Elucidating COPD pathogenesis by large-scale genetic analyses
Authors: Guy G Brusselle, Ken R Bracke
Journal: The Lancet Respiratory Medicine (2015)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome defined by the presence of chronic airflow limitation and associated with other clinical and pathological hallmarks, such as chronic bronchitis, emphysema, exacerbations, and comorbidities. COPD is a complex disease, suggesting that both genetic susceptibility and environmental exposures (eg, cigarette smoking and smoke from biomass fuels) contribute to its pathogenesis (figure). In The Lancet Respiratory Medicine, Louise Wain and colleagues1Wain LV Shrine N Miller S et al.Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank.Lancet Respir Med. 2015; (published online Sept 28.)http://dx.doi.org/10.1016/S2213-2600(15)00283-0Google Scholar report intriguing novel insights into the genetics of smoking behaviour and the airflow obstruction component of COPD. The genetic study done by the UK Biobank Lung Exome Variant Evaluation (UK BiLEVE) collaborators has many assets.1Wain LV Shrine N Miller S et al.Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank.Lancet Respir Med. 2015; (published online Sept 28.)http://dx.doi.org/10.1016/S2213-2600(15)00283-0Google Scholar First, big is beautiful in genetics. More than 500 000 individuals have been included in UK Biobank, and more than 50 000 individuals of European ancestry were examined in the current study on lung function genetics. Second, the investigators applied a smart sampling strategy, selecting individuals from the middle and extremes of the distribution of lung function (FEV1) among both never smokers and heavy smokers. Thanks to this nested case-control study design, they enriched the large sample for non-smoking participants with airflow limitation, in whom genetic risk factors are suspected to play a more important part. Third, they used a new custom Affymetrix array to undertake genome-wide genotyping of 807 411 variants, encompassing common (minor allele frequency [MAF] >5%) single nucleotide polymorphisms (SNPs), low-frequency variants (MAF 1–5%), and rare (MAF <1%) coding variants relevant to the UK population. Moreover, by using the 1000 Genomes and UK10K reference panels, this genotyping array provided the unprecedented opportunity to look for association with 28 509 962 genetic variants—imputed or genotyped—in each individual. Multiplying 28·5 million genetic variants by 50 000 participants leads to 1·425 × 1012 variants analysed—an astronomical number. What are the main findings? In the genetic association analyses of smoking behaviour, the investigators confirmed the strong association with the nicotinic acetylcholine receptors CHRNA3 and CHRNA5 at the 15q25 locus, and discovered five novel regions of association in or near NCAM1, TEX41/PABPC1P2, DNAH8, NOL4L, and LPPR5 (all p<5 × 10−8). For reasons of brevity, we will focus on the NCAM1 gene, a membrane-bound glycoprotein that mediates adhesion among neurons. Two of the novel signals suggest a functional role for NCAM1 in nicotine addiction, since one SNP (rs4466874) was located in an intron of NCAM1 on chromosome 11, and another SNP (rs10193706) located distantly on chromosome 2 modulates the level of expression of NCAM1 in brain tissue. Moreover, this second SNP is also an expression quantitative trait locus for the gene WDR61 in the substantia nigra, which plays an important part in reward and addiction. What insights did the genetic analyses of lung function and COPD provide? Comparing individuals with low FEV1 with those with high FEV1, the investigators discovered five novel genetic loci of lung function: NPNT, TET2, HLA-DQB1/HLA-DQA2, KANSL1, and TSEN54. The lead SNPs at these loci were more strongly associated with low FEV1 in never smokers (all p<5×10−8) than in heavy smokers, and were also associated with COPD (defined by spirometry as FEV1:FVC ratio <0·7 and percent predicted FEV1<80%). This finding might be surprising, since a low FEV1 can be caused by airflow obstruction—as in asthma or COPD—or by decreased lung volumes (ie, a restrictive syndrome due to heart failure, interstitial lung disease, or obesity). However, these findings are in line with recent evidence of different trajectories of lung function in the pathogenesis of COPD;2Lange P Celli B Agustí A et al.Lung-function trajectories leading to chronic obstructive pulmonary disease.N Engl J Med. 2015; 373: 111-122Crossref PubMed Scopus (391) Google Scholar about half of the patients have an accelerated decline in lung function, whereas the other half have a normal decline, starting from an already impaired lung function at the age of 20–40 years caused by impaired lung development or growth, or both.2Lange P Celli B Agustí A et al.Lung-function trajectories leading to chronic obstructive pulmonary disease.N Engl J Med. 2015; 373: 111-122Crossref PubMed Scopus (391) Google Scholar The investigators confirmed that the HHIP gene, which is involved in fetal lung development and is one of the top hits of the first genome-wide association studies of lung function, is a COPD susceptibility gene.3Hancock DB Eijgelsheim M Wilk JB et al.Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.Nat Genet. 2010; 42: 45-52Crossref PubMed Scopus (477) Google Scholar Several of the newly discovered genes implicate epigenetic regulation in the pathogenesis of COPD. Epigenetic mechanisms modulate the expression of genes by regulating the methylation of DNA or by modifying histones within chromatin. KANSL1 encodes a key subunit of the histone acetyltransferase complex NSL1. Findings from pharmacological and genetic studies4Ito K Ito M Elliott WM et al.Decreased histone deacetylase activity in chronic obstructive pulmonary disease.N Engl J Med. 2005; 352: 1967-1976Crossref PubMed Scopus (833) Google Scholar, 5Loth DW Artigas MS Gharib SA et al.Genome-wide association analysis identifies six new loci associated with forced vital capacity.Nat Genet. 2014; 46: 669-677Crossref PubMed Scopus (105) Google Scholar have shown roles for histone deacetylases HDAC2 and HDAC4 in the pathogenesis of COPD.4Ito K Ito M Elliott WM et al.Decreased histone deacetylase activity in chronic obstructive pulmonary disease.N Engl J Med. 2005; 352: 1967-1976Crossref PubMed Scopus (833) Google Scholar, 5Loth DW Artigas MS Gharib SA et al.Genome-wide association analysis identifies six new loci associated with forced vital capacity.Nat Genet. 2014; 46: 669-677Crossref PubMed Scopus (105) Google Scholar Since the amount of acetylation of histones within the nucleus determines to what extent specific regions of DNA are accessible to transcription factors, and thus gene activation, these genetic variants might modulate inflammatory responses in the lungs. The gene TET2 encodes methylcytosine dioxygenase 2, which catalyses the conversion of 5-methylcytosine to 5-hydroxymethylcytosine to mediate DNA methylation. TET2, together with key transcription factors, regulates the differentiation of Th1 and Th17 CD4+ T cells and promotes the expression of interferon-γ and interleukin-17 in these lymphocytes, which suggests that TET2 has a role in autoimmune diseases.6Ichiyama K Chen T Wang X et al.The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.Immunity. 2015; 42: 613-626Summary Full Text Full Text PDF PubMed Scopus (224) Google Scholar Moreover, the association of low FEV1 with the HLA region on chromosome 6 (HLA-DQB1) also suggests that adaptive immune responses such as Th17 responses might contribute to the development of COPD.1Wain LV Shrine N Miller S et al.Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank.Lancet Respir Med. 2015; (published online Sept 28.)http://dx.doi.org/10.1016/S2213-2600(15)00283-0Google Scholar, 7Brusselle GG Joos GF Bracke KR New insights into the immunology of chronic obstructive pulmonary disease.Lancet. 2011; 378: 1015-1026Summary Full Text Full Text PDF PubMed Scopus (539) Google Scholar Although the HLA region has been associated with allergic asthma,8Moffatt MF Gut IG Demenais F et al.A large-scale, consortium-based genomewide association study of asthma.N Engl J Med. 2010; 363: 1211-1221Crossref PubMed Scopus (1494) Google Scholar the genetic association persisted in individuals without doctor-diagnosed asthma. What are the next steps? First, the novel genetic associations with lung function and COPD should be replicated in independent cohorts and investigated in people of other ethnic origins. Second, the causative SNPs need to be discovered through fine mapping and the functional role of the putative genes need to be elucidated through translational research approaches. Third, we are looking forward to new genetic studies in UK Biobank that investigate other lung function measurements (eg, FVC and FEV1:FVC ratio) and other hallmarks of COPD such as chronic bronchitis and emphysema. Thanks to the vast number of participants, the optimum genotyping arrays, and the smart study designs in UK Biobank, the future looks bright for unravelling the genetic cause of COPD. We declare no competing interests. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK BiobankBy sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. Full-Text PDF Open Access