Farahi Neda, Paige Ellie, Balla Jozef, Prudence Emily, Ferreira Ricardo C, Southwood Mark, Appleby Sarah L, Bakke Per, Gulsvik Amund, Litonjua Augusto A, Sparrow David, Silverman Edwin K, Cho Michael H, Danesh John, Paul Dirk S, Freitag Daniel F, Chilvers Edwin R
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge CB1 8RN, Cambridge, UK.
Hum Mol Genet. 2017 Apr 15;26(8):1584-1596. doi: 10.1093/hmg/ddx053.
The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.
白细胞介素-6受体（IL-6R）基因中的Asp358Ala变异体与哮喘、自身免疫性疾病和心血管疾病有关，但尚未研究其在慢性阻塞性肺疾病（COPD）等其他呼吸道疾病中的作用。本研究的目的是评估Asp358Ala与COPD或哮喘风险之间是否存在关联，并探讨Asp358Ala变异体在中性粒细胞sIL-6R脱落及其在肺部的促炎作用中的作用。我们使用来自英国生物银行和ECLIPSE COPD队列的数据进行了逻辑回归。结果与另外三个COPD队列（共7519例病例和35653例对照）的汇总数据进行了荟萃分析，结果显示Asp358Ala与COPD之间无关联（OR = 1.02 [95% CI：0.96, 1.07]）。英国生物银行的数据显示Asp358Ala变异体与特应性哮喘之间存在正相关（OR = 1.07 [1.01, 1.13]）。在一系列使用37名参与者血液样本的体外研究中，我们发现Asp358Ala次要等位基因携带者中性粒细胞sIL-6R的脱落比非携带者更多。用纯合子携带者血清培养的人肺动脉内皮细胞显示次要等位基因携带者中MCP-1释放增加，加入托珠单抗后差异消除。总之，有证据表明中性粒细胞可能是肺部sIL-6R的重要来源，Asp358Ala变异体可能对肺细胞有促炎作用。然而，我们未能找到Asp358Ala与COPD之间存在关联的证据。
