Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia
Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia
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DOI：
10.1038/ejhg.2010.191
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发表时间：
2011-04-01
影响因子：
5.2
通讯作者：
Martin, Nicholas G.
中科院分区：
文献类型：
--
作者：
Ferreira, Manuel A. R.;McRae, Allan F.;Martin, Nicholas G.
全基因组关联研究随后的复制提供了一个强大的方法来绘制哮喘的遗传风险因素。我们试图寻找与哮喘相关的新变异，并试图复制与先前报道的四个基因座（ORMDL3, PDE4D， DENND1B和IL1RL1）的关联。对来自澳大利亚的986例哮喘患者和1846例无哮喘对照者进行了个体单核苷酸多态性（snp）、罕见拷贝数变异（CNVs）和总体CNV负担的全基因组关联分析。SNP分析中最相关的位点是ORMDL3 （rs6503525， P=4.8 × 10(-7)）。其他5个位点与P < 10（-5）相关，最显著的是趋化因子CXC基序配体14 （CXCL14）基因（rs31263， P=7.8 × 10(-6)）。我们没有发现与最近报道的PDE4D、DENND1B和ILR1L1的特定风险变异相关的证据。然而，考虑到所有测试的变异（rs10197862，基因范围P=0.01）后，IL1RL1中与先前报道的低连锁不平衡的变异与哮喘风险相关。这种关联在独立队列中得到了令人信服的证实（P=2.4 x 10(-4)）。染色体17q21上300 kb的缺失与哮喘风险相关，但这并没有达到实验范围内的意义。哮喘病例和对照组的CNV率、长度和受缺失或重复影响的基因数量相当。总之，我们确认了哮喘风险与ORMDL3变异之间的关联，并确定了IL1RL1的一个新的风险变异。在更大的队列中对17q21缺失进行随访是有必要的。欧洲人类遗传学杂志（2011）19,458 -464；doi: 10.1038 / ejhg.2010.191;2010年12月8日在线发布
Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P=4.8 x 10(-7)). Five other loci were associated with P < 10(-5), most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P=7.8 x 10(-6)). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P=0.01). This association replicated convincingly in an independent cohort (P=2.4 x 10(-4)). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted. European Journal of Human Genetics (2011) 19, 458-464; doi:10.1038/ejhg.2010.191; published online 8 December 2010