Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.
Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.
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DOI：
10.1136/thoraxjnl-2015-207876
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发表时间：
2016-06
期刊：
影响因子：
10
通讯作者：
Wain LV
中科院分区：
文献类型：
--
作者：
Jackson VE;Ntalla I;Sayers I;Morris R;Whincup P;Casas JP;Amuzu A;Choi M;Dale C;Kumari M;Engmann J;Kalsheker N;Chappell S;Guetta-Baranes T;McKeever TM;Palmer CN;Tavendale R;Holloway JW;Sayer AA;Dennison EM;Cooper C;Bafadhel M;Barker B;Brightling C;Bolton CE;John ME;Parker SG;Moffat MF;Wardlaw AJ;Connolly MJ;Porteous DJ;Smith BH;Padmanabhan S;Hocking L;Stirrups KE;Deloukas P;Strachan DP;Hall IP;Tobin MD;Wain LV
在对常见变异的全基因组关联研究中，基因组的几个区域已被证明与COPD有关。确定与COPD风险和气流受限严重程度相关的罕见和潜在功能性单核苷酸多态(SNPs)。使用外显子组阵列对3226名目前或以前吸烟者进行了基因分型，这些吸烟者的肺功能指标表明全球慢性阻塞性肺疾病倡议(GOLD)2 COPD或更糟。使用曾经吸烟的对照组(n=4784)进行COPD风险分析。在病例中测试了与预测FEV1的百分比的相关性。我们跟踪了来自英国生物库种群子集的独立样本中的感兴趣信号(p<；10−5)，并通过荟萃分析外显子组阵列数据和英国生物库数据中两个阵列上表示的变体，进行了更强大的发现研究。在相关的变异中，有两个位于以前未报道的慢性阻塞性肺疾病的区域；在MOCS3中有一个低频率的非同义SNP(rs7269297，pDiscovery=3.08×10−6，复制前=0.019)；在IFIT3中有一个罕见的SNP，在Meta分析中出现(rs140549288，pmeta=8.56×10−6)。在病例预测FEV1的Meta分析中，以前未报道的区域SERPINA12中的剪接变异体显示出最强的相关性(rs140198372，pMETA=5.72×10−6)。我们还证实了之前报道的MMP12、HHIP、GPR126和CHRNA5与COPD风险的关联。在新区域中没有关联达到严格的外显子范围显著阈值(p<；3.7x10−7)。这项研究确定了几个与COPD风险和气流受限严重程度有关的因素，包括值得进一步研究的新区域MOCS3、IFIT3和SERPINA12。
Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7). This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.