），尤其是该单倍型的纯合个体（p(c)=0.0005；RR 3.0）。重要的是，在186例无肛周疾病的患者中未发现与H2的关联。未证实IBD5与NOD2/CARD15之间存在上位性。
IBD5风险单倍型仅与CD相关。基因型-表型分析显示，在肛周CD患者中观察到的关联最为强烈。虽然所涉及的确切基因尚不清楚，但这些数据为CD临床异质性的遗传基础提供了进一步的分子证据。
