Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children.
Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children.
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DOI：
10.1371/journal.pgen.1000623
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
London SJ
中科院分区：
文献类型：
--
作者：
Hancock DB;Romieu I;Shi M;Sienra-Monge JJ;Wu H;Chiu GY;Li H;del Rio-Navarro BE;Willis-Owen SA;Weiss ST;Raby BA;Gao H;Eng C;Chapela R;Burchard EG;Tang H;Sullivan PF;London SJ
人们已经研究了许多哮喘的候选基因，但复制方式各不相同。利用全基因组关联研究（GWASs），已经确定了各种复杂疾病的新候选基因。我们在492名患有哮喘的墨西哥儿童中进行了GWAS，主要是通过皮肤点刺试验进行的特应性，他们的父母使用Illumina HumanHap 550 K BeadChip来识别儿童哮喘的新遗传变异。采用对数线性回归和对数加性风险模型，对通过质量控制的520，767个常染色体单核苷酸多态性（SNPs）与儿童哮喘的相关性进行了检测。11个最显著相关的GWAS SNP在一项独立研究中进行了重复性测试，该研究使用对数线性分析对177名患有儿童期发作哮喘和特应性的墨西哥病例-父母三人组进行了研究。染色体9q21.31 SNP rs 2378383（GWAS中p=7.10×10−6）位于分裂4的转导素样增强子（TLE 4）上游，p值为0.03，在复制研究中具有相同的关联方向和幅度（合并p= 6.79×10−7）。 染色体9 q上的遗传学分析支持rs 2378383次要等位基因（G）与儿童哮喘负相关。这项工作确定染色体9q21.31作为一个新的易感基因座儿童哮喘在墨西哥人。此外，诺华研究基金会对51个人体组织的全基因组表达数据的分析显示，与50个其他组织相比，肺中表达的基因中SNP的GWAS显著性水平中位数与肺中不表达的基因差异最显著，支持我们总体GWAS发现的生物学可解释性和儿童哮喘的多基因病因学。哮喘是一种主要的慢性儿童疾病，据推测具有很强的遗传成分，但没有明确显示基因会影响哮喘的发展。很少有哮喘的遗传学研究包括西班牙裔人群。在这里，我们对492名患有哮喘的墨西哥儿童进行了一项全基因组哮喘相关研究，主要是通过皮肤点刺试验进行的特应性哮喘，以及他们的父母，以确定儿童哮喘的新遗传变异。我们涉及染色体9q21.31（一个新的儿童哮喘候选区域）TLE 4或附近的几个多态性，并在一项对墨西哥种族特应性儿童发作哮喘患者及其父母的独立研究中复制了一个多态性。西班牙裔有不同比例的美洲原住民，欧洲人和非洲人的祖先，我们发现美洲原住民的祖先比预期的少在染色体9q21.31。这表明，染色体9q21.31可能是儿童哮喘种族差异的基础，未来的复制在美洲原住民血统的人群中最有效。对公开的全基因组表达数据的分析显示，与其他50种组织相比，肺中表达的基因中的关联信号与肺中不表达的基因差异最显著，这支持了总体GWAS发现的生物学可信性和哮喘的多基因病因学。
Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case–parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10×10−6 in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79×10−7). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma. Asthma is a leading chronic childhood disease with a presumed strong genetic component, but no genes have been definitely shown to influence asthma development. Few genetic studies of asthma have included Hispanic populations. Here, we conducted a genome-wide association study of asthma in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents to identify novel genetic variation for childhood asthma. We implicated several polymorphisms in or near TLE4 on chromosome 9q21.31 (a novel candidate region for childhood asthma) and replicated one polymorphism in an independent study of childhood-onset asthmatics with atopy and their parents of Mexican ethnicity. Hispanics have differing proportions of Native American, European, and African ancestries, and we found less Native American ancestry than expected at chromosome 9q21.31. This suggests that chromosome 9q21.31 may underlie ethnic differences in childhood asthma and that future replication would be most effective in populations with Native American ancestry. Analysis of publicly available genome-wide expression data revealed that association signals in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of the overall GWAS findings and the multigenic etiology of asthma.
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DOI：
10.1164/rccm.200309-1293oc
发表时间：
2004-02-01
影响因子：
24.7
作者：
Burchard, EG;Avila, PC;Silverman, EK
通讯作者：
Silverman, EK
影响因子：
5.4
作者：
Brady, Gareth;Whiteman, Hannah J.;Farrell, Paul J.
通讯作者：
Farrell, Paul J.
影响因子：
6.4
作者：
Milili, M;Gauthier, L;Schiff, C
通讯作者：
Schiff, C
影响因子：
3.5
作者：
de Bakker, Paul I. W.;Ferreira, Manuel A. R.;Voight, Benjamin F.
通讯作者：
Voight, Benjamin F.
影响因子：
5
作者：
Gauderman, WJ
通讯作者：
Gauderman, WJ