Is Pi MZ a risk factor for the development of chronic obstructive pulmonary disease (COPD)? That is the question many authors have tried to answer during the last decades, but the results of published studies are still conflicting.

A very high percentage of patients with COPD have been smokers, but not all smokers develop COPD. There must be other contributing factors and, with a Pi MZ prevalence of 3–5% in many Western countries, it is relevant to determine whether this genotype is an additional risk factor for COPD.¹ Furthermore, if a dose-response relation exists, it is biologically plausible since plasma levels of α₁-antitrypsin (AAT) are reduced to about 60% in Pi MZ subjects compared with those with the normal Pi MM genotype, and Pi Z individuals with very low levels of AAT have a significantly increased risk for emphysema.

There are a number of reasons for the discrepancy between the studies conducted on this subject. Firstly, smoking is a very significant confounder in the development of emphysema which is almost impossible to control for. Secondly, many studies have been subject to various types of bias, particularly selection bias. Thirdly, only a few studies have been sufficiently large to produce a significant result and very few studies have been population based. Finally, the phenotypic appearance of the Pi MZ genotype may be heterogenic.

In the studies of a causal relationship of a risk factor (Pi MZ genotype) and the development of a disease (COPD) there are two types of designs: case-control studies and cohort studies. Cohort studies …