Jackson, Victoria E., Ntalla, Ioanna, Sayers, Ian, Morris, Richard, Whincup, Peter, Casas, Juan-Pablo, Amuzu, Antoinette, Choi, Minkyoung, Dale, Caroline, Kumari, Meena, Engmann, Jorgen, Kalsheker, Noor, Chappell, Sally, Guetta-Baranes, Tamar, McKeever, Tricia M., Palmer, Colin N.A., Tavendale, Roger, Holloway, John W., Sayer, Avan A., Dennison, Elaine M., Cooper, Cyrus, Bafadhel, Mona, Barker, Bethan, Brightling, Chris, Bolton, Charlotte E., John, Michelle E., Parker, Stuart G., Moffat, Miriam F., Wardlaw, Andrew J., Connolly, Martin J., Porteous, David J., Smith, Blair H., Padmanabhan, Sandosh, Hocking, Lynne, Stirrups, Kathleen E., Deloukas, Panos, Strachan, David P., Hall, Ian P., Tobin, Martin D. and Wain, Louise V. (2016) Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12. Thorax, 71 (6), 501-509. (doi:10.1136/thoraxjnl-2015-207876). (PMID:26917578)
Abstract
Background: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.
Objective: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.
Methods: 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.
Results: 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).
Conclusions: 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.
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- Faculties (pre 2018 reorg) > Faculty of Medicine (pre 2018 reorg) > Human Development & Health (pre 2018 reorg)
Current Faculties > Faculty of Medicine > Human Development and Health > Human Development & Health (pre 2018 reorg)
Human Development and Health > Human Development & Health (pre 2018 reorg) - Current Faculties > Faculty of Medicine > Human Development and Health > Medical Research Council Lifecourse Epidemiology Unit
Human Development and Health > Medical Research Council Lifecourse Epidemiology Unit
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