COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

Abstract

Since the discovery of severe alpha-1 antitrypsin deficiency as a genetic risk factor for emphysema, there has been ongoing debate over whether individuals with intermediate deficiency with one protease inhibitor Z allele (PiMZ, or MZ) are at some risk for emphysema. This is important, because MZ individuals comprise 2-5% of the general population. In this review we summarise the evidence about the risks of the MZ population to develop emphysema or asthma. We discuss the different study designs that have tried to answer this question. The risk of emphysema is more pronounced in case-control than in population-based studies, perhaps due to inadequate power. Carefully designed family studies show an increased risk of emphysema in MZ smokers. This is supported by the rapid decline in lung function of MZ individuals when compared to the general population after massive environmental exposures. The risk of asthma in MZ subjects is less studied, and more literature is needed before firm conclusions can be made. Augmentation therapy in MZ individuals is not supported by any objective studies. MZ smokers are at increased risk for emphysema that is more pronounced when other environmental challenges are present.

FIGURE 1

Distribution of alpha-1 antitrypsin (AAT) levels among an MZ cohort (n=2923). Bars and numbers represent subjects with the corresponding level of AAT depicted on the x-axis. Data obtained from the Alpha-1 Coded Testing Study at the Medical University of South Carolina (Charleston, SC, USA) [7].

FIGURE 2

Frequency of the alpha-1 antitrypsin phenotypes in the targeted screening programme carried out by Greulich et al. [15] in Germany over the period 2003–2015. Reproduced and modified from [15] with permission.

FIGURE 3

Conceptual model of the balance between alpha-1 antitrypsin (AAT) and neutrophil elastase, by genotype.

FIGURE 4

Conceptual framework of the interaction between environmental exposure including smoking, alpha-1 antitrypsin (AAT) level and/or AAT genotype, other genetic factors and chronic obstructive pulmonary disease (COPD) risk. Note that there are no studies that show that genotype is more important than blood concentration of AAT for COPD risk assessment.