Chronic Obstructive Pulmonary Disease
ICD-11: CA22
Disease Overview
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by airflow limitation, emphysema, and chronic bronchitis. Pathophysiology involves chronic inflammation, protease–antiprotease imbalance, oxidative stress, and airway remodeling. Alpha-1 antitrypsin deficiency (SERPINA1) causes ~1% of cases but illuminates mechanism. Genetic susceptibility: heritability is ~40–70%; SNP-based h² is ~0.12. Key genes include SERPINA1 (protease inhibitor), HHIP (hedgehog signaling, lung development), FAM13A, and loci near MMP12. Cigarette smoking is the dominant environmental cause; gene–smoking interactions are well-established. Only ~15–20% of smokers develop COPD, highlighting genetic susceptibility. Air pollution and occupational exposures contribute. Early-life lung development and adolescent smoking shape disease trajectory.
Lung function peaks in early adulthood; exposures during ages 10–24 affect lifetime trajectory. Smoking initiation in adolescence is a major modifiable risk; earlier onset amplifies genetic susceptibility. Alpha-1 antitrypsin deficiency may present in young adults. Asthma in adolescence increases COPD risk (asthma–COPD overlap). Secondhand smoke, air pollution, and occupational exposures during school/early work years matter. Genetic testing for SERPINA1 may be indicated in early-onset or family-history cases. PRS utility in adolescents is limited; smoking cessation remains primary prevention.
Genetic Architecture Summary
| Gene | Variant | GWAS p | Evidence | Strength |
|---|---|---|---|---|
| SERPINA1 | Z allele (Glu342Lys) | — | Alpha-1 antitrypsin; protease inhibitor; deficiency causes early-onset emphysema; illuminates protease–antiprotease hypothesis | 0.98 |
| HHIP | rs1828591 | 1.0e-25 | Hedgehog-interacting protein; lung development; affects FEV1 and COPD susceptibility | 0.88 |
| FAM13A | rs7671167 | 1.0e-20 | Lung eQTL; Wnt signaling; COPD and lung function | 0.82 |
| MMP12 | rs626750 | 1.0e-15 | Matrix metalloproteinase; elastin degradation; emphysema pathogenesis | 0.78 |
Heritability
h² SNP: 0.12; h² narrow-sense: 0.55 — SpiroMeta and COPDGene consortia (2019)
PRS notes: COPD PRS show modest predictive ability (AUC ~0.58–0.65). SERPINA1 testing is clinically indicated for early-onset or family history. Transferability is limited: European discovery; SERPINA1 Z allele frequency varies by ancestry. PRS may stratify risk in smokers; G×E (smoking) is critical but not fully integrated. Clinical utility is investigational; smoking cessation remains paramount.
Exposure Modifier Panel
| Exposure | Direction | Strength | Confidence | Mechanism hypothesis |
|---|---|---|---|---|
| tobacco | amplify | 0.98 | HIGH | Cigarette smoke causes inflammation, protease–antiprotease imbalance, oxidative stress; dominant environmental cause; gene–smoking interaction |
| air-pollution | amplify | 0.75 | HIGH | PM2.5 and occupational dusts exacerbate COPD; accelerate decline; amplify genetic susceptibility |
| diet-quality | buffer | 0.5 | MEDIUM | Antioxidant-rich diet may reduce oxidative stress; vitamin D and omega-3s; observational evidence |
| obesity-exposure | unknown | 0.45 | LOW | Obesity affects lung mechanics and inflammation; paradoxically some studies show protective effect (obesity paradox) in severe COPD |
Population Equity Notes
GWAS ancestry breakdown: COPD GWAS are predominantly European (~85%); COPDGene and SpiroMeta include some diverse participants
Transferability notes: SERPINA1 Z allele is most common in Europeans; S and other variants vary by ancestry. HHIP and other loci may transfer; effect sizes vary. PRS performance in non-European populations is reduced. Smoking prevalence and access to care differ globally.
Data gaps: Under-representation of diverse ancestries; G×E (smoking) across populations; early-life determinants; never-smoker COPD genetics.
Tissue Context
Visualizations
Risk Shift by Exposure Stratum
Population-level data only — does not predict individual risk
Tissue Relevance
References
- 1.Sakornsakolpat P, et al. (2019). Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-types and phenotypes. Nature Genetics. doi:10.1038/s41588-019-0541-7
- 2.Stoller JK, Aboussouan LS (2012). Alpha-1 antitrypsin deficiency. The Lancet. doi:10.1016/S0140-6736(11)60939-9
- 3.Zhou X, et al. (2012). HHIP haploinsufficiency causes emphysema. Nature Genetics. doi:10.1038/ng.2342
- 4.Schikowski T, et al. (2014). Air pollution and COPD. European Respiratory Journal. doi:10.1183/09031936.00002914
- 5.Varraso R, et al. (2015). Diet and COPD. BMJ. doi:10.1136/bmj.h2862