Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.
Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.
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DOI：
10.1016/s0140-6736(11)60874-x
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发表时间：
2011-09-10
期刊：
影响因子：
168.9
通讯作者：
Thompson, Philip J.
中科院分区：
文献类型：
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作者：
Ferreira, Manuel A. R.;Matheson, Melanie C.;Duffy, David L.;Marks, Guy B.;Hui, Jennie;Le Souef, Peter;Danoy, Patrick;Baltic, Svetlana;Nyholt, Dale R.;Jenkins, Mark;Hayden, Catherine;Willemsen, Gonneke;Ang, Wei;Kuokkanen, Mikko;Beilby, John;Cheah, Faang;de Geus, Eco J. C.;Ramasamy, Adaikalavan;Vedantam, Sailaja;Salomaa, Veikko;Madden, Pamela A.;Heath, Andrew C.;Hopper, John L.;Visscher, Peter M.;Musk, Bill;Leeder, Stephen R.;Jarvelin, Marjo-Riitta;Pennell, Craig;Boomsma, Dorret I.;Hirschhorn, Joel N.;Walters, Haydn;Martin, Nicholas G.;James, Alan;Jones, Graham;Abramson, Michael J.;Robertson, Colin F.;Dharmage, Shyamali C.;Brown, Matthew A.;Montgomery, Grant W.;Thompson, Philip J.
我们的目的是确定影响哮喘风险的新的遗传变异，因为这些可能提供新的见解哮喘的分子机制。我们对来自澳大利亚的2，669名医生诊断的哮喘患者和4，528名对照进行了全基因组关联研究（GWAS）。将我们的结果与GABRIEL联盟的结果（n= 26，475）结合后，优先考虑7个位点进行复制，并在来自4个计算机模拟队列的另外25，358个独立样本中进行了测试。基于GABRIEL研究的结果构建了遗传负荷的定量多SNP评分，并在我们的澳大利亚GWAS数据集中测试了其与哮喘的相关性。两个位点在重复队列中被证实与哮喘风险相关，并在所有现有研究的综合分析中达到全基因组意义（n= 57 800）：rs4129267（OR=1.09，组合P=2.4×10−8）在白细胞介素-6受体基因（IL 6 R）和rs7130588中（OR=1.09，P=1.8×10−8）位于染色体11q13.5上富含亮氨酸重复序列的32基因（LRRC 32，也称为GARP）附近。11q13.5位点与哮喘患者的特应性状态显著相关（OR = 1.33，P = 7×10−4），表明它是过敏性哮喘的危险因素，而不是非过敏性哮喘的危险因素。多SNP关联结果与哮喘风险的高度多基因贡献一致，包括可能与其他免疫相关疾病（如NDFIP 1，HLA-B，LPP和BACH 2）共享的弱效应位点。IL-6 R相关性进一步支持了细胞因子信号转导失调影响哮喘风险的假设，并提高了IL-6 R拮抗剂（托珠单抗）可能有效治疗该疾病的可能性，可能是以基因型依赖性方式。11q13.5位点的结果表明，它直接增加了过敏性致敏的风险，这反过来又增加了随后发生哮喘的风险。需要进行更大规模或更注重功能的研究来表征许多对哮喘具有适度影响的位点，这些位点仍有待确定。资金来源的完整清单见本文件末尾。
We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying asthma. We performed a genome-wide association study (GWAS) in 2,669 physician-diagnosed asthmatics and 4,528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-SNP scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR=1.09, combined P=2.4×10−8) in the interleukin-6 receptor gene (IL6R) and rs7130588 (OR=1.09, P=1.8×10−8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR = 1.33, P = 7×10−4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-SNP association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that may be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. A full list of funding sources appears at the end of the paper.