Genetic variation in the beta subunit of the high affinity IgE receptor and atopy and asthma
Genetic variation in the beta subunit of the high affinity IgE receptor and atopy and asthma
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高亲和力 IgE 受体 β 亚基的遗传变异与特应性和哮喘
DOI：
10.1111/j.1365-2222.2006.02535.x
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发表时间：
2006
影响因子：
6.1
通讯作者：
W. Cookson
中科院分区：
文献类型：
--
作者：
J. Hopkin;W. Cookson
本期有两篇文章提供了进一步的证据，证明高亲和力IgE(FceRI-b)的β亚基的遗传变异，特别是基因启动子变异体，在-109位用T取代C核苷酸，可能有助于哮喘的发生或表达。Kim等人。来自韩国的[1]报道，T-109通过增强基因启动子活性来上调β功能，这是通过在细胞系中的转基因实验确定的。T-109还与阿司匹林敏感型哮喘患者金黄色葡萄球菌肠毒素高IgE的存在有关。该小组认为，该变体可能因此通过增加携带金黄色葡萄球菌肠毒素IgE的肺肥大细胞上的β表达而增加哮喘的表达。Hizawa等人。来自日本的[2]报道，T-109(以及单倍型分析中的CC-654)与较少的哮喘有关。在同一项研究中，他们表明血浆激活物抑制物1(PAI-1)的5G等位基因与较少的哮喘相关，并且这两个基因座的变异可能在影响哮喘风险方面存在交互作用。该小组认为，由于跨越整个基因的不同变体的共同遗传，FceRI-b变体的功能影响仍然很难确定。他们对PAI-1的5G/4G变体的观察建立在之前的观察基础上，即这种功能变体(与5G相比，4G显示出转录增强，因此功能上调)对抑制纤溶，从而抑制肥大细胞驱动的炎症后支气管重塑产生影响。破解常见疾病的遗传学为未来改进预防和治疗带来了巨大的希望[3]；但破解这种疾病的挑战一直并将继续是严峻的。这源于异质的分子病理学，它来自于将临床病例集中在一个旗帜下，例如“哮喘”。这反过来又反映了这样一个现实，即常见疾病的遗传风险在很大程度上存在于共同的遗传变异中，每个变异都会产生适度的而不是重大的功能影响。当个体在多个基因座上持有致病变异(多基因障碍)时，就会发生临床疾病；此外，在同一临床疾病的不同个体中，在不同基因座持有的变异的组合也会有所不同(遗传异质性)。哮喘和特应性过敏的分子遗传学研究很好地说明了这些复杂性。观察到了遗传连锁的多个染色体区域。有些主要与哮喘有关，有些则与过敏症有关。其中一些特定的基因座，例如那些影响Th-2信号的基因[4，5]，很容易从分子病理学的角度理解--其他的如ADAM33，PHF11和GPRA[6]是富有成效的正在进行的研究的对象。以某种方式在某些人群中复制了许多联系和联系--但病例系列和族裔群体的结果不同的情况比比皆是。多基因效应很重要，不同基因座上的一些常见变异与环境相互作用，导致临床表型。因此，组合基因的优势比实质上大于单基因座的优势比，例如Th-2信号中Il-13、IL4Ra和Stat-6的组合基因的优势比[5]。在某些情况下，可能会第一次看到这些哮喘和特应性变异体的进化起源，例如它们可能对寄生虫感染的保护[7，8]。那么，FceRI-b基因变异在哮喘和特应性疾病中的具体作用是什么呢？Kim等人和Hizawa等人的报告。支持基因的重要作用--但共同强调了基因座上解开的复杂性。通过染色体11q13的FceRI-b是第一个与哮喘和特应性疾病相关的非人类白细胞抗原基因座[9，10]。尽管早期没有复制，但现在很明显，遗传对应：朱利安·M·霍普金教授，医学院和生命科学研究所，格罗夫大楼，威尔士大学斯旺西，斯旺西，SA2 8PP。电话：01792 295149传真：01792 513054电子邮件：j.m.Hopkin@swansea.ac.uk临床和实验过敏
This issue features two articles providing further evidence that genetic variants of the beta subunit of the high affinity IgE (FceRI-b) and in particular a gene promoter variant, substituting T for C nucleotide at position -109 may contribute to the development or expression of asthma. Kim et al. from Korea [1] report that T -109 up-regulates beta function through enhanced gene promoter activity, as determined by transfection experiments in cell lines. T -109 also associates with the presence of high IgE to staphylococcal enterotoxin in aspirin sensitive asthmatics. The group consider that the variant may hence augment the expression of asthma through increased beta expression on pulmonary mast cells holding IgE to staphylococcal enterotoxin. Hizawa et al. from Japan [2] report that T -109 (and also CC -654 in haplotype analysis) associate with less asthma. In the same study they show that the 5G allele of plasma activator inhibitor 1 (PAI-1) associates with less asthma, and that the variants at both loci may interact in their effects on the risk of asthma. The group consider that the functional impact of variants of FceRI-b remain difficult to pin down because of the co-inheritance of different variants spanning the whole gene. Their observations of the 5G/4G variant of PAI-1 build on previous observations that this functional variant (4G shows enhanced transcription and hence up-regulated function in comparison with 5G) impacts on inhibition of fibrinolysis and hence remodeling of the bronchus after mast cell driven inflammation. Unraveling the genetics of common diseases holds great promise for improved prevention and treatments in the future [3]; but the challenge in this unraveling has been and continues to be serious. This derives from the heterogeneous molecular pathology that comes from lumping clinical cases under one banner such as ‘‘asthma’’. This is in turn a reflection of the reality that the genetic risks for the common diseases reside very largely in common genetic variants, each promoting moderate rather than major functional effect. Clinical disease ensues when individuals hold disease-promoting variants at a number of loci (polygenic disorder); moreover the combination of variants held at different loci in different individuals with same clinical disease will vary (genetic heterogeneity). The study of the molecular genetics of both asthma and atopic allergy exemplifies these complexities well. Multiple chromosomal regions of genetic linkage have been observed. Some are related principally to asthma, others to atopy. Some of the specific loci implicated, such as those that impact on Th-2 signalling [4,5], are readily understandable in molecular pathological terms–others such as ADAM33, PHF11 and GPRA [6] are the subject of productive on-going investigation. Very many linkages and associations have been replicated in some way and in some populations–but instances of variable results across case series and ethnic groups abound. Polygenic effects are important, where a number of common variants at different loci interact with the environment to result in clinical phenotypes. Hence odds ratios for combined genotypes are substantially greater than ORs for single loci, eg odds ratios for combined genotypes at Il-13, IL4Ra and STAT-6 in Th-2 signalling [5]. In some instances, there may be the first glimpses of the evolutionary origin of these asthma and atopy promoting variants, for example in their possible protection against parasitic worm infections [7,8]. What then specifically of the role of genetic variants FceRI-b in asthma and atopy? The reports of Kim et al and Hizawa et al. support a significant role for the gene–but together re-emphasise unraveled complexities at the locus. FceRI-b–through chromosome 11q13 was the first non-HLA locus linked to asthma and atopy [9,10]. Despite early non-replications it’s evident now that genetic Correspondence: Professor Julian M. Hopkin, School of Medicine & Institute of Life Science, Grove Building, University of Wales Swansea, Swansea, SA2 8PP. Tel: 01792 295149 Fax: 01792 513054 Email: j.m.hopkin@swansea.ac.uk Clinical and Experimental Allergy, 36, 855–857
影响因子：
6.1
作者：
Hizawa, N.;Maeda, Y.;Nishimura, M.
通讯作者：
Nishimura, M.