Analyses of associations with asthma in four asthma population samples from Canada and Australia
Analyses of associations with asthma in four asthma population samples from Canada and Australia
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DOI：
10.1007/s00439-009-0643-8
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发表时间：
2009-05-01
期刊：
影响因子：
5.3
通讯作者：
Hudson, Thomas J.
中科院分区：
文献类型：
--
作者：
Daley, Denise;Lemire, Mathieu;Hudson, Thomas J.
哮喘、特应性和相关表型是异质的复杂特征，同时存在遗传和环境风险因素。已经进行了广泛的研究，超过一百个基因与哮喘和特应性表型相关，但这些发现中的许多未能在随后的研究中复制。为了将真正的关联与假阳性分开，需要使用标准化设计（基因分型，表型和分析）在大量表征良好的样本中检查候选基因。为了复制先前的关联，我们合并了四项研究的力量和资源，并对5，565名个体进行了基因分型，使用相同的861个单核苷酸多态性（SNP），一个共同的基因分型平台和相对协调的表型，对93个先前与哮喘和相关表型相关的候选基因进行了遗传关联研究。我们使用通用等位基因似然比检验来检验SNPs与哮喘、特应性、特应性哮喘和气道高反应性的二分结果之间的关联。任何基因中没有SNP达到所有测试的SNP、表型和基因的校正后存活的显著性水平。即使通过进行基于基因的分析（一次一个基因，就好像没有其他基因被分型一样）和根据先前的关联证据对SNP进行分层，放松了通常严格的多重检验校正，也没有基因给出强有力的复制证据。有微弱的证据表明：哮喘中的IL 13、IFNGR 2、EDN 1和VDR;特应性哮喘中的IL 18、TBXA 2 R、IFNGR 2和VDR;气道高反应性中的TLR 9、TBXA 2 R、VDR、NOD 2和STAT 6;特应性哮喘中的TLR 10、IFNGR 2、STAT 6、VDR和NPSR 1。此外，我们发现了过量的SNP，其效应大小较小（OR < 1.4）。复制率低可能是由于效应量小，表型定义的差异，不同的环境效应和/或遗传异质性。为了帮助未来的哮喘基因复制研究，编辑了一个综合数据库，可在http://genapha.icapture.ubc.ca上向科学界提供。
Asthma, atopy, and related phenotypes are heterogeneous complex traits, with both genetic and environmental risk factors. Extensive research has been conducted and over hundred genes have been associated with asthma and atopy phenotypes, but many of these findings have failed to replicate in subsequent studies. To separate true associations from false positives, candidate genes need to be examined in large well-characterized samples, using standardized designs (genotyping, phenotyping and analysis). In an attempt to replicate previous associations we amalgamated the power and resources of four studies and genotyped 5,565 individuals to conduct a genetic association study of 93 previously associated candidate genes for asthma and related phenotypes using the same set of 861 single-nucleotide polymorphisms (SNPs), a common genotyping platform, and relatively harmonized phenotypes. We tested for association between SNPs and the dichotomous outcomes of asthma, atopy, atopic asthma, and airway hyperresponsiveness using a general allelic likelihood ratio test. No SNP in any gene reached significance levels that survived correction for all tested SNPs, phenotypes, and genes. Even after relaxing the usual stringent multiple testing corrections by performing a gene-based analysis (one gene at a time as if no other genes were typed) and by stratifying SNPs based on their prior evidence of association, no genes gave strong evidence of replication. There was weak evidence to implicate the following: IL13, IFNGR2, EDN1, and VDR in asthma; IL18, TBXA2R, IFNGR2, and VDR in atopy; TLR9, TBXA2R, VDR, NOD2, and STAT6 in airway hyperresponsiveness; TLR10, IFNGR2, STAT6, VDR, and NPSR1 in atopic asthma. Additionally we found an excess of SNPs with small effect sizes (OR < 1.4). The low rate of replication may be due to small effect size, differences in phenotypic definition, differential environmental effects, and/or genetic heterogeneity. To aid in future replication studies of asthma genes a comprehensive database was compiled and is available to the scientific community at http://genapha.icapture.ubc.ca.