Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease
Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease
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DOI：
10.1086/373880
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发表时间：
2003-04-01
影响因子：
9.8
通讯作者：
Mathew, CG
中科院分区：
文献类型：
--
作者：
Mirza, MM;Fisher, SA;Mathew, CG
最近有报道称，染色体5 q31上细胞因子基因簇中一个跨越250 kb的常见单倍型与加拿大家族中的克罗恩病（CD）密切相关。我们在一个大型的欧洲CD患者队列中通过传播不平衡检验（TDT）（P = 0.016）和病例对照关联研究（P = 0.008）重复了这一发现，尽管疾病风险的增加很小（纯合子的优势比为1.49，95%CI 1.11-2.0）。在溃疡性结肠炎（UC）的家庭或个人中未检测到相关性。根据CD易感基因CARD 15的突变状态对TDT样本中患有CD的后代进行分层，结果显示，与5 q31风险单倍型的关联仅存在于至少具有一种已知CARD 15疾病易感等位基因的后代中（P = .044）。5 q31风险单倍型频率在有一个或两个CARD 15突变的无关CD患者中为53.1%，而对照组为43.7%（P = .0001），但在没有CARD 15突变的CD患者中没有显著升高（45.4%，p = .41）。Kaplan-Meier生存分析显示，5 q31风险单倍型纯合子的发病年龄明显较早（P = .0019）。这些发现表明，5 q31（IBD 5）基因座的遗传变异可能加速克罗恩病的发病，并与CARD 15合作致病。
A common haplotype spanning 250 kb in the cytokine gene cluster on chromosome 5q31 has recently been reported to be strongly associated with Crohn disease ( CD) in Canadian families. We have replicated this finding by both the transmission-disequilibrium test (TDT) (P = .016) and in a case-control association study (P = .008) in a large European cohort of patients with CD, although the increase in disease risk was small ( odds ratio 1.49 for homozygotes, 95% CI 1.11-2.0). No association was detected in families or individuals with ulcerative colitis (UC). Stratification of offspring with CD in the TDT sample by mutation status in the CD susceptibility gene CARD15 showed that the association with the 5q31 risk haplotype was present only in offspring with at least one of the known CARD15 disease susceptibility alleles (P = .044). The 5q31 risk haplotype frequency was 53.1% in unrelated individuals with CD who had one or two CARD15 mutations versus 43.7% in control subjects (P = .0001) but was not significantly elevated in individuals with CD who had no CARD15 mutations (45.4%, p = .41). Kaplan-Meier survival analysis of age at disease onset showed a significantly earlier onset in homozygotes for the 5q31 risk haplotype (P = .0019). These findings suggest that genetic variants at the 5q31 ( IBD5) locus may hasten the onset of Crohn disease and cooperate with CARD15 in disease causation.