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Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

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.

SUBMITTER: Jackson VE

PROVIDER: S-EPMC4893124 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

Jackson Victoria E VE Ntalla Ioanna I Sayers Ian I Morris Richard R Whincup Peter P Casas Juan-Pablo JP Amuzu Antoinette A Choi Minkyoung M Dale Caroline C Kumari Meena M Engmann Jorgen J Kalsheker Noor N Chappell Sally S Guetta-Baranes Tamar T McKeever Tricia M TM Palmer Colin N A CN Tavendale Roger R Holloway John W JW Sayer Avan A AA Dennison Elaine M EM Cooper Cyrus C Bafadhel Mona M Barker Bethan B Brightling Chris C Bolton Charlotte E CE John Michelle E ME Parker Stuart G SG Moffat Miriam F MF Wardlaw Andrew J AJ Connolly Martin J MJ Porteous David J DJ Smith Blair H BH Padmanabhan Sandosh S Hocking Lynne L Stirrups Kathleen E KE Deloukas Panos P Strachan David P DP Hall Ian P IP Tobin Martin D MD Wain Louise V LV

Thorax 20160225 6

<h4>Background</h4>Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.<h4>Objective</h4>To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.<h4>Methods</h4>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 w ...[more]

PMID: 26917578

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Project description:Study objectivesThe presence of flow limitation during sleep is associated with adverse health consequences independent of obstructive sleep apnea (OSA) severity (apnea-hypopnea index, AHI), but remains extremely challenging to quantify. Here we present a unique library and an accompanying automated method that we apply to investigate flow limitation during sleep.MethodsA library of 117,871 breaths (N = 40 participants) were visually classified (certain flow limitation, possible flow limitation, normal) using airflow shape and physiological signals (ventilatory drive per intra-esophageal diaphragm EMG). An ordinal regression model was developed to quantify flow limitation certainty using flow-shape features (e.g. flattening, scooping); breath-by-breath agreement (Cohen's ƙ); and overnight flow limitation frequency (R2, %breaths in certain or possible categories during sleep) were compared against visual scoring. Subsequent application examined flow limitation frequency during arousals and stable breathing, and associations with ventilatory drive.ResultsThe model (23 features) assessed flow limitation with good agreement (breath-by-breath ƙ = 0.572, p < 0.001) and minimal error (overnight flow limitation frequency R2 = 0.86, error = 7.2%). Flow limitation frequency was largely independent of AHI (R2 = 0.16) and varied widely within individuals with OSA (74[32-95]%breaths, mean[range], AHI > 15/h, N = 22). Flow limitation was unexpectedly frequent but variable during arousals (40[5-85]%breaths) and stable breathing (58[12-91]%breaths), and was associated with elevated ventilatory drive (R2 = 0.26-0.29; R2 < 0.01 AHI v. drive).ConclusionsOur method enables quantification of flow limitation frequency, a key aspect of obstructive sleep-disordered breathing that is independent of the AHI and often unavailable. Flow limitation frequency varies widely between individuals, is prevalent during arousals and stable breathing, and reveals elevated ventilatory drive. Clinical trial registration: The current observational physiology study does not qualify as a clinical trial.

Dataset Information

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

Publications

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

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