Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus.
Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus.
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全基因组扫描在总血清IgE水平上鉴定出FCER1A是新的敏感性基因座。
DOI：
10.1371/journal.pgen.1000166
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发表时间：
2008-08
期刊：
影响因子：
4.5
通讯作者：
Illig, Thomas
中科院分区：
文献类型：
--
作者：
Weidinger, Stephan;Gieger, Christian;Rodriguez, Elke;Baurecht, Hansjoerg;Mempel, Martin;Klopp, Norman;Gohlke, Henning;Wagenpfeil, Stefan;Ollert, Markus;Ring, Johannes;Behrendt, Heidrun;Heinrich, Joachim;Novak, Natalija;Bieber, Thomas;Kraemer, Ursula;Berdel, Dietrich;von Berg, Andrea;Bauer, Carl Peter;Herbarth, Olf;Koletzko, Sibylle;Prokisch, Holger;Mehta, Divya;Meitinger, Thomas;Depner, Martin;von Mutius, Erika;Liang, Liming;Moffatt, Miriam;Cookson, William;Kabesch, Michael;Wichmann, H. -Erich;Illig, Thomas
高水平的血清IgE被认为是寄生虫和蠕虫暴露的标志。此外，它们与过敏性疾病有关，在抗肿瘤防御中起关键作用，并且是自身免疫性疾病的重要介质。总IgE是一种强遗传性状。在一项全基因组关联研究（GWAS）中，我们在基于人群的KORA S3/F3研究的1，530名个体中检测了353，569个SNP与血清IgE水平的关联。在四个独立的基于人群的研究样本中进行了重复（总共n = 9，769个个体）。 染色体1 q23上编码IgE高亲和力受体（FCER 1A）α链的基因的功能变体（rs 2251746和rs 2427837）与所有队列中的总IgE水平密切相关，在联合分析中P值为1.85×10−20和7.08×10−19，在事后分析中显示与过敏性致敏的额外相关性（P = 7.78×10−4和P = 1.95×10−3）。 “顶部”SNP显著影响嗜碱性粒细胞上FCER 1A的细胞表面表达，全基因组表达谱表明FCER 1A通过加塔-2表达的有趣的新调控机制。染色体5 q31上的RAD 50基因多态性与IgE水平一致相关（P值为6.28×10−7 - 4.46×10−8），并增加了特应性湿疹和哮喘的风险。此外，STAT 6被证实为调节IgE水平的易感位点。在这第一个GWAS总IgE FCER 1A被确定和复制作为新的易感基因座，在共同的遗传变异影响血清IgE水平。此外，RAD 50基因内的变异可能代表染色体5 q31上细胞因子基因簇内的其他因子，强调需要在这个有趣的区域进行进一步研究。我们的数据进一步证实了STAT 6变异与血清IgE水平的相关性。高水平的血清IgE被认为是寄生虫和蠕虫暴露的标志。此外，它们与过敏性疾病有关，在抗肿瘤防御中起关键作用，并且是自身免疫性疾病的重要介质。有强有力的证据表明，血清IgE水平的调节是在一个强大的遗传控制。然而，尽管有许多位点和候选基因连锁和相关的特应性相关性状，很少一直与总IgE。这项研究描述了第一个大规模的全基因组总IgE扫描。通过检查来自四个独立的基于人群的队列的> 11，000名德国个体，我们发现染色体1 q23上编码IgE高亲和力受体（FCER 1A）α链的基因的功能变体与总IgE水平密切相关。此外，我们的数据证实了STAT 6变异与血清IgE水平的相关性，并表明RAD 50基因内的变异可能代表染色体5 q31上细胞因子基因簇内的其他因素，强调了在这一有趣区域进行进一步研究的必要性。
High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85×10−20 and 7.08×10−19 in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78×10−4 and P = 1.95×10−3). The “top” SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28×10−7−4.46×10−8) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels. High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. There is strong evidence that the regulation of serum IgE levels is under a strong genetic control. However, despite numerous loci and candidate genes linked and associated with atopy-related traits, very few have been associated consistently with total IgE. This study describes the first large-scale, genome-wide scan on total IgE. By examining >11,000 German individuals from four independent population-based cohorts, we show that functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 are strongly associated with total IgE levels. In addition, our data confirm association of STAT6 variation with serum IgE levels, and suggest that variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region.
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DOI：
10.1164/ajrccm.161.3.9903128
发表时间：
2000-03-01
影响因子：
24.7
作者：
Hizawa, N;Yamaguchi, E;Kawakami, Y
通讯作者：
Kawakami, Y
影响因子：
14.2
作者：
Maier, Lisa M.;Howson, Joanna M. M.;Strachan, David P.
通讯作者：
Strachan, David P.
影响因子：
14.2
作者：
LEBOWITZ, MD;BARBEE, R;BURROWS, B
通讯作者：
BURROWS, B
影响因子：
32.4
作者：
Lee, GR;Fields, PE;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
56.9
作者：
MARSH, DG;NEELY, JD;BEATY, TH
通讯作者：
BEATY, TH