Chronic obstructive pulmonary disease (COPD) is defined as airflow obstruction that is not fully reversible. It results from abnormal inflammation following exposure to noxious particles or gases.1 This is typically exposure to cigarette smoke but may also include exposure to biomass fuels and some industrial dusts. COPD clusters within families, suggesting that heritable factors play a role in the pathogenesis of this disease.2 3 The only genetic factor that is widely accepted to be associated with COPD is severe deficiency of α₁-antitrypsin.4 This depletes an important member of the antiproteinase screen and causes excessive intrapulmonary inflammation.5 6 Indeed, even asymptomatic non-smoking heterozygotes for the Z allele (PiMZ) without airflow obstruction have increased intrapulmonary inflammation.7

Severe α₁-antitrypsin deficiency is found in only 1–2% of all individuals with COPD. There is growing interest in the genetic factors that predispose to COPD in those individuals who do not have α₁-antitrypsin deficiency. Early papers focused on association studies that looked at genetic variation within individuals with COPD compared with those individuals who were matched for all factors that are associated with COPD (most importantly age, smoking history and ethnic background) but who did not have airflow obstruction. The studies were typically small (100–150 cases and controls) and were often confounded by failure to match cases and controls carefully. There was often the issue of correcting for multiple comparisons as well as the inherent complexity of the COPD phenotype.8 Larger family-based studies have shown the independent clustering of the airway disease and emphysema component of COPD within families.9 This suggests that different genetic factors predispose to each of these components of the phenotype. The only way of overcoming the inherent variation in COPD is to focus on groups of well-characterised individuals with …