Chronic obstructive pulmonary disease risk: does genetics hold the answer?
Authors: Daiana Stolz
Journal: The Lancet Respiratory Medicine (2020)

Chronic obstructive pulmonary disease (COPD) is a slowly but steadily progressing pandemic.1Dransfield M Stolz D Kleinert S Lancet COPD CommissionersTowards eradication of chronic obstructive pulmonary disease: a Lancet Commission.Lancet. 2019; 393: 1786-1788Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar According to the Global Burden of Disease Study,2GBD 2015 Chronic Respiratory Disease CollaboratorsGlobal, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.Lancet Respir Med. 2017; 5: 691-706Summary Full Text Full Text PDF PubMed Scopus (924) Google Scholar the prevalence of COPD increased by almost 45% from 1990 to 2015, accounting for 251 million cases globally in 2016. Cigarette smoking is the most common risk factor for COPD in high-income countries. However, up to 65% of COPD cases worldwide are not linked to active or second-hand smoking. Factors in early life, such as low birthweight and childhood respiratory infections, as well as indoor and outdoor pollution, are being increasingly recognised as risk factors for COPD in later life. However, given the widespread exposure to these factors, it is striking that most individuals will never develop airflow obstruction. Some have argued that only a small proportion of smokers, the so-called susceptible minority of about 15%, will ever get COPD.3Fletcher C Peto R Tinker C Speizer FE The natural history of chronic bronchitis and emphysema. Oxford University Press, Oxford1976Google Scholar A potential explanation is that COPD has been traditionally diagnosed by lung function testing, specifically by FEV1/FVC ratio, which is not sensitive enough to detect incipient disease. Spirometry also does not detect tissue destruction (ie, emphysema), a prominent COPD phenotype. Regardless of the sensitivity of the tests used to assess the presence of the disease, evidence indicates that susceptibility to COPD varies between individuals. There is widespread agreement that genetic factors are involved in this variance, but the extent to which genomics could be clinically useful in quantifying individual risk of COPD is unclear. Heritability estimates for COPD range between 20% and 40% for airflow limitation and are up to 60% for smoking phenotypes.4Zhou JJ Cho MH Castaldi PJ Hersh CP Silverman EK Laird NM Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers.Am J Respir Crit Care Med. 2013; 188: 941-947Crossref PubMed Scopus (64) Google Scholar Genome-wide association studies (GWASs) assessing common genetic polymorphisms (eg, single nucleotide polymorphisms [SNPs]) have identified numerous genetic variants associated with COPD. However, similar to other non-mendelian conditions, the effect of each genetic variant on COPD risk is small. To gain further insight into the role of genetics in disease risk, multiple SNPs can be combined into a single genetic risk score. Each of the variants, regardless of genome-wide significance, can be weighted on the basis of GWAS-derived information to create a polygenic risk score, which incorporates variants that are enriched and those associated with anthropometric features and lung development pathways. In The Lancet Respiratory Medicine, Matthew Moll and colleagues5Moll M Sakornsakolpat P Shrine N et al.Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.Lancet Respir Med. 2020; 8: 696-708Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar describe a polygenic risk score for FEV1 and FEV1/FVC, generated using data from around 400 000 participants and around 2·5 million SNPs and validated in nine cohorts of multiple ethnicities. The authors focused on an association with moderate-to-severe COPD. Their findings suggest that the polygenic risk score was significantly associated with COPD and that the odds ratio (OR) for COPD in individuals with the highest scores (tenth decile) was greatly increased as compared with those with the lowest scores (first decile; OR 7·99 [95% CI 6·56–9·72] in Europeans and 4·83 [3·45–6·77] in non-Europeans). The polygenic risk score was not only associated with severe and frequent exacerbations, but also with several patterns of airway disease and emphysema related to ten distinct CT imaging phenotypes previously described in the COPDGene study.6Oelsner EC Ortega VE Smith BM et al.A genetic risk score associated with chronic obstructive pulmonary disease susceptibility and lung structure on computed tomography.Am J Respir Crit Care Med. 2019; 200: 721-731Crossref PubMed Scopus (15) Google Scholar Patterns of lung function growth and decline were also predicted by the polygenic risk score, in both the crude and adjusted analyses. Is this major progress? Despite the large number of patients, SNPs, and cohorts included in the analysis by Moll and colleagues, the predictive ability of the polygenic risk score to detect COPD was lower than that of a simple model including only clinical variables (age, sex, and smoking pack-years) and the area under the curve for polygenic risk score was modest (0·68). To take an optimistic approach, the identification of individuals who are susceptible to COPD for the cost of approximately US$100 per person could be justified, given that this information could streamline preventive measures related to tobacco and environmental exposure. In addition, the polygenic risk score was not correlated with smoking pack-years, thus it provides risk information independently from smoking history. The pessimists among us might point out that the polygenic risk score might identify, at best, 15–20% of individuals that will develop COPD and that preventive measures to preserve lung health should be put in place universally anyway.7Horváth I Barry M Brusselle G et al.The European Respiratory Society's 10 principles for lung health.Eur Respir J. 2018; 521801373Crossref PubMed Scopus (6) Google Scholar, 8Stolz D Christ-Crain M Morgenthaler NG et al.Copeptin, C-reactive protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD.Chest. 2007; 131: 1058-1067Summary Full Text Full Text PDF PubMed Scopus (206) Google Scholar Although previously we might have hoped to identify one key biomarker for COPD, we know now that the complexity and heterogeneity of COPD will demand our best combined efforts towards scientific and clinical progress.9Stolz D Meyer A Rakic J Boeck L Scherr A Tamm M Mortality risk prediction in COPD by a prognostic biomarker panel.Eur Respir J. 2014; 44: 1557-1570Crossref PubMed Scopus (32) Google Scholar A genetic risk score for lung function might not provide further prediction of exacerbations beyond lung function impairment. However, the polygenic risk score does appear to identify those at highest risk of airflow obstruction; to capture patterns of reduced lung growth in children; and to reflect the heterogeneity of emerging and established chest CT scan phenotypes. Many questions are left outstanding. In the future, should each person at risk due to lifestyle factors (eg, smoking) undergo polygenic risk score testing to inform clinical care? Could distinct polygenic risk score panels addressing susceptibility and phenotype association prove more powerful to predict disease? Could a polygenic risk score in non-smoking individuals produce diverse results? Could a polygenic risk score ever serve as a preclinical surrogate marker to inform phenotype-specific therapy? The answers might not be all in the genes, but they are definitely worth considering. I have received grants from AstraZeneca, Curetis, and Boston Scientific, and speaker fees from AstraZeneca, Novartis, GlaxoSmithKline, Roche, Zambon, Pfizer, Schwabe Pharma, and Vifor. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohortsA risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. Full-Text PDF Open Access