Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1):: evidence of association with alopecia areata in the Down syndrome region
Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1):: evidence of association with alopecia areata in the Down syndrome region
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DOI：
10.1007/s004390050037
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发表时间：
2000-06-01
期刊：
影响因子：
5.3
通讯作者：
Cork, MJ
中科院分区：
文献类型：
--
作者：
Tazi-Ahnini, R;di Giovine, FS;Cork, MJ
斑秃是一种以斑片状脱发为特征的慢性炎症性疾病，伴有毛囊T细胞的浸润。再生障碍性贫血的发病率约占总人口的0.1%，但在唐氏综合征(DS)中这一比例增加到9%。DS与21号染色体的一个额外拷贝(全部或部分)相关，DS区域可能包括与AA发病相关的基因。MX1是干扰素诱导的P78蛋白(MXA)的编码基因。MxA蛋白对流感病毒具有抵抗力，我们先前已经证明MxA蛋白在再生障碍性贫血患者的皮损生长期毛球中强烈表达，但在正常毛囊中不表达。因此，我们研究了MX1在再障发病机制中的可能作用。为了在MX1区域建立可用聚合酶链式反应方法筛选的标记，我们定义了人类MX1外显子/内含子的组织结构，并用构象敏感凝胶电泳法筛选外显子和内含子。我们发现MX1基因有17个外显子，长度超过33kb。从外显子6到外显子16的区域大小和序列在人和鼠之间高度保守。对MX1基因4747个碱基进行筛选，发现内含子6有4个单核苷酸多态。这些多态集中在147个碱基之间，表现出很强的连锁不平衡。在病例对照研究中，我们发现MX1(+9959)基因多态性与再生障碍性贫血显著相关(优势比1.79，95%可信区间1.21~2.66，x~2=8.464，P=0.0036)。斑片状AA(轻度疾病)和发病年龄早的患者发病风险较大(优势比2.34，95%可信区间1.24~4.43，P=0.0072)，为AA的遗传异质性提供了新的证据。我们证明了MX1基因与疾病之间的遗传关联，支持这一假设，即这是再生障碍性贫血的一个新的候选基因。
Alopecia areata (AA) is a chronic inflammatory disease characterised by patchy hair loss with T cell infiltration of hair follicles. AA occurs in approximately 0.1% of the general population, but this is increased to 9% in Down syndrome (DS). DS is associated with an additional copy (full or partial) of chromosome 21, and the DS region may potentially include genes involved in the pathogenesis of AA. MX1 is the gene encoding the interferon-induced p78 protein (MxA). MxA protein confers resistance to influenza viruses, and we have previously shown that MxA protein is strongly expressed in lesional anagen hair bulbs from patients with AA bur not in normal follicles. We therefore studied the possible involvement of MX1 in the pathogenesis of AA. To establish markers in the MX1 region which could be screened by PCR-based methods, we defined the human MX1 exon/intron organisation and screened the exons and the introns by conformation-sensitive gel electrophoresis. We found that the MX1 gene contains 17 exons extending over 33 kb. The size and sequence of the region from exon 6 to exon 16 are highly conserved between human and mouse. Screening of 4747 bp within the MX1 gene revealed four single nucleotide polymorphisms in intron 6. These polymorphisms are concentrated within 147 bp and show strong linkage disequilibrium. In a case-control association study for the MX1 (+9959) polymorphism in 165 AA patients and 510 controls we found a significant association of this marker with AA (odds ratio 1.79, 95% CI 1.21-2.66, chi(2)=8.464, P=0.0036). The risk of disease was greater for patchy AA (mild disease) and with early age at onset (odds ratio 2.34, 95% CI 1.24-4.43, P=0.0072), providing new evidence of genetic heterogeneity in AA. Our demonstration of genetic association between the MX1 gene and disease supports the hypothesis that this is a new candidate gene in AA.